Prescription Drugs: OxyContin Abuse and Diversion and Efforts to Address the Problem
Published: 2003-12-19T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: Amid heightened awareness that many patients with cancer and other chronic diseases suffer from undertreated pain, the Food and Drug Administration (FDA) approved Purdue Pharma's controlled-release pain reliever OxyContin in 1995. Sales grew rapidly, and by 2001 OxyContin had become the most prescribed brandname narcotic medication for treating moderate-to-severe pain. In early 2000, reports began to surface about abuse and diversion for illicit use of OxyContin, which contains the opioid oxycodone. GAO was asked to examine concerns about these issues. Specifically, GAO reviewed (1) how OxyContin was marketed and promoted, (2) what factors contributed to the abuse and diversion of OxyContin, and (3) what actions have been taken to address OxyContin abuse and diversion.
section_title: What GAO Found
paragraphs: Purdue conducted an extensive campaign to market and promote OxyContin using an expanded sales force to encourage physicians, including primary care specialists, to prescribe OxyContin not only for cancer pain but also as an initial opioid treatment for moderate-to-severe noncancer pain. OxyContin prescriptions, particularly those for noncancer pain, grew rapidly, and by 2003 nearly half of all OxyContin prescribers were primary care physicians. The Drug Enforcement Administration (DEA) has expressed concern that Purdue's aggressive marketing of OxyContin focused on promoting the drug to treat a wide range of conditions to physicians who may not have been adequately trained in pain management. FDA has taken two actions against Purdue for OxyContin advertising violations. Further, Purdue did not submit an OxyContin promotional video for FDA review upon its initial use in 1998, as required by FDA regulations. Several factors may have contributed to the abuse and diversion of OxyContin. The active ingredient in OxyContin is twice as potent as morphine, which may have made it an attractive target for misuse. Further, the original label's safety warning advising patients not to crush the tablets because of the possible rapid release of a potentially toxic amount of oxycodone may have inadvertently alerted abusers to methods for abuse. Moreover, the significant increase in OxyContin's availability in the marketplace may have increased opportunities to obtain the drug illicitly in some states. Finally, the history of abuse and diversion of prescription drugs, including opioids, in some states may have predisposed certain areas to problems with OxyContin. However, GAO could not assess the relationship between the increased availability of OxyContin and locations of abuse and diversion because the data on abuse and diversion are not reliable, comprehensive, or timely. Federal and state agencies and Purdue have taken actions to address the abuse and diversion of OxyContin. FDA approved a stronger safety warning on OxyContin's label. In addition, FDA and Purdue collaborated on a risk management plan to help detect and prevent OxyContin abuse and diversion, an approach that was not used at the time OxyContin was approved. FDA plans to provide guidance to the pharmaceutical industry by September 2004 on risk management plans, which are an optional feature of new drug applications. DEA has established a national action plan to prevent abuse and diversion of OxyContin. State agencies have investigated reports of abuse and diversion. In addition to developing a risk management plan, Purdue has initiated several OxyContin-related educational programs, taken disciplinary action against sales representatives who improperly promoted OxyContin, and referred physicians suspected of improper prescribing practices to the authorities.

section_title: Letter
paragraphs: Patients with cancer may suffer from fairly constant pain for months or  years. Patients with other diseases or conditions, such as rheumatoid  arthritis, osteoarthritis, chronic back pain, or sickle cell anemia, may also  suffer from pain that lasts for extended periods of time. Since 1986, the  World Health Organization (WHO) and others have reported that the  inadequate treatment of cancer and noncancer pain is a serious public  health concern. To address this concern, efforts have been made to better  educate health care professionals on the need to improve the treatment of  both cancer and noncancer pain, including the appropriate role of  prescription drugs.
Amid the heightened awareness that many people were suffering from  undertreated pain, in 1995 the Food and Drug Administration (FDA)  approved the new drug OxyContin, a controlled-release semisynthetic  opioid analgesic manufactured by Purdue Pharma L.P., for the treatment  of moderate-to-severe pain lasting more than a few days. According to  Purdue, OxyContin provides patients with continuous relief from pain  over a 12-hour period, reduces pain fluctuations, requires fewer daily  doses to help patients adhere to their prescribed regimen more easily,  allows them to sleep through the night, and allows a physician to increase  the OxyContin dose for a patient as needed to relieve pain. Sales of the  drug increased rapidly following its introduction to the marketplace in  1996. By 2001, sales had exceeded $1 billion annually, and OxyContin had  become the most frequently prescribed brand-name narcotic medication  for treating moderate-to-severe pain in the United States.
In early 2000, media reports began to surface in several states that  OxyContin was being abused—that is, used for nontherapeutic purposes  or for purposes other than those for which it was prescribed—and illegally  diverted. According to FDA and the Drug Enforcement Administration  (DEA), the abuse of OxyContin is associated with serious consequences,  including addiction, overdose, and death. When OxyContin was approved,  the federal government classified it as a schedule II controlled substance  under the Controlled Substances Act because it has a high potential for  abuse and may lead to severe psychological or physical dependence. DEA  has characterized the pharmacological effects of OxyContin, and its active  ingredient oxycodone, as similar to those of heroin. Media reports  indicated that abusers were crushing OxyContin tablets and snorting the  powder or dissolving it in water and injecting it to defeat the intended  controlled-release effect of the drug and attain a “rush” or “high” through  the body’s rapid absorption of oxycodone. During a December 2001  congressional hearing, witnesses from DEA and other law enforcement  officials from Kentucky, Virginia, and West Virginia described the growing  problem of abuse and diversion of OxyContin. Questions were raised  about what factors may have caused the abuse and diversion, including  whether Purdue’s efforts to market the drug may have contributed to the  problem. In February 2002, another congressional hearing was conducted  on federal, state, and local efforts to decrease the abuse and diversion of  OxyContin.
Because of your concerns about these issues, you asked us to examine the  marketing and promotion of OxyContin and its abuse and diversion.  Specifically, we addressed the following questions:  1.  How has Purdue marketed and promoted OxyContin?  2.  What factors contributed to the abuse and diversion of OxyContin?  3.  What actions have been taken to address OxyContin abuse and  diversion?
To identify how Purdue marketed and promoted OxyContin, we  interviewed Purdue officials and analyzed company documents and data.  We also interviewed selected Purdue sales representatives who were high  and midrange sales performers during 2001 and physicians who were  among the highest prescribers of OxyContin. To determine how Purdue’s  marketing and promotion of OxyContin compared to that of other drugs,  we examined the promotional materials and information related to FDA  actions and interviewed officials from companies that manufacture and  market three other opioid drugs, Avinza, Kadian, and Oramorph SR, that  like OxyContin are classified as schedule II controlled substances.  Because of their concern about the proprietary nature of the information,  the three companies that market these drugs did not provide us with the  same level of detail about the marketing and promotion of their drugs as  did Purdue. We also examined data from DEA on promotional  expenditures for OxyContin and two other schedule II controlled  substances. To examine what factors may have contributed to the abuse  and diversion of OxyContin, we interviewed officials from DEA, FDA, and  Purdue and physicians who prescribe OxyContin. We also analyzed IMS  Health data on sales of OxyContin nationwide and Purdue’s distribution of  sales representatives, as part of an effort to compare the areas with large  sales growth and more sales representatives per capita with the areas  where abuse and diversion problems were identified. However, limitations  on the abuse and diversion data prevented an assessment of the  relationship between the availability of OxyContin and areas where the  drug was abused or diverted. To determine what actions have been taken  to address OxyContin abuse and diversion, we interviewed FDA officials  and examined FDA information regarding the drug’s approval and  marketing and promotion. We also interviewed DEA officials and  examined how DEA determined the prevalence of OxyContin abuse and  diversion nationally. In addition, we examined state efforts to identify  those involved in the abuse and diversion of OxyContin. We also reviewed  actions taken by Purdue to address this problem. (See app. I for a detailed  discussion of our methodology.)
We performed our work from August 2002 through October 2003, in  accordance with generally accepted government auditing standards.
subsections: section_title: Background
paragraphs: Ensuring that pharmaceuticals are available for those with legitimate  medical need while combating the abuse and diversion of prescription  drugs involves the efforts of both federal and state government agencies.  Under the FD&C Act, FDA is responsible for ensuring that drugs are safe  and effective before they are available in the marketplace. The Controlled  Substances Act, which is administered by DEA, provides the legal  framework for the federal government’s oversight of the manufacture and  wholesale distribution of controlled substances, that is, drugs and other  chemicals that have a potential for abuse. The states address certain issues  involving controlled substances through their own controlled substances  acts and their regulation of the practice of medicine and pharmacy. In  response to concerns about the influence of pharmaceutical marketing  and promotional activities on physician prescribing practices, both the  pharmaceutical industry and the Department of Health and Human  Services’s (HHS) Office of Inspector General have issued voluntary  guidelines on appropriate marketing and promotion of prescription drugs.
subsections: section_title: Medical Treatment of Pain
paragraphs: As the incidence and prevalence of painful diseases have grown along with  the aging of the population, there has been a growing acknowledgment of  the importance of providing effective pain relief. Pain can be characterized  in terms of intensity—mild to severe—and duration—acute (sudden onset)  or chronic (long term). The appropriate medical treatment varies  according to these two dimensions.
In 1986, WHO determined that cancer pain could be relieved in most if not  all patients, and it encouraged physicians to prescribe opioid analgesics.  WHO developed a three-step analgesic ladder as a practice guideline to  provide a sequential use of different drugs for cancer pain management.  For the first pain step, treatment with nonopioid analgesics, such as  aspirin or ibuprofen, is recommended. If pain is not relieved, then an  opioid such as codeine should be used for mild-to-moderate pain as the  second step. For the third step—moderate-to-severe pain—opioids such as  morphine should be used.
Beginning in the mid-1990s, various national pain-related organizations  issued pain treatment and management guidelines, which included the use  of opioid analgesics in treating both cancer and noncancer pain. In 1995,  the American Pain Society recommended that pain should be treated as  the fifth vital sign to ensure that it would become common practice for  health care providers to ask about pain when conducting patient  evaluations. The practice guidelines issued by the Agency for Health Care  Policy and Research provided physicians and other health care  professionals with information on the management of acute pain in 1992  and cancer pain in 1994, respectively. Health care providers and hospitals  were further required to ensure that their patients received appropriate  pain treatment when the Joint Commission on Accreditation of Healthcare  Organizations (JCAHO), a national health care facility standards-setting  and accrediting body, implemented its pain standards for hospital  accreditation in 2001.
