Prescription Drugs: OxyContin Abuse and Diversion and Efforts to 
Address the Problem (19-DEC-03, GAO-04-110).			 
                                                                 
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.					 
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-04-110 					        
    ACCNO:   A09046						        
  TITLE:     Prescription Drugs: OxyContin Abuse and Diversion and    
Efforts to Address the Problem					 
     DATE:   12/19/2003 
  SUBJECT:   Drug abuse 					 
	     Drugs						 
	     Strategic planning 				 
	     Controlled substances				 
	     Marketing						 
	     Advertising					 

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GAO-04-110

United States General Accounting Office

GAO

                       Report to Congressional Requesters

December 2003

PRESCRIPTION DRUGS

        OxyContin Abuse and Diversion and Efforts to Address the Problem

GAO-04-110

Highlights of GAO-04-110, a report to congressional requesters

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.

To improve efforts to prevent or identify abuse and diversion of
controlled substances such as OxyContin, FDA's risk management plan
guidance should encourage pharmaceutical manufacturers with new drug
applications to submit plans that contain a strategy for identifying
potential problems with abuse and diversion. FDA concurred with GAO's
recommendation. DEA agreed that such risk management plans are important,
and Purdue stated that the report appeared to be fair and balanced.

www.gao.gov/cgi-bin/getrpt?GAO-04-110.

To view the full product, including the scope and methodology, click on
the link above. For more information, contact Marcia Crosse at (202)
512-7119.

December 2003

PRESCRIPTION DRUGS

OxyContin Abuse and Diversion and Efforts to Address the Problem

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.

Contents

  Letter

Results in Brief
Background
Purdue Conducted an Extensive Campaign to Market and Promote

OxyContin
Several Factors May Have Contributed to OxyContin Abuse and
Diversion, but Relationship to Availability Cannot Be Assessed
Federal and State Agencies and Purdue Have Taken Actions to

Prevent Abuse and Diversion of OxyContin
Conclusions
Recommendation for Executive Action
Agency and Purdue Comments and Our Evaluation

                                       1

                                      4 7

16

29

34 41 42 43

Appendix I Scope and Methodology

Appendix II	Summary of FDA Changes to the Original Approved OxyContin
Label

Appendix III Databases Used to Monitor Abuse and Diversion of

  OxyContin and Its Active Ingredient Oxycodone 51

DAWN Data 51
NFLIS Data 51
STRIDE Data 52
National Survey on Drug Use and Health Data 52
Monitoring the Future Survey Data 52

Appendix IV Comments from the Food and Drug Administration

  Appendix V	Comments from the Drug Enforcement
  Administration 56

  Tables

Table 1: Sales Representative Positions Available for OxyContin Promotion,
1996 through 2002

       Table 2: Total OxyContin Sales and Prescriptions for 1996 through
                2002 with Percentage Increases from Year to Year
         Table 3: Selected Language Approved by FDA in Warning Sections

of OxyContin Labels, 1995 and 2001

Table 4: Selected Language Approved by FDA in the Indication Sections of
OxyContin Labels, 1995 and 2001

Table 5: FDA Changes to the Original OxyContin Label Made from June 1996
through July 2001

19 31 35 35 48

  Figure

Figure 1: Promotional Spending for Three Opioid Analgesics in First 6
Years of Sales

Abbreviations

DAWN Drug Abuse Warning Network
DEA Drug Enforcement Administration
FDA Food and Drug Administration
FD&C Act Federal Food, Drug and Cosmetic Act
HHS Department of Health and Human Services
HIDTA High Intensity Drug Trafficking Area
JCAHO Joint Commission on Accreditation of Healthcare

Organizations NFLIS National Forensic Laboratory Information System ONDCP
Office of National Drug Control Policy PDUFA Prescription Drug User Fee
Act of 1992 PhRMA Pharmaceutical Research and Manufacturers of America
RADARS Researched Abuse, Diversion, and Addiction-Related

Surveillance SAMHSA Substance Abuse and Mental Health Services

Administration STRIDE System to Retrieve Information from Drug Evidence
WHO World Health Organization

This is a work of the U.S. government and is not subject to copyright
protection in the United States. It may be reproduced and distributed in
its entirety without further permission from GAO. However, because this
work may contain copyrighted images or other material, permission from the
copyright holder may be necessary if you wish to reproduce this material
separately.