OxyContin, a schedule II drug manufactured by Purdue Pharma L.P., was  approved by FDA in 1995 for the treatment of moderate-to-severe pain  lasting more than a few days, as indicated in the original label. OxyContin  followed Purdue’s older product, MS Contin, a morphine-based product  that was approved in 1984 for a similar intensity and duration of pain and  during its early years of marketing was promoted for the treatment of  cancer pain. The active ingredient in OxyContin tablets is oxycodone, a  compound that is similar to morphine and is also found in oxycodone- combination pain relief drugs such as Percocet, Percodan, and Tylox.  Because of its controlled-release property, OxyContin contains more  active ingredient and needs to be taken less often (twice a day) than these  other oxycodone-containing drugs. The OxyContin label originally  approved by FDA indicated that the controlled-release characteristics of  OxyContin were believed to reduce its potential for abuse. The label also  contained a warning that OxyContin tablets were to be swallowed whole,  and were not to be broken, chewed, or crushed because this could lead to  the rapid release and absorption of a potentially toxic dose of oxycodone.  Such a safety warning is customary for schedule II controlled-release  medications. FDA first approved the marketing and use of OxyContin in  10-, 20-, and 40-milligram controlled-release tablets. FDA later approved  80- and 160-milligram controlled-release tablets for use by patients who  were already taking opioids. In July 2001, FDA approved the revised label  to state that the drug is approved for the treatment of moderate-to-severe  pain in patients who require “a continuous around-the-clock analgesic for  an extended period of time.” (See app. II for a summary of the changes  that were made by FDA to the original OxyContin label.)
OxyContin sales and prescriptions grew rapidly following its market  introduction in 1996. Fortuitous timing may have contributed to this  growth, as the launching of the drug occurred during the national focus on  the inadequacy of patient pain treatment and management. In 1997,  OxyContin’s sales and prescriptions began increasing significantly, and  they continued to increase through 2002. In both 2001 and 2002,  OxyContin’s sales exceeded $1 billion, and prescriptions were over 7  million. The drug became Purdue’s main product, accounting for 90  percent of the company’s total prescription sales by 2001.
Media reports of OxyContin abuse and diversion began to surface in 2000.  These reports first appeared in rural areas of some states, generally in the  Appalachian region, and continued to spread to other rural areas and  larger cities in several states. Rural communities in Maine, Kentucky, Ohio,  Pennsylvania, Virginia, and West Virginia were reportedly being devastated  by the abuse and diversion of OxyContin. For example, media reports told  of persons and communities that had been adversely affected by the rise of  addiction and deaths related to OxyContin. One report noted that drug  treatment centers and emergency rooms in a particular area were  receiving new patients who were addicted to OxyContin as early as 1999.  Pain patients, teens, and recreational drug users who had abused  OxyContin reportedly entered drug treatment centers sweating and  vomiting from withdrawal. In West Virginia, as many as one-half of the  approximately 300 patients admitted to a drug treatment clinic in 2000  were treated for OxyContin addiction. The media also reported on deaths  due to OxyContin. For example, a newspaper’s investigation of autopsy  reports involving oxycodone-related deaths found that OxyContin had  been involved in over 200 overdose deaths in Florida since 2000. In  another case, a forensic toxicologist commented that he had reviewed a  number of fatal overdose cases in which individuals took a large dose of  OxyContin, in combination with alcohol or other drugs.
After learning about the initial reports of abuse and diversion of  OxyContin in Maine in 2000, Purdue formed a response team made up of  its top executives and physicians to initiate meetings with federal and  state officials in Maine to gain an understanding of the scope of the  problem and to devise strategies for preventing abuse and diversion. After  these meetings, Purdue distributed brochures to health care professionals  that described several steps that could be taken to prevent prescription  drug abuse and diversion. In response to the abuse and diversion reports,  DEA analyzed data collected from medical examiner autopsy reports and  crime scene investigation reports. The most recent data available from  DEA show that as of February 2002, the agency had verified 146 deaths  nationally involving OxyContin in 2000 and 2001.
According to Purdue, as of early October 2003, over 300 lawsuits  concerning OxyContin were pending against Purdue, and 50 additional  lawsuits had been dismissed. The cases involve many allegations,  including, for example, that Purdue used improper sales tactics and  overpromoted OxyContin causing the drug to be inappropriately  prescribed by physicians, and that Purdue took inadequate actions to  prevent addiction, abuse, and diversion of the drug. The lawsuits have  been brought in 25 states and the District of Columbia in both federal and  state courts.
section_title: Controlled Substances Act
paragraphs: The Controlled Substances Act established a classification structure for  drugs and chemicals used in the manufacture of drugs that are designated  as controlled substances. Controlled substances are classified by DEA  into five schedules on the basis of their medicinal value, potential for  abuse, and safety or dependence liability. Schedule I drugs—including  heroin, marijuana, and LSD—have a high potential for abuse and no  currently accepted medical use. Schedule II drugs—which include opioids  such as morphine and oxycodone, the primary ingredient in OxyContin— have a high potential for abuse among drugs with an accepted medical use  and may lead to severe psychological or physical dependence. Drugs on  schedules III through V have medical uses and successively lower  potentials for abuse and dependence. Schedule III drugs include anabolic  steroids, codeine, hydrocodone in combination with aspirin or  acetaminophen, and some barbiturates. Schedule IV contains such drugs  as the antianxiety drugs diazepam (Valium) and alprazolam (Xanax).  Schedule V includes preparations such as cough syrups with codeine. All  scheduled drugs except those in schedule I are legally available to the  public with a prescription.
section_title: FDA’s Regulation of Prescription Drugs
paragraphs: Under the FD&C Act and implementing regulations, FDA is responsible for  ensuring that all new drugs are safe and effective. FDA reviews scientific  and clinical data to decide whether to approve drugs based on their  intended use, effectiveness, and the risks and benefits for the intended  population, and also monitors drugs for continued safety after they are in  use.
FDA also regulates the advertising and promotion of prescription drugs  under the FD&C Act. FDA carries out this responsibility by ensuring that  prescription drug advertising and promotion is truthful, balanced, and  accurately communicated. The FD&C Act makes no distinction between  controlled substances and other prescription drugs in the oversight of  promotional activities. FDA told us that the agency takes a risk-based  approach to enforcement, whereby drugs with more serious risks, such as  opioids, are given closer scrutiny in monitoring promotional messages and  activities, but the agency has no specific guidance or policy on this  approach. The FD&C Act and its implementing regulations require that all  promotional materials for prescription drugs be submitted to FDA at the  time the materials are first disseminated or used, but it generally is not  required that these materials be approved by FDA before their use. As a  result, FDA’s actions to address violations occur after the materials have  already appeared in public. In fiscal year 2002, FDA had 39 staff positions  dedicated to oversight of drug advertising and promotion of all  pharmaceuticals distributed in the United States. According to FDA, most  of the staff focuses on the oversight of promotional communications to  physicians. FDA officials told us that in 2001 it received approximately  34,000 pieces of promotional material, including consumer advertisements  and promotions to physicians, and received and reviewed 230 complaints  about allegedly misleading advertisements, including materials directed at  health professionals.
FDA issues two types of letters to address violations of the FD&C Act:  untitled letters and warning letters. Untitled letters are issued for  violations such as overstating the effectiveness of the drug, suggesting a  broader range of indicated uses than the drug has been approved for, and  making misleading claims because of inadequate context or lack of  balanced information. Warning letters are issued for more serious  violations, such as those involving safety or health risks, or for continued  violations of the act. Warning letters generally advise a pharmaceutical  manufacturer that FDA may take further enforcement actions, such as  seeking judicial remediation, without notifying the company and may ask  the manufacturer to conduct a new advertising campaign to correct  inaccurate impressions left by the advertisements.
Under the Controlled Substances Act, FDA notifies DEA if FDA is  reviewing a new drug application for a drug that has a stimulant,  depressant, or hallucinogenic effect on the central nervous system and has  abuse potential. FDA performs a medical and scientific assessment as  required by the Controlled Substances Act, and recommends to DEA an  initial schedule level to be assigned to a new controlled substance.
FDA plans to provide guidance to the pharmaceutical industry on the  development, implementation, and evaluation of risk management plans as  a result of the reauthorization of the Prescription Drug User Fee Act of  1992 (PDUFA). FDA expects to issue this guidance by September 30,  2004. FDA defines a risk management program as a strategic safety  program that is designed to decrease product risks by using one or more  interventions or tools beyond the approved product labeling. Interventions  used in risk management plans may include postmarketing surveillance,  education and outreach programs to health professionals or consumers,  informed consent agreements for patients, limitations on the supply or  refills of products, and restrictions on individuals who may prescribe and  dispense drug products. All drug manufacturers have the option to develop  and submit risk management plans to FDA as part of their new drug  applications.
section_title: DEA’s Regulation of Controlled Substances
paragraphs: DEA is the primary federal agency responsible for enforcing the  Controlled Substances Act. DEA has the authority to regulate transactions  involving the sale and distribution of controlled substances at the  manufacturer and wholesale distributor levels. DEA registers legitimate  handlers of controlled substances—including manufacturers, distributors,  hospitals, pharmacies, practitioners, and researchers—who must comply  with regulations relating to drug security and accountability through the  maintenance of inventories and records. All registrants, including  pharmacies, are required to maintain records of controlled substances that  have been manufactured, purchased, and sold. Manufacturers and  distributors are also required to report their annual inventories of  controlled substances to DEA. The data provided to DEA are available for  use in monitoring the distribution of controlled substances throughout the  United States and identifying retail-level registrants that received unusual  quantities of controlled substances. DEA regulations for schedule II  prescription drugs, unlike those for other prescription drugs, require that  each prescription must be written and signed by the physician and may  not be telephoned in to the pharmacy except in an emergency. Also, a  prescription for a schedule II drug may not be refilled. A physician is  required to provide a new prescription each time a patient obtains more of  the drug. DEA also sets limits on the quantity of schedule II controlled  substances that may be produced in the United States in any given year.  Specifically, DEA sets aggregate production quotas that limit the  production of bulk raw materials used in the manufacture of controlled  substances. DEA determines these quotas based on a variety of data  including sales, production, inventories, and exports. Individual  companies must apply to DEA for manufacturing or procurement quotas  for specific pharmaceutical products. For example, Purdue has a  procurement quota for oxycodone, the principle ingredient in OxyContin,  that allows the company to purchase specified quantities of oxycodone  from bulk manufacturers.
section_title: States’ Regulation of the Practice of Medicine and Pharmacy and Role in Monitoring Illegal Use and Diversion of Prescription Drugs
paragraphs: State laws govern the prescribing and dispensing of prescription drugs by  licensed health care professionals. Each state requires that physicians  practicing in the state be licensed, and state medical practice laws  generally outline standards for the practice of medicine and delegate the  responsibility of regulating physicians to state medical boards. States also  require pharmacists and pharmacies to be licensed. The regulation of the  practice of pharmacy is based on state pharmacy practice acts and  regulations enforced by the state boards of pharmacy. According to the  National Association of Boards of Pharmacy, all state pharmacy laws  require that records of prescription drugs dispensed to patients be  maintained and that state pharmacy boards have access to the prescription  records. State regulatory boards face new challenges with the advent of  Internet pharmacies, because they enable pharmacies and physicians to  anonymously reach across state borders to prescribe, sell, and dispense  prescription drugs without complying with state requirements. In some  cases, consumers can purchase prescription drugs, including controlled  substances, such as OxyContin, from Internet pharmacies without a valid  prescription.
In addition to these regulatory boards, 15 states operate prescription drug  monitoring programs as a means to control the illegal diversion of  prescription drugs that are controlled substances. Prescription drug  monitoring programs are designed to facilitate the collection, analysis, and  reporting of information on the prescribing, dispensing, and use of  controlled substances within a state. They provide data and analysis to  state law enforcement and regulatory agencies to assist in identifying and  investigating activities potentially related to the illegal prescribing,  dispensing, and procuring of controlled substances. For example,  physicians in Kentucky can use the program to check a patient’s  prescription drug history to determine if the individual may be “doctor  shopping” to seek multiple controlled substance prescriptions. An  overriding goal of prescription drug monitoring programs is to support  both the state laws ensuring access to appropriate pharmaceutical care by  citizens and the state laws deterring diversion. As we have reported, state  prescription drug monitoring programs offer state regulators an efficient  means of detecting and deterring illegal diversion. However, few states  proactively analyze prescription data to identify individuals, physicians, or  pharmacies that have unusual use, prescribing, or dispensing patterns that  may suggest potential drug diversion or abuse. Although three states can  respond to requests for information within 3 to 4 hours, providing  information on suspected illegal prescribing, dispensing, or doctor  shopping at the time a prescription is written or sold would require states  to improve computer capabilities. In addition, state prescription drug  monitoring programs may require additional legal authority to analyze data  proactively.
section_title: Guidelines for Marketing Drugs to Health Care Professionals
paragraphs: At the time that OxyContin was first marketed, there were no industry or  federal guidelines for the promotion of prescription drugs. Voluntary  guidelines regarding how drug companies should market and promote  their drugs to health care professionals were issued in July 2002 by the  Pharmaceutical Research and Manufacturers of America (PhRMA). In  April 2003, HHS’s Office of Inspector General issued voluntary guidelines  for how drug companies should market and promote their products to  federal health care programs. Neither set of guidelines distinguishes  between controlled and noncontrolled substances.
PhRMA’s voluntary code of conduct for sales representatives states that  interactions with health care professionals should be to inform these  professionals about products, to provide scientific and educational  information, and to support medical research and education. The  question-and-answer section of the code addresses companies’ use of  branded promotional items, stating, for example, that golf balls and sports  bags should not be distributed because they are not primarily for the  benefit of patients, but that speaker training programs held at golf resorts  may be acceptable if participants are receiving extensive training. Purdue  adopted the code.
In April 2003, HHS’s Office of Inspector General issued final voluntary  guidance for drug companies’ interactions with health care professionals  in connection with federal health care programs, including Medicare and  Medicaid. Among the guidelines were cautions for companies against  offering inappropriate travel, meals, and gifts to influence the prescribing  of drugs; making excessive payments to physicians for consulting and  research services; and paying physicians to switch their patients from  competitors’ drugs.
section_title: Purdue Conducted an Extensive Campaign to Market and Promote OxyContin
paragraphs: Purdue conducted an extensive campaign to market and promote  OxyContin that focused on encouraging physicians, including those in  primary care specialties, to prescribe the drug for noncancer as well as  cancer pain. To implement its OxyContin campaign, Purdue significantly  increased its sales force and used multiple promotional approaches.  OxyContin sales and prescriptions grew rapidly following its market  introduction, with the growth in prescriptions for noncancer pain  outpacing the growth in prescriptions for cancer pain. DEA has expressed  concern that Purdue marketed OxyContin for a wide variety of conditions  to physicians who may not have been adequately trained in pain  management. Purdue has been cited twice by FDA for OxyContin  advertisements in medical journals that violated the FD&C Act. FDA has  also taken similar actions against manufacturers of two of the three  comparable schedule II controlled substances we examined, to ensure that  their marketing and promotion were truthful, balanced, and accurately  communicated. In addition, Purdue provided two promotional videos to  physicians that, according to FDA appear to have made unsubstantiated  claims and minimized the risks of OxyContin. The first video was available  for about 3 years without being submitted to FDA for review.
subsections: section_title: Purdue Focused on Promoting OxyContin for Treatment of Noncancer Pain
paragraphs: From the outset of the OxyContin marketing campaign, Purdue promoted  the drug to physicians for noncancer pain conditions that can be caused  by arthritis, injuries, and chronic diseases, in addition to cancer pain.  Purdue directed its sales representatives to focus on the physicians in  their sales territories who were high opioid prescribers. This group  included cancer and pain specialists, primary care physicians, and  physicians who were high prescribers of Purdue’s older product, MS  Contin. One of Purdue’s goals was to identify primary care physicians who  would expand the company’s OxyContin prescribing base. Sales  representatives were also directed to call on oncology nurses, consultant  pharmacists, hospices, hospitals, and nursing homes.
From OxyContin’s launch until its July 2001 label change, Purdue used two  key promotional messages for primary care physicians and other high  prescribers. The first was that physicians should prescribe OxyContin for  their pain patients both as the drug “to start with and to stay with.” The  second contrasted dosing with other opioid pain relievers with OxyContin  dosing as “the hard way versus the easy way” to dose because OxyContin’s  twice-a-day dosing was more convenient for patients. Purdue’s sales  representatives promoted OxyContin to physicians as an initial opioid  treatment for moderate-to-severe pain lasting more than a few days, to be  prescribed instead of other single-entity opioid analgesics or short-acting  combination opioid pain relievers. Purdue has stated that by 2003 primary  care physicians had grown to constitute nearly half of all OxyContin  prescribers, based on data from IMS Health, an information service  providing pharmaceutical market research. DEA’s analysis of physicians  prescribing OxyContin found that the scope of medical specialties was  wider for OxyContin than five other controlled-release, schedule II  narcotic analgesics. DEA expressed concern that this resulted in  OxyContin’s being promoted to physicians who were not adequately  trained in pain management.
Purdue’s promotion of OxyContin for the treatment of noncancer pain  contributed to a greater increase in prescriptions for noncancer pain than  for cancer pain from 1997 through 2002. According to IMS Health data,  the annual number of OxyContin prescriptions for noncancer pain  increased nearly tenfold, from about 670,000 in 1997 to about 6.2 million in  2002. In contrast, during the same 6 years, the annual number of  OxyContin prescriptions for cancer pain increased about fourfold, from  about 250,000 in 1997 to just over 1 million in 2002. The noncancer  prescriptions therefore increased from about 73 percent of total  OxyContin prescriptions to about 85 percent during that period, while the  cancer prescriptions decreased from about 27 percent of the total to about  15 percent. IMS Health data indicated that prescriptions for other schedule  II opioid drugs, such as Duragesic and morphine products, for noncancer  pain also increased during this period. Duragesic prescriptions for  noncancer pain were about 46 percent of its total prescriptions in 1997,  and increased to about 72 percent of its total in 2002. Morphine products,  including, for example, Purdue’s MS Contin, also experienced an increase  in their noncancer prescriptions during the same period. Their noncancer  prescriptions were about 42 percent of total prescriptions in 1997, and  increased to about 65 percent in 2002. DEA has cited Purdue’s focus on  promoting OxyContin for treating a wide range of conditions as one of the  reasons the agency considered Purdue’s marketing of OxyContin to be  overly aggressive.
section_title: Purdue Significantly Increased Its Sales Force to Market and Promote OxyContin
paragraphs: Purdue significantly increased its sales force to market and promote  OxyContin to physicians and other health care practitioners. In 1996,  Purdue began promoting OxyContin with a sales force of approximately  300 representatives in its Prescription Sales Division. Through a 1996  copromotion agreement, Abbott Laboratories provided at least another  300 representatives, doubling the total OxyContin sales force. By 2000,  Purdue had more than doubled its own internal sales force to 671. The  expanded sales force included sales representatives from the Hospital  Specialty Division, which was created in 2000 to increase promotional  visits on physicians located in hospitals. (See table 1.)
The manufacturers of two of the three comparable schedule II drugs have  smaller sales forces than Purdue. Currently, the manufacturer of Kadian  has about 100 sales representatives and is considering entering into a  copromotion agreement. Elan, the current owner of Oramorph SR, has  approximately 300 representatives, but told us that it is not currently  marketing Oramorph SR. The manufacturer of Avinza had approximately  50 representatives at its product launch. In early 2003, Avinza’s  manufacturer announced that more than 700 additional sales  representatives would be promoting the drug under its copromotion  agreement with the pharmaceutical manufacturer Organon—for a total of  more than 800 representatives.
By more than doubling its total sales representatives, Purdue significantly  increased the number of physicians to whom it was promoting OxyContin.  Each Purdue sales representative has a specific sales territory and is  responsible for developing a list of about 105 to 140 physicians to call on  who already prescribe opioids or who are candidates for prescribing  opioids. In 1996, the 300-plus Purdue sales representatives had a total  physician call list of approximately 33,400 to 44,500. By 2000, the nearly  700 representatives had a total call list of approximately 70,500 to 94,000  physicians. Each Purdue sales representative is expected to make about 35  physician calls per week and typically calls on each physician every 3 to 4  weeks. Each hospital sales representative is expected to make about 50  calls per week and typically calls on each facility every 4 weeks.