United States General Accounting Office Washington, DC 20548

December 23, 2003

The Honorable Frank R. Wolf
Chairman
Subcommittee on Commerce, Justice, State, and the Judiciary,

and Related Agencies
Committee on Appropriations
House of Representatives

The Honorable James C. Greenwood
Chairman
Subcommittee on Oversight and Investigations
Committee on Energy and Commerce
House of Representatives

The Honorable Harold Rogers
House of Representatives

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.,1 for the treatment
of moderate-to-severe pain lasting more than a few days.2 According to

1OxyContin is an opioid analgesic-a narcotic substance that relieves a
person's pain without causing the loss of consciousness. Hereafter, we
refer to the company as Purdue.

2As discussed later in this report, FDA approved the revised OxyContin
label in July 2001 to describe the time frame as "when a continuous
around-the-clock analgesic is needed for an extended period of time."

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.3 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.4 According to FDA and the Drug Enforcement Administration (DEA),
the abuse of OxyContin is associated with serious consequences, including
addiction, overdose, and death.5 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.6 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

3According to FDA, there is no known limit to the amount of oxycodone, the
active ingredient in OxyContin, that can be used to treat pain.

4Prescription drug diversion can involve such activities as "doctor
shopping" by individuals who visit numerous physicians to obtain multiple
prescriptions, prescription forgery, and pharmacy theft. Diversion can
also involve illegal sales of prescription drugs by physicians, patients,
or pharmacists, as well as obtaining controlled substances from Internet
pharmacies without a valid prescription.

5According to the National Institute on Drug Abuse, addiction is a
chronic, relapsing disease, characterized by compulsive drug seeking and
use and by neurochemical and molecular changes in the brain, whereas
physical dependence is an adaptive physiological state that can occur with
regular drug use and results in withdrawal symptoms when drug use is
discontinued.

6Under the Controlled Substances Act, which was enacted in 1970, drugs are
classified as controlled substances and placed into one of five schedules
based on their medicinal value, potential for abuse, and safety or
dependence liability. Schedule I drugs have no medicinal value; have not
been approved by FDA; and along with schedule II drugs, have the highest
potential for abuse. Schedule II drugs have the highest potential for
abuse of any approved drugs.

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.7 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.8

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.9 Because of their
concern about the proprietary nature of the information,

7OxyContin, Hearings of the Subcommittee on the Departments of Commerce,
Justice, and State, the Judiciary, and Related Agencies, House Committee
on Appropriations, 107th Cong. Part 10 (Dec. 11, 2001).

8OxyContin: Balancing Risks and Benefits, Hearing of the Senate Committee
on Health, Education, Labor, and Pensions, 107th Cong. 287 (Feb. 12,
2002).

9Avinza was approved by FDA in 2002 and is marketed by Ligand
Pharmaceuticals; Kadian was approved in 1996 and is marketed by
Alpharma-US Human Pharmaceuticals; and Oramorph SR was approved in 1991
and is now owned by Elan Corporation, which told us it is not currently
marketing the drug.

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.

                                Results in Brief

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. OxyContin
sales and prescriptions grew rapidly following its market introduction in
1996, with the growth in prescriptions for noncancer pain outpacing the
growth in prescriptions for cancer pain from 1997 through 2002. By 2003,
nearly half of all OxyContin prescribers were primary care physicians. 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.
Purdue has been cited twice by FDA for using potentially false or
misleading medical journal advertisements for OxyContin that violated the
Federal Food, Drug and Cosmetic Act (FD&C Act), including one
advertisement that failed to include warnings about the potentially fatal
risks associated with OxyContin use. Further, Purdue did

not submit an OxyContin promotional video for FDA review at the time of
its initial distribution in 1998, as required by FDA regulations.
Therefore, FDA did not have the opportunity to review the video at the
time of its distribution to ensure that the information it contained was
truthful, balanced, and accurately communicated. FDA reviewed a similar
video in 2002 and told us that the video appeared to have made
unsubstantiated claims about OxyContin and minimized its risks.

Several factors may have contributed to OxyContin's abuse and diversion.
OxyContin's controlled-release formulation, which made the drug beneficial
for the relief of moderate-to-severe pain over an extended period of time,
enabled the drug to contain more of the active ingredient oxycodone than
other, non-controlled-release oxycodone-containing drugs. This feature may
have made OxyContin an attractive target for abuse and diversion,
according to DEA. OxyContin's controlled-release formulation, which
delayed the drug's absorption, also led FDA to include language in the
original label stating that OxyContin had a lower potential for abuse than
other oxycodone products. FDA officials thought that the
controlled-release feature would make the drug less attractive to abusers.
However, FDA did not recognize that the drug could be dissolved in water
and injected, which disrupted the controlled-release characteristics and
created an immediate rush or high, thereby increasing the potential for
abuse. In addition, the safety warning on the label that advised patients
not to crush the tablets because a rapid release of a potentially toxic
amount of the drug could result-a customary precaution for
controlledrelease medications-may have inadvertently alerted abusers to a
possible method for misusing the drug. The rapid growth in OxyContin
sales, which increased the drug's availability in the marketplace, may
have made it easier for abusers to obtain the drug for illicit purposes.
Further, some geographic areas have been shown to have a history of
prescription drug abuse and diversion that may have predisposed some
states to the abuse and diversion of OxyContin. However, we could not
assess the relationship between the increased availability of OxyContin
and locations where it is being abused and diverted because the data on
abuse and diversion are not reliable, comprehensive, or timely.