Purdue stated it offered a “better than industry average” salary and sales  bonuses to attract top sales representatives and provide incentives to  boost OxyContin sales as it had done for MS Contin. Although the sales  representatives were primarily focused on OxyContin promotion, the  amount of the bonus depended on whether a representative met the sales  quotas in his or her sales territory for all company products. As  OxyContin’s sales increased, Purdue’s growth-based portion of the bonus  formula increased the OxyContin sales quotas necessary to earn the same  base sales bonus amounts. The amount of total bonuses that Purdue  estimated were tied to OxyContin sales increased significantly from about  $1 million in 1996, when OxyContin was first marketed, to about $40  million in 2001. Beginning in 2000, when the newly created hospital  specialty representatives began promoting OxyContin, their estimated  total bonuses were approximately $6 million annually. In 2001, the average  annual salary for a Purdue sales representative was $55,000, and the  average annual bonus was $71,500. During the same year, the highest  annual sales bonus was nearly $240,000, and the lowest was nearly  $15,000. In 2001, Purdue decided to limit the sales bonus a representative  could earn based on the growth in prescribing of a single physician after a  meeting with the U.S. Attorney for the Western District of Virginia at  which the company was informed of the possibility that a bonus could be  based on the prescribing of one physician.
section_title: Purdue Employed Multiple Approaches to Market and Promote OxyContin
paragraphs: In addition to expanding its sales force, Purdue used multiple approaches  to market and promote OxyContin. These approaches included expanding  its physician speaker bureau and conducting speaker training conferences,  sponsoring pain-related educational programs, issuing OxyContin starter  coupons for patients’ initial prescriptions, sponsoring pain-related Web  sites, advertising OxyContin in medical journals, and distributing  OxyContin marketing items to health care professionals.
In our report on direct-to-consumer advertising, we found that most  promotional spending is targeted to physicians. For example, in 2001, 29  percent of spending on pharmaceutical promotional activities was related  to activities of pharmaceutical sales representatives directed to  physicians, and 2 percent was for journal advertising—both activities  Purdue uses for its OxyContin promotion. The remaining 69 percent of  pharmaceutical promotional spending involved sampling (55 percent),  which is the practice of providing drug samples during sales visits to  physician offices, and direct-to-consumer advertising (14 percent)—both  activities that Purdue has stated it does not use for OxyContin.
According to DEA’s analysis of IMS Health data, Purdue spent  approximately 6 to 12 times more on promotional efforts during  OxyContin’s first 6 years on the market than it had spent on its older  product, MS Contin, during its first 6 years, or than had been spent by  Janssen Pharmaceutical Products, L.P., for one of OxyContin’s drug  competitors, Duragesic. (See fig. 1.)
During the first 5 years that OxyContin was marketed, Purdue conducted  over 40 national pain management and speaker training conferences,  usually in resort locations such as Boca Raton, Florida, and Scottsdale,  Arizona, to recruit and train health care practitioners for its national  speaker bureau. The trained speakers were then made available to speak  about the appropriate use of opioids, including oxycodone, the active  ingredient in OxyContin, to their colleagues in various settings, such as  local medical conferences and grand round presentations in hospitals  involving physicians, residents, and interns. Over the 5 years, these  conferences were attended by more than 5,000 physicians, pharmacists,  and nurses, whose travel, lodging, and meal costs were paid by the  company. Purdue told us that less than 1 percent annually of the  physicians called on by Purdue sales representatives attended these  conferences. Purdue told us it discontinued conducting these conferences  in fall 2000. Purdue’s speaker bureau list from 1996 through mid-2002  included nearly 2,500 physicians, of whom over 1,000 were active  participants. Purdue has paid participants a fee for speaking based on the  physician’s qualifications; the type of program and time commitment  involved; and expenses such as airfare, hotel, and food. The company  currently marketing the comparable drug Avinza has a physician speaker  bureau, but does not sponsor speaker training and conferences at resort  locations. Kadian’s current company does not have a physician speaker  bureau and has not held any conferences.
From 1996, when OxyContin was introduced to the market, to July 2002,  Purdue has funded over 20,000 pain-related educational programs through  direct sponsorship or financial grants. These grants included support for  programs to provide physicians with opportunities to earn required  continuing medical education credits, such as grand round presentations  at hospitals and medical education seminars at state and local medical  conferences. During 2001 and 2002, Purdue funded a series of nine  programs throughout the country to educate hospital physicians and staff  on how to comply with JCAHO’s pain standards for hospitals and to  discuss postoperative pain treatment. Purdue was one of only two drug  companies that provided funding for JCAHO’s pain management  educational programs. Under an agreement with JCAHO, Purdue was the  only drug company allowed to distribute certain educational videos and a  book about pain management; these materials were also available for  purchase from JCAHO’s Web site. Purdue’s participation in these activities  with JCAHO may have facilitated its access to hospitals to promote  OxyContin.
For the first time in marketing any of its products, Purdue used a patient  starter coupon program for OxyContin to provide patients with a free  limited-time prescription. Unlike patient assistance programs, which  provide free prescriptions to patients in financial need, a coupon program  is intended to enable a patient to try a new drug through a one-time free  prescription. A sales representative distributes coupons to a physician,  who decides whether to offer one to a patient, and then the patient  redeems it for a free prescription through a participating pharmacy. The  program began in 1998 and ran intermittently for 4 years. In 1998 and 1999,  each sales representative had 25 coupons that were redeemable for a free  30-day supply. In 2000 each representative had 90 coupons for a 7-day  supply, and in 2001 each had 10 coupons for a 7-day supply.  Approximately 34,000 coupons had been redeemed nationally when the  program was terminated following the July 2001 OxyContin label change.  The manufacturers of two of the comparable drugs we examined—Avinza  and Kadian—used coupon programs to introduce patients to their  products. Avinza’s coupon program requires patients to make a copayment  to cover part of the drug’s cost.
Purdue has also used Web sites to provide pain-related information to  consumers and others. In addition to its corporate Web site, which  provides product information, Purdue established the “Partners Against  Pain” Web site in 1997 to provide consumers with information about pain  management and pain treatment options. According to FDA, the Web site  also contained information about OxyContin. Separate sections provide  information for patients and caregivers, medical professionals, and  institutions. The Web site includes a “Find a Doctor” feature to enable  consumers to find physicians who treat pain in their geographic area. As  of July 2002, over 33,000 physicians were included. Ligand, which markets  Avinza, one of the comparable drugs, has also used a corporate Web site to  provide product information. Purdue has also funded Web sites, such as  FamilyPractice.com, that provide physicians with free continuing medical  educational programs on pain management. Purdue has also provided  funding for Web site development and support for health care groups such  as the American Chronic Pain Association and the American Academy of  Pain Medicine. In addition, Purdue is one of 28 corporate donors—which  include all three comparable drug companies—listed on the Web site of  the American Pain Society, the mission of which is to improve pain-related  education, treatment, and professional practice. Purdue also sponsors  painfullyobvious.com, which it describes as a youth-focused “message  campaign designed to provide information—and stimulate open  discussions—on the dangers of abusing prescription drugs.”
Purdue also provided its sales representatives with 14,000 copies of a  promotional video in 1999 to distribute to physicians. Entitled From One  Pain Patient to Another: Advice from Patients Who Have Found Relief,  the video was to encourage patients to report their pain and to alleviate  patients’ concerns about taking opioids. Purdue stated that the video was  to be used “in physician waiting rooms, as a ‘check out’ item for an office’s  patient education library, or as an educational tool for office or hospital  staff to utilize with patients and their families.” Copies of the video were  also available for ordering on the “Partners Against Pain” Web site from  June 2000 through July 2001. The video did not need to be submitted to  FDA for its review because it did not contain any information about  OxyContin. However, the video included a statement that opioid  analgesics have been shown to cause addiction in less than 1 percent of  patients. According to FDA, this statement has not been substantiated.
As part of its marketing campaign, Purdue distributed several types of  branded promotional items to health care practitioners. Among these  items were OxyContin fishing hats, stuffed plush toys, coffee mugs with  heat-activated messages, music compact discs, luggage tags, and pens  containing a pullout conversion chart showing physicians how to calculate  the dosage to convert a patient to OxyContin from other opioid pain  relievers. In May 2002, in anticipation of PhRMA’s voluntary guidance for  sales representatives’ interactions with health care professionals, Purdue  instructed its sales force to destroy any remaining inventory of non-health- related promotional items, such as stuffed toys or golf balls. In early 2003,  Purdue began distributing an OxyContin branded goniometer—a range  and motion measurement guide. According to DEA, Purdue’s use of  branded promotional items to market OxyContin was unprecedented  among schedule II opioids, and was an indicator of Purdue’s aggressive  and inappropriate marketing of OxyContin.
Another approach Purdue used to promote OxyContin was to place  advertisements in medical journals. Purdue’s annual spending for  OxyContin advertisements increased from about $700,000 in 1996 to about  $4.6 million in 2001. All three companies that marketed the comparable  drugs have also used medical journal advertisements to promote their  products.
section_title: OxyContin Advertisements Violated the FD&C Act
paragraphs: Purdue has been cited twice by FDA for using advertisements in  professional medical journals that violated the FD&C Act. In May 2000,  FDA issued an untitled letter to Purdue regarding a professional medical  journal advertisement for OxyContin. FDA noted that among other  problems, the advertisement implied that OxyContin had been studied for  all types of arthritis pain when it had been studied only in patients with  moderate-to-severe osteoarthritis pain, the advertisement suggested  OxyContin could be used as an initial therapy for the treatment of  osteoarthritis pain without substantial evidence to support this claim, and  the advertisement promoted OxyContin in a selected class of patients— the elderly—without presenting risk information applicable to that class of  patients. Purdue agreed to stop dissemination of the advertisement. The  second action taken by FDA was more serious. In January 2003, FDA  issued a warning letter to Purdue regarding two professional medical  journal advertisements for OxyContin that minimized its risks and  overstated its efficacy, by failing to prominently present information from  the boxed warning on the potentially fatal risks associated with OxyContin  and its abuse liability, along with omitting important information about the  limitations on the indicated use of OxyContin. The FDA requested that  Purdue cease disseminating these advertisements and any similar violative  materials and provide a plan of corrective action. In response, Purdue  issued a corrected advertisement, which called attention to the warning  letter and the cited violations and directed the reader to the prominently  featured boxed warning and indication information for OxyContin. The  FDA letter was one of only four warning letters issued to drug  manufacturers during the first 8 months of 2003.
In addition, in follow-up discussions with Purdue officials on the January  2003 warning letter, FDA expressed concerns about some of the  information on Purdue’s “Partners Against Pain” Web site. The Web site  appeared to suggest unapproved uses of OxyContin for postoperative pain  that may have been inconsistent with OxyContin’s labeling and lacked risk  information about the drug. For example, one section of the Web site did  not disclose that OxyContin is not indicated for pain in the immediate  postoperative period—the first 12 to 24 hours following surgery—for  patients not previously taking the drug, because its safety in this setting  has not been established. The Web site also did not disclose that  OxyContin is indicated for postoperative pain in patients already taking  the drug or for use after the first 24 hours following surgery only if the  pain is moderate to severe and expected to persist for an extended period  of time. Purdue voluntarily removed all sections of the Web site that were  of concern to FDA.
FDA has also sent enforcement letters to other manufacturers of  controlled substances for marketing and promotion violations of the  FD&C Act. For example, in 1996, FDA issued an untitled letter to Zeneca  Pharmaceuticals, at the time the promoter of Kadian, for providing  information about the drug to a health professional prior to its approval in  the United States. Roxane Laboratories, the manufacturer of Oramorph  SR, was issued four untitled letters between 1993 and 1995 for making  misleading and possibly false statements. Roxane used children in an  advertisement even though Oramorph SR had not been evaluated in  children, and a Roxane sales representative issued a promotional letter to  a pharmacist that claimed, among other things, that Oramorph SR was  superior to MS Contin in providing pain relief. FDA has sent no  enforcement letters to Ligand Pharmaceuticals concerning Avinza.
section_title: Purdue Distributed an OxyContin Video without FDA’s Review That Appears to Have Made Unsubstantiated Claims and Minimized Risks
paragraphs: Beginning in 1998, Purdue, as part of its marketing and promotion of  OxyContin, distributed 15,000 copies of an OxyContin video to physicians  without submitting it to FDA for review. This video, entitled I Got My Life  Back: Patients in Pain Tell Their Story, presented the pain relief  experiences of various patients and the pain medications, including  OxyContin, they had been prescribed. FDA regulations require  pharmaceutical manufacturers to submit all promotional materials for  approved prescription drug products to the agency at the time of their  initial use. Because Purdue did not comply with this regulation, FDA did  not have an opportunity to review the video to ensure that the information  it contained was truthful, balanced, and accurately communicated. Purdue  has acknowledged the oversight of not submitting the video to FDA for  review. In February 2001, Purdue submitted a second version of the video  to FDA, which included information about the 160-milligram OxyContin  tablet. FDA did not review this second version until October 2002, after we  inquired about its content. FDA told us it found that the second version of  the video appeared to make unsubstantiated claims regarding OxyContin’s  effect on patients’ quality of life and ability to perform daily activities and  minimized the risks associated with the drug.
The 1998 video used a physician spokesperson to describe patients with  different pain syndromes and the limitations that each patient faced in his  or her daily activities. Each patient’s pain treatment was discussed, along  with the dose amounts and brand names of the prescription drugs,  including OxyContin, that either had been prescribed in the past or were  being prescribed at that time. The physician in the videos also stated that  opioid analgesics have been shown to cause addiction in less than 1  percent of patients—a fact that FDA has stated has not been substantiated.  At the end of the video, the OxyContin label was scrolled for the viewer.
In 2000, Purdue submitted another promotional video to FDA entitled I  Got My Life Back: A Two Year Follow up of Patients in Pain, and it  submitted a second version of this video in 2001, which also included  information on the 160-milligram OxyContin tablet. Purdue distributed  12,000 copies of these videos to physicians. Both versions scrolled the  OxyContin label at the end of the videos. FDA stated that it did not review  either of these videos for enforcement purposes because of limited  resources. Distribution of all four Purdue videos was discontinued by July  2001, in response to OxyContin’s labeling changes, which required the  company to modify all of its promotional materials, but copies of the  videos that had already been distributed were not retrieved and destroyed.
FDA said that it receives numerous marketing and promotional materials  for promoted prescription drugs and that while every effort is made to  review the materials, it cannot guarantee that all materials are reviewed  because of limited resources and competing priorities. FDA officials also  stated that pharmaceutical companies do not always submit promotional  materials as required by regulations and that in such instances FDA would  not have a record of the promotional pieces.
section_title: Several Factors May Have Contributed to OxyContin Abuse and Diversion, but Relationship to Availability Cannot Be Assessed
paragraphs: There are several factors that may have contributed to the abuse and  diversion of OxyContin. OxyContin’s formulation as a controlled-release  opioid that is twice as potent as morphine may have made it an attractive  target for abuse and diversion. In addition, the original label’s safety  warning advising patients not to crush the tablets because of the possible  rapid release of a potentially toxic amount of oxycodone may have  inadvertently alerted abusers to possible methods for misuse. Further, the  rapid growth in OxyContin sales increased the drug’s availability in the  marketplace and may have contributed to opportunities to obtain the drug  illicitly. The history of abuse and diversion of prescription drugs in some  geographic areas, such as those within the Appalachian region, may have  predisposed some states to problems with OxyContin. However, we could  not assess the relationship between the growth in OxyContin prescriptions  or increased availability with the drug’s abuse and diversion because the  data on abuse and diversion are not reliable, comprehensive, or timely.
subsections: section_title: OxyContin’s Formulation May Have Made It an Inviting Drug for Abuse and Diversion
paragraphs: While OxyContin’s potency and controlled-release feature may have made  the drug beneficial for the relief of moderate-to-severe pain over an  extended period of time, DEA has stated that those attributes of its  formulation have also made it an attractive target for abuse and diversion.  According to recent studies, oxycodone, the active ingredient in  OxyContin, is twice as potent as morphine. In addition, OxyContin’s  controlled-release feature allows a tablet to contain more active ingredient  than other, non-controlled-release oxycodone-containing drugs.
One factor that may have contributed to the abuse and diversion of  OxyContin was FDA’s original decision to label the drug as having less  abuse potential than other oxycodone products because of its controlled- release formulation. FDA officials said when OxyContin was approved the  agency believed that the controlled-release formulation would result in  less abuse potential because, when taken properly, the drug would be  absorbed slowly, without an immediate rush or high. FDA officials  acknowledged that the initial wording of OxyContin’s label was  “unfortunate” but was based on what was known about the product at that  time.
FDA officials told us that abusers typically seek a drug that is intense and  fast-acting. When OxyContin was approved, FDA did not recognize that if  the drug is dissolved in water and injected its controlled-release  characteristics could be disrupted, creating an immediate rush or high and  thereby increasing the potential for misuse and abuse. DEA officials told  us that OxyContin became a target for abusers and diverters because the  tablet contained larger amounts of active ingredient and the controlled- release formulation was easy for abusers to compromise.
The safety warning on the OxyContin label may also have contributed to  the drug’s potential for abuse and diversion, by inadvertently providing  abusers with information on how the drug could be misused. The label  included the warning that the tablets should not be broken, chewed, or  crushed because such action could result in the rapid release and  absorption of a potentially toxic dose of oxycodone. FDA places similar  safety warnings on other drugs to ensure that they are used properly. FDA  officials stated that neither they nor other experts anticipated that  crushing the controlled-release tablet and intravenously injecting or  snorting the drug would become widespread and lead to a high level of  abuse.
section_title: OxyContin’s Wide Availability May Have Increased Opportunities for Illicit Use
paragraphs: The large amount of OxyContin available in the marketplace may have  increased opportunities for abuse and diversion. Both DEA and Purdue  have stated that an increase in a drug’s availability in the marketplace may  be a factor that attracts interest by those who abuse and divert drugs.  Following its market introduction in 1996, OxyContin sales and  prescriptions grew rapidly through 2002. In 2001 and 2002 combined, sales  of OxyContin approached $3 billion, and over 14 million prescriptions for  the drug were dispensed. (See table 2.) OxyContin also became the top- selling brand-name narcotic pain reliever in 2001 and was ranked 15th on a  list of the nation’s top 50 prescription drugs by retail sales.
section_title: History of Prescription Drug Abuse in Some States May Have Predisposed Them to Problems with OxyContin
paragraphs: According to DEA, the abuse and diversion of OxyContin in some states  may have reflected the geographic area’s history of prescription drug  abuse. The White House Office of National Drug Control Policy (ONDCP)  designates geographic areas with illegal drug trade activities for allocation  of federal resources to link local, state, and federal drug investigation and  enforcement efforts. These areas, known as High-Intensity Drug  Trafficking Areas (HIDTA), are designated by ONDCP in consultation with  the Attorney General, the Secretary of the Treasury, heads of drug control  agencies, and governors in the states involved.
According to a 2001 HIDTA report, the Appalachian region, which  encompasses parts of Kentucky, Tennessee, Virginia, and West Virginia,  has been severely affected by prescription drug abuse, particularly pain  relievers, including oxycodone, for many years. Three of the four states— Kentucky, Virginia, and West Virginia—were among the initial states to  report OxyContin abuse and diversion. Historically, oxycodone,  manufactured under brand names such as Percocet, Percodan, and Tylox,  was among the most diverted prescription drugs in Appalachia. According  to the report, OxyContin has become the drug of choice of abusers in  several areas within the region. The report indicates that many areas of the  Appalachian region are rural and poverty-stricken, and the profit potential  resulting from the illicit sale of OxyContin may have contributed to its  diversion and abuse. In some parts of Kentucky, a 20-milligram OxyContin  tablet, which can be purchased by legitimate patients for about $2, can be  sold illicitly for as much as $25. The potential to supplement their incomes  can lure legitimate patients into selling some of their OxyContin to street  dealers, according to the HIDTA report.
section_title: Limitations on Abuse and Diversion Data Prevent Assessment of the Relationship with OxyContin’s Availability
paragraphs: The databases DEA uses to track the abuse and diversion of controlled  substances all have limitations that prevent an assessment of the  relationship between the availability of OxyContin and areas where the  drug is being abused or diverted. Specifically, these databases, which  generally do not provide information on specific brand-name drugs such  as OxyContin, are based on data gathered from limited sources in specific  geographic areas and have a significant time lag. As a result, they do not  provide reliable, complete, or timely information that could be used to  identify abuse and diversion of a specific drug.
DEA officials told us that it is difficult to obtain reliable data on what  controlled substances are being abused by individuals and diverted from  pharmacies because available drug abuse and diversion tracking systems  do not capture data on a specific brand-name product or indicate where a  drug product is being abused and diverted on a state and local level.  Because of the time lags in reporting information, the data reflect a  delayed response to any emerging drug abuse and diversion problem. For  example, the Drug Abuse Warning Network (DAWN) estimates national  drug-related emergency department visits or deaths involving abused  drugs using data collected by the Substance Abuse and Mental Health  Services Administration (SAMHSA). The data are collected from hospital  emergency departments in 21 metropolitan areas that have agreed to  voluntarily report drug-abuse-related information from a sample of patient  medical records, and from medical examiners in 42 metropolitan areas.  However, DAWN cannot make estimates for rural areas, where initial  OxyContin abuse and diversion problems were reported to be most  prevalent, nor does it usually provide drug-product-specific information,  and its data have a lag time of about 1 year. DEA stated that development  of enhanced data collection systems is needed to provide “credible, legally  defensible evidence concerning drug abuse trends in America.”