Since 2000, federal and state agencies and Purdue have taken several
actions to try to address abuse and diversion of OxyContin. In July 2001,
FDA approved a revised OxyContin label adding the highest level of safety
warning that FDA can place on an approved drug product. The agency also
collaborated with Purdue to develop and implement a risk management plan
to help detect and prevent abuse and diversion of OxyContin. Risk
management plans were not used at the time OxyContin was approved.

The plans are an optional feature of new drug applications that are
intended to decrease product risks by using one or more interventions or
tools beyond the approved product labeling. FDA plans to provide guidance
on risk management plans to the pharmaceutical industry by September 2004.
Also at the federal level, DEA initiated 257 OxyContinrelated abuse and
diversion cases in fiscal years 2001 and 2002, which resulted in 302
arrests and about $1 million in fines. At the state level, Medicaid fraud
control units have investigated OxyContin abuse and diversion; however,
they do not maintain precise data on the number of investigations and
enforcement actions completed. Similarly, state medical licensure boards
have investigated complaints about physicians who were suspected of abuse
and diversion of controlled substances, but they could not provide data on
the number of investigations involving OxyContin. Purdue has initiated
education programs and other activities for physicians, pharmacists, and
the public to address OxyContin abuse and diversion. Purdue has also taken
disciplinary action against its sales representatives who improperly
promoted OxyContin and has referred physicians who were suspected of
misprescribing OxyContin to the appropriate authorities. Although Purdue
has used very specific information on physician prescribing practices to
market and promote OxyContin since its approval, it was not until October
2002 that Purdue began to use this information and other indicators to
identify patterns of prescribing that could point to possible improper
sales representative promotion or physician abuse and diversion of
OxyContin.

To improve efforts to prevent or identify the abuse and diversion of
schedule II controlled substances such as oxycodone, we recommend that
FDA's risk management plan guidance encourage the 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.

We received comments on a draft of this report from FDA, DEA, and Purdue.
FDA agreed with our recommendation that risk management plans for schedule
II controlled substances contain a strategy for monitoring and identifying
potential abuse and diversion problems. DEA reiterated its statement that
Purdue's aggressive marketing of OxyContin exacerbated the abuse and
diversion problems and noted that it is essential that risk management
plans be put in place prior to the introduction of controlled substances
into the marketplace. Purdue said the report appeared to be fair and
balanced, but that we should add the media as one of the factors
contributing to abuse and diversion problems

with OxyContin. We incorporated their technical comments where
appropriate.

                                   Background

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,10 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.

                           Medical Treatment of Pain

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.

10Title II of the Comprehensive Drug Abuse Prevention and Control Act of
1970 (Pub. L. No. 91-513, S:S:100 et seq., 84 Stat. 1236, 1242 et seq.).

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 sign11 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.12 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

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.13
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
oxycodonecombination 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

11The other four vital signs physicians use to assess patients are pulse,
blood pressure, core temperature, and respiration.

12In 1999, the name of the Agency for Health Care Policy and Research was
changed to the Agency for Healthcare Research and Quality. The agency,
which is part of HHS, is responsible for supporting research designed to
improve the quality of health care, reduce its costs, and broaden access
to essential services.

13When we refer to OxyContin's label we are also referring to the drug's
package insert that contains the same information about the product.

other oxycodone-containing drugs.14 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.15 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

14For example, according to Purdue's comparable dose guide a patient
taking one Percodan 4.5-milligram tablet or one Tylox 5-milligram tablet
every 6 hours can be converted to either a 10-or a 20-milligram OxyContin
tablet to be taken every 12 hours. For a 12-hour dosing period, one
OxyContin tablet replaces two Percodan or Tylox tablets, and one OxyContin
tablet contains twice as much oxycodone as one of the other tablets.

15In April 2001, Purdue discontinued distribution of the 160-milligram
tablets because of OxyContin abuse and diversion concerns.