DEA relies primarily on reports from its field offices to determine where  abuse and diversion are occurring. DEA officials stated that the initial  areas that experienced OxyContin abuse and diversion problems included  rural areas within 8 states—Alaska, Kentucky, Maine, Maryland, Ohio,  Pennsylvania, Virginia, and West Virginia. In July 2002, DEA told us that it  learned that OxyContin abuse and diversion problems had spread into  larger areas of the initial 8 states, as well as parts of 15 other states, to  involve almost half of the 50 states. According to DEA officials, while  DEA field offices continue to report OxyContin as a drug of choice among  abusers, OxyContin has not been and is not now considered the most  highly abused and diverted prescription drug nationally. OxyContin is the  most abused single-entity prescription product according to those DEA  state and divisional offices that report OxyContin abuse.
section_title: Federal and State Agencies and Purdue Have Taken Actions to Prevent Abuse and Diversion of OxyContin
paragraphs: Since becoming aware of reports of abuse and diversion of OxyContin,  federal and state agencies and Purdue have taken actions intended to  address these problems. To protect the public health, FDA has  strengthened OxyContin label warnings and requested that Purdue  develop and implement an OxyContin risk management plan. In addition,  DEA has stepped up law enforcement actions to prevent abuse and  diversion of OxyContin. State Medicaid fraud control units have also  attempted to identify those involved in the abuse and diversion of  OxyContin. Purdue has initiated drug abuse and diversion education  programs, taken disciplinary actions against sales representatives who  improperly promote OxyContin, and referred physicians who were  suspected of improperly prescribing OxyContin to the appropriate  authorities. However, until fall 2002 Purdue did not analyze its  comprehensive physician prescribing reports, which it routinely uses in  marketing and promoting OxyContin, and other indicators to identify  possible physician abuse and diversion.
subsections: section_title: Reports of Abuse and Diversion Led to Label Changes and Other Actions by FDA
paragraphs: Reports of abuse and diversion of OxyContin that were associated with an  increasing incidence of addiction, overdose, and death prompted FDA to  revise the drug’s label and take other actions to protect the public health.  In July 2001, FDA reevaluated OxyContin’s label and made several changes  in an effort to strengthen the “Warnings” section of the label. FDA added a  subsection—“Misuse, Abuse, and Diversion of Opioids”—to stress that  physicians and pharmacists should be alert to the risk of misuse, abuse,  and diversion when prescribing or dispensing OxyContin. FDA also added  a black box warning—the highest level of warning FDA can place on an  approved drug product. FDA highlighted the language from the original  1995 label—stating that OxyContin is a schedule II controlled substance  with an abuse liability similar to morphine—by moving it into the black  box. Also, while the original label suggested that taking broken, chewed,  or crushed OxyContin tablets “could lead to the rapid release and  absorption of a potentially toxic dose of oxycodone,” a more strongly  worded warning in the black box stated that taking the drug in this manner  “leads to rapid release and absorption of a potentially fatal dose of  oxycodone” (emphasis added). (See table 3.) In addition to the black box  warning, FDA also changed the language in the original label that  described the incidence of addiction inadvertently induced by physician  prescribing as rare if opioids are legitimately used in the management of  pain. The revised label stated that data are not available to “establish the  true incidence of addiction in chronic patients.”
As mentioned earlier, the indication described in the original label was  also revised to clarify the appropriate time period for which OxyContin  should be prescribed for patients experiencing moderate-to-severe pain.  The language in the 1995 label was changed from “where use of an opioid  analgesic is appropriate for more than a few days” to “when a continuous,  around-the-clock analgesic is needed for an extended period of time.” (See  table 4.) A summary of changes made by FDA to the original OxyContin  label is given in appendix II.
Beginning in early 2001, FDA collaborated with Purdue to develop and  implement a risk management plan to help identify and prevent abuse and  diversion of OxyContin. As a part of the risk management plan in  connection with the labeling changes, Purdue was asked by FDA to revise  all of its promotional materials for OxyContin to reflect the labeling  changes. In August 2001, FDA sent a letter to Purdue stating that all future  promotional materials for OxyContin should prominently disclose the  information contained in the boxed warning; the new warnings that  address misuse, abuse, diversion, and addiction; and the new precautions  and revised indication for OxyContin. Purdue agreed to comply with this  request.
FDA officials told us that it is standard procedure to contact a drug  manufacturer when the agency becomes aware of reports of abuse and  diversion of a drug product so that FDA and the drug manufacturer can  tailor a specific response to the problem. While FDA’s experience with  risk management plans is relatively new, agency officials told us that  OxyContin provided the opportunity to explore the use of the plans to help  identify abuse and diversion problems. FDA is currently making decisions  about whether risk management plans will be requested for selected  opioid products. Also, in September 2003, FDA’s Anesthetic and Life  Support Drugs Advisory Committee held a public hearing to discuss its  current review of proposed risk management plans for opioid analgesic  drug products to develop strategies for providing patients with access to  pain treatment while limiting the abuse and diversion of these products.
FDA has also taken other actions to address the abuse and diversion of  OxyContin. It put information on its Web site for patients regarding the  appropriate use of OxyContin. FDA worked with Purdue to develop  “Dear Health Care Professional” letters, which the company distributed  widely to health care professionals to alert them that the package insert  had been revised to clarify the indication and strengthen the warnings  related to misuse, abuse, and diversion. FDA also has worked with DEA,  SAMHSA, the National Institute on Drug Abuse, ONDCP, and the Centers  for Disease Control and Prevention to share information and insights on  the problem of abuse and diversion of OxyContin.
section_title: DEA Developed an Action Plan to Deter OxyContin Abuse and Diversion
paragraphs: In April 2001, DEA developed a national action plan to deter abuse and  diversion of OxyContin. According to DEA officials, this marked the first  time the agency had targeted a specific brand-name product for  monitoring because of the level and frequency of abuse and diversion  associated with the drug. Key components of the action plan include  coordinating enforcement and intelligence operations with other law  enforcement agencies to target people and organizations involved in abuse  and diversion of OxyContin, pursuing regulatory and administrative action  to limit abusers’ access to OxyContin, and building national outreach  efforts to educate the public on the dangers related to the abuse and  diversion of OxyContin. DEA has also set Purdue’s procurement quota for  oxycodone at levels lower than the levels requested by Purdue.
DEA has increased enforcement efforts to prevent abuse and diversion of  OxyContin. From fiscal year 1996 through fiscal year 2002, DEA initiated  313 investigations involving OxyContin, resulting in 401 arrests. Most of  the investigations and arrests occurred after the initiation of the action  plan. Since the plan was enacted, DEA initiated 257 investigations and  made 302 arrests in fiscal years 2001 and 2002. Among those arrested were  several physicians and pharmacists. Fifteen health care professionals  either voluntarily surrendered their controlled substance registrations or  were immediately suspended from registration by DEA. In addition, DEA  reported that $1,077,500 in fines was assessed and $742,678 in cash was  seized by law enforcement agencies in OxyContin-related cases in 2001  and 2002.
Among several regulatory and administrative actions taken to limit  abusers’ access to OxyContin and controlled substances, DEA’s Office of  Diversion Control, in collaboration with the Department of Justice’s Office  of Justice Programs, Bureau of Justice Assistance, provides grants to  states for the establishment of prescription drug monitoring programs. The  conference committee report for the fiscal year 2002 appropriation to the  Department of Justice directed the Office of Justice Programs to make a  $2 million grant in support of the Harold Rogers Prescription Drug  Monitoring Program, which enhances the capacity of regulatory and law  enforcement agencies to collect and analyze controlled substance  prescription data. The program provided grants to establish new  monitoring programs in Ohio, Pennsylvania, Virginia, and West Virginia.  California, Kentucky, Massachusetts, Nevada, and Utah also received  grants to enhance existing monitoring programs.
DEA has also attempted to raise national awareness of the dangers  associated with abuse and diversion of OxyContin. In October 2001 DEA  joined 21 national pain and health organizations in issuing a consensus  statement calling for a balanced policy on prescription medication use.  According to the statement, such a policy would acknowledge that health  care professionals and DEA share responsibility for ensuring that  prescription medications, such as OxyContin, are available to patients who  need them and for preventing these drugs from becoming a source of  abuse and diversion. DEA and the health organizations also called for a  renewed focus on educating health professionals, law enforcement, and  the public about the appropriate use of opioid pain medications in order to  promote responsible prescribing and limit instances of abuse and  diversion. DEA is also working with FDA to encourage state medical  boards to require, as a condition of their state licensing, that physicians  obtain continuing medical education on pain management.
When OxyContin was first introduced to the market in 1996, DEA granted  Purdue’s initial procurement quota request for oxycodone. According to  DEA, increases in the quota were granted for the first several years.  Subsequently, concern over the dramatic increases in sales caused DEA to  request additional information to support Purdue’s requests to increase  the quota. In the last several years, DEA has taken the additional step of  lowering the procurement quota requested by Purdue for the manufacture  of OxyContin as a means for addressing abuse and diversion. However,  DEA has cited the difficulty of determining an appropriate level while  ensuring that adequate quantities were available for legitimate medical  use, as there are no direct measures available to establish legitimate  medical need.
section_title: State Agencies Have Responded to Reports of OxyContin Abuse and Diversion
paragraphs: State Medicaid fraud control units and medical licensure boards have  taken action in response to reports of abuse and diversion of OxyContin.  State Medicaid fraud control units have conducted investigations of abuse  and diversion of OxyContin, but generally do not maintain precise data on  the number of investigations and enforcement actions completed.  Although complete information was not available from directors of state  Medicaid fraud control units in Kentucky, Maryland, Pennsylvania,  Virginia, and West Virginia with whom we spoke, each of those directors  told us that abuse and diversion of OxyContin is a problem in his or her  state. The directors told us that they had investigated cases that involved  physicians or individuals who had either been indicted or prosecuted for  writing medically unnecessary OxyContin prescriptions in exchange for  cash or sexual relationships.
State medical licensure boards have also responded to complaints about  physicians who were suspected of abuse and diversion of controlled  substances, but like the Medicaid fraud control units, the boards generally  do not maintain data on the number of investigations that involved  OxyContin. Representatives of state boards of medicine in Kentucky,  Pennsylvania, Virginia, and West Virginia told us that they have received  complaints from various sources, such as government agencies, health  care professionals, and anonymous tipsters, about physicians suspected of  abuse and diversion of controlled substances. However, each of the four  representatives stated that his or her board does not track the complaints  by specific drug type and consequently cannot determine whether the  complaints received allege physicians’ misuse of OxyContin. Each of the  four representatives also told us that his or her medical licensure board  has adopted or strengthened guidelines or regulations for physicians on  prescribing, administering, and dispensing controlled substances in the  treatment of chronic pain. For example, in March 2001, the Kentucky  Board of Medical Licensure adopted guidelines to clarify the board’s  position on the use of controlled substances for nonterminal/nonmalignant  chronic pain. The boards of medicine in Pennsylvania, Virginia, and West  Virginia each have guidelines for the appropriate use of controlled  substances that are similar to those adopted by Kentucky.
section_title: Purdue Is Implementing a Risk Management Plan for OxyContin
paragraphs: In response to concerns about abuse and diversion of OxyContin, in April  2001 FDA and Purdue began to discuss the development of a risk  management plan to help detect and prevent abuse and diversion of  OxyContin. Purdue submitted its risk management plan to FDA for review  in August 2001. The plan includes some actions that Purdue proposed to  take, as well as others that it has already taken. Purdue’s risk management  plan includes actions such as strengthening the safety warnings on  OxyContin’s label for professionals and patients, training Purdue’s sales  force on the revised label, conducting comprehensive education programs  for health care professionals, and developing a database for identifying  and monitoring abuse and diversion of OxyContin.
Under the risk management plan, OxyContin’s label was strengthened,  effective in July 2001, by revising the physician prescribing information  and adding a black box warning to call attention to OxyContin’s potential  for misuse, abuse, and diversion. (See app. II.) Purdue trained its sales  force on the specifics of the revised label and provided sales  representatives with updated information on the appropriate use of opioid  analgesics, legal guidelines associated with promotion of its products, and  their responsibility and role in reporting adverse events. Purdue also  reiterated to its sales representatives that failure to promote products  according to the approved label, promotional materials, and applicable  FDA standards would result in disciplinary action by the company.  According to Purdue, from April 2001 through May 2003 at least 10 Purdue  employees were disciplined for using unapproved materials in promoting  OxyContin. Disciplinary actions included warning letters, suspension  without pay, and termination.
Purdue also has provided education programs for health care  professionals and the public under its risk management plan. For example,  in 2001 Purdue supported seminars that examined ways health care  professionals can help prevent abuse and diversion of opioids. Purdue  worked with DEA and other law enforcement agencies to develop and  implement antidiversion educational programs. In 2002, Purdue also  launched the Web site painfullyobvious.com to educate teenagers, parents,  law enforcement officers, and discussion leaders about the dangers of  prescription drug abuse.
Because reliable data on the abuse and diversion of controlled substance  drugs are not available, Purdue developed the Researched Abuse,  Diversion, and Addiction-Related Surveillance (RADARS) System, as part  of its risk management plan, to study the nature and extent of abuse of  OxyContin and other schedule II and III prescription medications and to  implement interventions to reduce abuse and diversion. According to  Purdue, RADARS collects and computes abuse, diversion, and addiction  rates for certain drugs based on population and determines national and  local trends.
Since the launch of OxyContin, Purdue has provided its sales force with  considerable information to help target physicians and prioritize sales  contacts within a sales territory. Sales representatives routinely receive  daily, weekly, monthly, and quarterly physician prescribing reports based  on IMS Health data that specify the physicians who have written  prescriptions for OxyContin and other opioid analgesics, and the number  of prescriptions written. Although this information has always been  available for use by Purdue and its sales representatives, it was not until  fall 2002 that Purdue directed its sales representatives to begin using 11  indicators to identify possible abuse and diversion and to report the  incidents to Purdue’s General Counsel’s Office for investigation. Among  the possible indicators are a sudden unexplained change in a physician’s  prescribing patterns that is not accounted for by changes in patient  numbers, information from credible sources such as a pharmacist that a  physician or his or her patients are diverting medications, or a physician  who writes a large number of prescriptions for patients who pay with  cash. As of September 2003, Purdue—through its own investigations—had  identified 39 physicians and other health care professionals who were  referred to legal, medical, or regulatory authorities for further action. Most  of the 39 referrals stemmed from reports by Purdue’s sales force.
Other actions included in the plan that were taken by Purdue prior to  submission of its risk management plan include discontinuance of the 160- milligram tablet of OxyContin to reduce the risk of overdose from this  dosage strength, the development of unique markings for OxyContin  tablets intended for distribution in Mexico and Canada to assist law  enforcement in identifying OxyContin illegally smuggled into the United  States, and the distribution of free tamper-resistant prescription pads  designed to prevent altering or copying of the prescription. Purdue also  implemented a program in 2001 to attempt to predict “hot spots” where  OxyContin abuse and diversion were likely to occur, but discontinued the  program in 2002 when Purdue concluded that nearly two-thirds of the  counties identified had no abuse and diversion.
section_title: Conclusions
paragraphs: At present, both federal agencies and the states have responsibilities  involving prescription drugs and their abuse and diversion. FDA is  responsible for approving new drugs and ensuring that the materials drug  companies use to market and promote these drugs are truthful, balanced,  and accurate. However, FDA examines these promotional materials only  after they have been used in the marketplace because the FD&C Act  generally does not give FDA authority to review these materials before the  drug companies use them. Moreover, the FD&C Act provisions governing  drug approval and promotional materials make no distinction between  controlled substances, such as OxyContin, and other prescription drugs.  DEA is responsible for registering handlers of controlled substances,  approving production quotas and monitoring distribution of controlled  substances to the retail level. It is the states, however, that are responsible  for overseeing the practice of medicine and pharmacy where drugs are  prescribed and dispensed. Some states have established prescription drug  monitoring programs to help them detect and deter abuse and diversion.  However, these programs exist in only 15 states and most do not  proactively analyze prescription data to identify individuals, physicians, or  pharmacies that have unusual use, prescribing, or dispensing patterns that  may suggest potential drug diversion or abuse.
The significant growth in the use of OxyContin to treat patients suffering  from chronic pain has been accompanied by widespread reports of abuse  and diversion that have in some cases led to deaths. The problem of abuse  and diversion has highlighted shortcomings at the time of approval in the  labeling of schedule II controlled substances, such as OxyContin, and in  the plans in place to detect misuse, as well as in the infrastructure for  detecting and preventing the abuse and diversion of schedule II controlled  substances already on the market.
Addressing abuse and diversion problems requires the collaborative  efforts of pharmaceutical manufacturers; the federal and state agencies  that oversee the approval and use of prescription drugs, particularly  controlled substances; the health care providers who prescribe and  dispense them; and law enforcement. After the problems with OxyContin  began to surface, FDA and Purdue collaborated on a risk management  plan to help detect and prevent abuse and diversion. Although risk  management plans were not in use when OxyContin was approved, they  are now an optional feature of new drug applications. FDA plans to  complete its guidance to the pharmaceutical industry on risk management  plans by September 30, 2004. The development of this guidance, coupled  with FDA’s current review of proposed risk management plans for  modified-release opioid analgesics, provides an opportunity to help ensure  that manufacturers include a strategy to monitor the use of these drugs  and to identify potential problems with abuse and diversion.
section_title: Recommendation for Executive Action
paragraphs: To improve efforts to prevent or identify the abuse and diversion of  schedule II controlled substances, we recommend that the Commissioner  of Food and Drugs ensure that FDA’s risk management plan guidance  encourages pharmaceutical manufacturers that submit new drug  applications for these substances to include plans that contain a strategy  for monitoring the use of these drugs and identifying potential abuse and  diversion problems.
section_title: Agency and Purdue Comments and Our Evaluation
paragraphs: We provided a draft of this report to FDA, DEA, and Purdue, the  manufacturer of OxyContin, for their review. FDA and DEA provided  written comments. (See apps. IV and V.) Purdue’s representatives provided  oral comments.
FDA said that it agreed with our recommendation that its risk  management plan guidance should encourage all pharmaceutical  manufacturers submitting new drug applications for schedule II controlled  substances to include strategies to address abuse and diversion concerns.  FDA stated that the agency is working on the risk management plan  guidance. FDA also noted that the FD&C Act makes no distinction  between controlled substances and other prescription drugs in its  provisions regulating promotion, but that as a matter of general policy, the  agency more closely scrutinizes promotion of drugs with more serious risk  profiles. However, FDA does not have written guidance that specifies that  promotional materials for controlled substances receive priority or special  attention over similar materials for other prescription drugs. Furthermore,  our finding that FDA did not review any of the OxyContin promotional  videos provided by Purdue until we brought them to the agency’s attention  raises questions about whether FDA provides extra attention to  promotional materials for controlled substances that by definition have a  high potential for abuse and may lead to severe psychological or physical  dependence. FDA recommended that we clarify our description of the  content of the warning letter issued to Purdue and provide additional  information describing the extent of the corrective action taken by  Purdue. FDA also recommended noting in the report that part of the risk  management plan in connection with the 2001 labeling changes was a  requirement that all OxyContin promotional materials be revised to reflect  the labeling changes and all future materials prominently disclose this  information. Finally, FDA noted that the promotional videos discussed in  the report were submitted by Purdue prior to the labeling change and  discontinued as a result of the labeling change. As we note in the report,  Purdue acknowledged that all the promotional videos were not submitted  to FDA at the time they were distributed. Moreover, although Purdue told  us that these videos were no longer distributed after the label change,  those videos that had been distributed were not collected and destroyed.  We revised the report to reflect FDA’s general comments. FDA also  provided technical comments that we incorporated where appropriate.
In its written comments, DEA agreed that the data on abuse and diversion  are not reliable, comprehensive, or timely, as we reported. DEA reiterated  its previous statement that Purdue’s aggressive marketing of OxyContin  fueled demand for the drug and exacerbated the drug’s abuse and  diversion. DEA also stated that Purdue minimized the abuse risk  associated with OxyContin. We agree with DEA that Purdue conducted an  extensive campaign to market and promote OxyContin using an expanded  sales force and multiple promotional approaches to encourage physicians,  including primary care specialists, to prescribe OxyContin as an initial  opioid treatment for noncancer pain, and that these efforts may have  contributed to the problems with abuse and diversion by increasing the  availability of the drug in the marketplace. However, we also noted that  other factors may have contributed to these problems. We also agree that  Purdue marketed OxyContin as having a low abuse liability, but we noted  that this was based on information in the original label approved by FDA.  DEA also acknowledged that the lack of a real measure of legitimate  medical need for a specific product (OxyContin), substance (oxycodone),  or even a class of substances (controlled release opioid analgesics) makes  it difficult to limit manufacturing as a means of deterring abuse and  diversion. DEA also noted that it is essential that risk management plans  be put in place prior to the introduction of controlled substances into the  marketplace, consistent with our recommendation. We revised the report  to provide some additional detail on problems associated with OxyContin  and Purdue’s marketing efforts. DEA provided some technical comments  on the draft report that we incorporated where appropriate.