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 2000.16 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.

16Doris Bloodsworth, "Pain Pill Leaves Death Trail: A Nine-Month
Investigation Raises Many Questions about Purdue Pharma's Powerful Drug
OxyContin," Orlando Sentinel, Oct. 19, 2003.

Controlled Substances Act

The Controlled Substances Act established a classification structure for
drugs and chemicals used in the manufacture of drugs that are designated
as controlled substances.17 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.18

                              FDA's Regulation of
                               Prescription Drugs

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.19 The FD&C Act makes no distinction between

17Section 201, classified to 21 U.S.C. S: 811.

18Some schedule V drugs that contain limited quantities of certain
narcotic and stimulant drugs are available over the counter, without a
prescription.

19FDA regulations require that promotional labeling and advertisements be
submitted to FDA at the time of initial dissemination (for labeling) and
initial publication (for advertisements). The FD&C Act defines labeling to
include all labels and other written, printed, or graphic matter
accompanying an article. For example, promotional materials commonly shown
or given to physicians, such as sales aids and branded promotional items,
are regulated as promotional labeling. FDA may also regulate promotion by
sales representatives on computer programs, through fax machines, or on
electronic bulletin boards.

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.20

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

20For details on FDA's oversight of drug advertising see U.S. General
Accounting Office, Prescription Drugs: FDA Oversight of Direct-to-Consumer
Advertising Has Limitations, GAO-03-177 (Washington, D.C.: Oct. 28, 2002).

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).21 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.

    DEA's Regulation of Controlled Substances

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

21The Prescription Drug User Fee Act of 1992, Pub. L. No. 102-571, title
I, 106 Stat. 4491, was reauthorized by the Food and Drug Modernization Act
of 1997, Pub. L. No. 105-115, 111 Stat. 2296, and, most recently, by the
Prescription Drug User Fee Amendments of 2002, Pub. L. No. 107-188, title
V, subtitle A, 116 Stat. 594, 687.

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.

    States' Regulation of the Practice of Medicine and Pharmacy and Role in
    Monitoring Illegal Use and Diversion of Prescription Drugs

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.22 In some
cases, consumers can purchase prescription drugs, including controlled
substances, such as OxyContin, from Internet pharmacies without a valid
prescription.

22For more details on Internet pharmacies, see U.S. General Accounting
Office, Internet Pharmacies: Adding Disclosure Requirements Would Aid
State and Federal Oversight, GAO-01-69 (Washington, D.C.: Oct. 19, 2000).

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.23

    Guidelines for Marketing Drugs to Health Care Professionals

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.

23For more details on these programs, see U.S. General Accounting Office,
Prescription Drugs: State Monitoring Programs Provide Useful Tool to
Reduce Diversion, GAO-02-634 (Washington, D.C.: May 17, 2002).

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.24 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.

  Purdue Conducted an Extensive Campaign to Market and Promote OxyContin

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

24In addition, the American Medical Association, a professional
association for physicians, issued guidelines in 1990 regarding gifts
given to physicians by drug industry representatives. For example,
physicians may accept individual gifts of nominal value that are related
to their work, such as notepads and pens, and may attend conferences
sponsored by drug companies that are educational and for which appropriate
disclosure of financial support or conflicts of interest is made.

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.

    Purdue Focused on Promoting OxyContin for Treatment of Noncancer Pain

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.25 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

25Following OxyContin's July 2001 label change, Purdue modified its
promotional messages but continued to focus on encouraging physicians to
prescribe OxyContin for patients taking pain relievers every 4 to 6 hours.
In 2003, Purdue began using the promotional claim "there can be life with
relief" in OxyContin promotion.

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 2002.26 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 2002.27
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 Duragesic28 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.

26IMS Health reported noncancer prescriptions written for the following
types of pain conditions: surgical aftercare; musculoskeletal disorders
including back and neck disorders, arthritis conditions, and injuries and
trauma including bone fractures; central nervous system disorders
including headache conditions such as migraines; genitourinary disorders
including kidney stones; and other types of general pain.

27The IMS Health data included information from the National Disease and
Therapeutics Index and the National Prescription Audit. The National
Disease and Therapeutics Index does not capture data from
anesthesiologists and dental specialties. The National Prescription Audit
data include retail pharmacy, long-term-care, and mail-order
prescriptions.

28Duragesic is a skin patch used to deliver the opioid pain reliever
fentanyl over a 72-hour period.

    Purdue Significantly Increased Its Sales Force to Market and Promote
    OxyContin

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.29 Through a 1996
copromotion agreement, Abbott Laboratories provided at least another 300
representatives, doubling the total OxyContin sales force.30 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.)