Purdue representatives provided oral comments on a draft of this report.  In general, they thought the report was fair and balanced; however, they  offered both general and technical comments. Specifically, Purdue stated  that the report should add the media as a factor contributing to the abuse  and diversion of OxyContin because media stories provided the public  with information on how to “get high” from using OxyContin incorrectly.  Our report notes that the safety warning on the original label may have  inadvertently alerted abusers to a possible method for misusing the drug.  However, we note that the original label was publicly available from FDA  once OxyContin was approved for marketing. Purdue also suggested that  we include Duragesic, also a schedule II opioid analgesic, as a fourth  comparable drug to OxyContin. The three comparable drugs we used in  the report were chosen in consultation with FDA as comparable opioid  analgesics to OxyContin, because they were time-released, morphine- based schedule II drugs formulated as tablets like OxyContin. In contrast,  Duragesic, which contains the opioid analgesic fentanyl and provides pain  relief over a 72-hour period, is formulated as a skin patch to be worn  rather than as a tablet. Purdue representatives also provided technical  comments that were incorporated where appropriate.
We also provided sections of this draft report to the manufacturers of  three comparative drugs we examined. Two of the three companies with a  drug product used as a comparable drug to OxyContin reviewed the  portions of the draft report concerning their own product, and provided  technical comments, which were incorporated where appropriate. The  third company did not respond to our request for comments.
As agreed with your offices, unless you publicly announce this report’s  contents earlier, we plan no further distribution until 30 days after its issue  date. At that time, we will send copies of this report to the Commissioner  of Food and Drugs, the Administrator of the Drug Enforcement  Administration, Purdue, and the other pharmaceutical companies whose  drugs we examined. We will also make copies available to others upon  request. In addition, the report will be available at no charge on the GAO  Web site at http://www.gao.gov.
If you or your staffs have any questions about this report, please call me at  (202) 512-7119 or John Hansen at (202) 512-7105. Major contributors to  this report were George Bogart, Darryl Joyce, Roseanne Price, and Opal  Winebrenner.
section_title: Appendix I: Scope and Methodology
paragraphs: To identify the strategies and approaches used by Purdue Pharma L.P.  (Purdue) to market and promote OxyContin, we interviewed Purdue  officials and analyzed company documents and data. Specifically, we  interviewed Purdue officials concerning its marketing and promotional  strategies for OxyContin, including its targeting of physicians with specific  specialties and its sales compensation plan to provide sales  representatives with incentives for the drug’s sales. We also interviewed  selected Purdue sales representatives who had high and midrange sales  during 2001 from Kentucky, Pennsylvania, Virginia, and West Virginia— four states that were initially identified by the Drug Enforcement Agency  (DEA) as having a high incidence of OxyContin drug abuse and  diversion—and from California, Massachusetts, and New Jersey—three  states that DEA did not initially identify as having problems with  OxyContin. We asked the sales representatives about their training,  promotional strategies and activities, and targeting of physicians. We also  interviewed physicians who were among the highest prescribers of  OxyContin regarding their experiences with Purdue sales representatives,  including the strategies used to promote OxyContin, as well as their  experiences with sales representatives of manufacturers of other opioid  analgesics. We reviewed Purdue’s quarterly action plans for marketing and  promoting OxyContin for 1996 through 2003, Purdue’s sales representative  training materials, and materials from ongoing OxyContin-related  litigation. To obtain information on how Purdue’s marketing and  promotion of OxyContin compared to that of other companies, we  identified, in consultation with the Food and Drug Administration (FDA),  three opioid analgesics that were similar to OxyContin. The three drugs— Avinza, Kadian, and Oramorph SR—are all time-released, morphine-based  analgesics that are classified as schedule II controlled substances. We  examined the promotional materials each drug’s manufacturer submitted  to FDA and any actions FDA had taken against the manufacturers related  to how the drugs were marketed or promoted. We also interviewed  company officials about how they marketed and promoted their respective  drugs. Because of their concerns about proprietary information, the three  companies did not provide us with the same level of detail about their  drugs’ marketing and promotion as did Purdue.
To examine factors that contributed to the abuse and diversion of  OxyContin, we reviewed DEA abuse and diversion data as part of an effort  to compare them with DEA’s OxyContin state distribution data and with  IMS Health data on the rates of OxyContin sales and prescription  dispensing to determine if they occurred in similar geographic areas. We  also analyzed the distribution of Purdue sales representatives by state and  compared them with the availability of OxyContin and abuse and diversion  data to determine whether states with high rates of OxyContin sales and  prescription dispensing and abuse and diversion problems had more sales  representatives per capita than other states. However, limitations in the  abuse and diversion data prevent an assessment of the relationship  between the availability of OxyContin and areas where the drug was  abused and diverted. We also reviewed the High Intensity Drug Trafficking  Area (HIDTA) reports on states with histories of illegal drug activities. We  interviewed DEA and FDA officials, physicians who prescribed  OxyContin, officials from physician licensing boards in selected states,  officials from national health practitioner groups, and company officials  and sales representatives about why OxyContin abuse and diversion have  occurred.
To determine the efforts federal and state agencies and Purdue have made  to identify and prevent abuse and diversion of controlled substances such  as OxyContin, we interviewed FDA officials and analyzed information  from FDA regarding the marketing and promotion of controlled  substances, specifically OxyContin; FDA’s decision to approve the original  label for OxyContin; and FDA’s subsequent decision to revise OxyContin’s  labeling, as well as FDA’s role in monitoring OxyContin’s marketing and  advertising activities. We also interviewed DEA officials about the  agency’s efforts to identify and prevent abuse and diversion, including its  national action plan for OxyContin, and how it determines the prevalence  of OxyContin abuse and diversion nationally. We also interviewed officials  from national practitioner associations, Medicaid fraud control units, and  physician licensing boards in states with initial reports of abuse and  diversion—Kentucky, Maryland, Pennsylvania, Virginia, and West  Virginia—regarding concerns they had about the abuse and diversion of  OxyContin. We reviewed Purdue’s OxyContin risk management plan  submissions to FDA from 2001 through 2003 to identify actions taken by  Purdue to address abuse and diversion of OxyContin.
section_title: Appendix II: Summary of FDA Changes to the Original Approved OxyContin Label
paragraphs: Table 5 provides a description of the changes made by FDA to sections of  the original OxyContin approved label from June 1996 through July 2001.  These changes included a black box warning, the strongest warning an  FDA-approved drug can carry, and specifically addressed areas of concern  related to the opioid characteristics of oxycodone and its risk of abuse and  diversion.
section_title: Appendix III: Databases Used to Monitor Abuse and Diversion of OxyContin and Its Active Ingredient Oxycodone
paragraphs: DEA uses several databases to monitor abuse and diversion of controlled  substances, including OxyContin and its active ingredient oxycodone.  Specifically, the agency monitors three major databases—the Drug Abuse  Warning Network (DAWN), the National Forensic Laboratory Information  System (NFLIS), and the System to Retrieve Information from Drug  Evidence (STRIDE). DEA also monitors other data sources to identify  trends in OxyContin abuse and diversion, such as the Substance Abuse  and Mental Health Services Administration’s (SAMHSA) National Survey  on Drug Use and Health, formerly the National Household Survey on Drug  Abuse, and the Monitoring the Future Study funded by the National  Institute on Drug Abuse.
subsections: section_title: DAWN Data
paragraphs: SAMHSA operates the DAWN system, which estimates national drug- related emergency department visits and provides death counts involving  abused drugs. DAWN collects data semiannually on drug abuse from  hospital emergency department admission and medical examiner data  from 21 metropolitan areas and a limited number of metropolitan medical  examiners who agree to voluntarily report medical record samples. The  emergency department and medical examiner data generally do not  differentiate oxycodone from OxyContin, unless the individual provides  the information to the hospital or identifiable tablets are found with the  person. Although samples from hospitals outside the 21 metropolitan areas  are also available, DAWN is not able to make drug-related emergency  department visit or death estimates for rural or suburban areas.
section_title: NFLIS Data
paragraphs: NFLIS, a DEA-sponsored project initiated in 1997, collects the results of  state and local forensic laboratories’ analyses of drugs seized as evidence  by law enforcement agencies. NFLIS is used to track drug abuse and  trafficking involving both controlled and noncontrolled substances and  reports results by a drug’s substance, such as oxycodone, and not by its  brand name. DEA stated that because new laboratories are being added,  its data should not yet be used for trending purposes. As of March 2003,   35 state laboratories and 52 local or municipal laboratories participated in  the project.
section_title: STRIDE Data
paragraphs: STRIDE, another DEA database, reports the results of chemical evidence  analysis done by DEA laboratories in drug diversion and trafficking cases.  Oxycodone data are reported by combining single and combination  oxycodone drugs and do not provide specific enough information to  distinguish OxyContin cases and exhibits. The database’s lag time, which  varies by laboratory, depends on how quickly the findings are entered  after the seizure of the drug substance and its analysis.
section_title: National Survey on Drug Use and Health Data
paragraphs: The National Survey on Drug Use and Health, another SAMHSA database,  is used to develop national and state estimates of trends in drug  consumption. Prior to 2001, the self-reported survey asked participants if  they had illicitly used any drug containing oxycodone. In 2001, the survey  included a separate section for pain relievers, and asked participants if  they had used OxyContin, identifying it by its brand name, that had not  been prescribed for them. State samples from the survey are combined to  make national- and state-level estimates of drug use, and because the  estimated numbers derived for OxyContin are so small, it is not possible to  project illicit OxyContin use on a regional, state, or county basis.
section_title: Monitoring the Future Survey Data
paragraphs: The Monitoring the Future Survey, funded by the National Institute on  Drug Abuse and conducted by the University of Michigan, annually  monitors the illicit use of drugs by adolescent students in the 8th, 10th,  and 12th grades. The 2002 survey included new questions using the brand  names of four drugs, including OxyContin, in its survey on the annual and  30-day prevalence of drug use.
section_title: Appendix IV: Comments from the Food and Drug Administration
section_title: Appendix V: Comments from the Drug Enforcement Administration