Table 1: Sales Representative Positions Available for OxyContin Promotion,
1996 through 2002

            Positions availablea 1996 1997 1998 1999 2000 2001 2002

           Purdue Prescription Sales Division 318  319  377  471  562 641 641 
           Purdue Hospital Specialty Division    0    0    0    0 109 125 126 
                    Subtotal-All Purdue sales                             
                              representatives 318  319  377  471  671 766 767 

Abbott Laboratories sales

b

                  representatives 300 300 300 300 300 300 300

                     Total 618 619 677 771 971 1,066 1,067

Source: GAO analysis of Purdue data.

aAll positions were not necessarily filled in a given year.

bUnder the OxyContin copromotion agreement, Abbott Laboratories provided
at least 300 sales representatives each year.

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

29These sales representatives were also responsible for promoting other
Purdue products.

30Abbott Laboratories sales representatives' promotion of OxyContin is
limited to hospitalbased anesthesiologists and surgeons and major
hospitals, medical centers, and freestanding pain clinics.

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.

    Purdue Employed Multiple Approaches to Market and Promote OxyContin

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.31 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.)

31U.S. General Accounting Office, Prescription Drugs: FDA Oversight of
Direct-to-Consumer Advertising Has Limitations, GAO-03-177 (Washington,
D.C.: Oct. 28, 2002).

Figure 1: Promotional Spending for Three Opioid Analgesics in First 6
Years of Sales

Absolute dollars in millions 30

25

20

15

10

5

0 Year 1 Year 2 Year 3 Year 4 Year 5 Year 6

MS Contin: 1984-1989

OxyContin: 1996-2001

Duragesic: 1991-1996

Source: DEA and IMS Health, Integrated Promotional Service Audit.

Note: Dollars are 2002 adjusted.

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.32
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

32During 2000 through 2002, JCAHO sponsored a series of educational
programs on pain management standards with various cosponsors, including
pain-related groups such as the American Pain Society and the American
Academy of Pain Medicine.

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.33 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.34 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

33The "Find a Doctor" feature is a physician listing service provided by
the National Physicians DataSource, LLC.

34Purdue has also helped to fund the Dannemiller Memorial Education
Foundation and the American Academy of Physician Assistants Web sites.

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.35 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-healthrelated 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.

OxyContin Advertisements Purdue has been cited twice by FDA for using
advertisements in Violated the FD&C Act professional medical journals that
violated the FD&C Act. In May 2000, FDA issued an untitled letter to
Purdue regarding a professional medical

35It is common drug industry practice for companies to provide conversion
tables for sales representatives to distribute to health care
practitioners. Purdue used a similar pen for its older product, MS Contin.

journal advertisement for OxyContin.36 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.37 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.38 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.39 The FDA letter was one of only four warning letters issued to
drug manufacturers during the first 8 months of 2003.40

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

36FDA indicated that in 2000, it issued 75 untitled letters to 46 drug
manufacturers, as well as 4 warning letters to 4 drug manufacturers, for
using promotional activities that violated the FD&C Act.

37The advertisement appeared in the New England Journal of Medicine in May
2000.

38The advertisements appeared in the Journal of the American Medical
Association in October and November 2002.

39According to FDA, the corrective advertisement ran for 3 months and
appeared in approximately 30 medical journals.

40FDA indicated that from January through August 2003, it issued 4 warning
letters to four manufacturers and 12 untitled letters to seven drug
manufacturers for using promotional activities that violated the FD&C Act.

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,41 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.

    Purdue Distributed an OxyContin Video without FDA's Review That Appears to
    Have Made Unsubstantiated Claims and Minimized Risks

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

41Zeneca Pharmaceuticals promoted Kadian for Faulding Laboratories, the
drug's manufacturer at that time.

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.

  Several Factors May Have Contributed to OxyContin Abuse and Diversion, but
  Relationship to Availability Cannot Be Assessed

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.

    OxyContin's Formulation May Have Made It an Inviting Drug for Abuse and
    Diversion

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.42 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
controlledrelease 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.

42See, for example, G.B. Curtis, et al. "Relative Potency of
Controlled-Release Oxycodone and Morphine in a Postoperative Pain Model,"
European Journal of Clinical Pharmacology, vol. 55, no. 6 (1999):
55:425-429.

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
controlledrelease 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.

    OxyContin's Wide Availability May Have Increased Opportunities for Illicit
    Use

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
topselling 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.43

43This information is from the National Institute for Health Care
Management's Prescription Drug Expenditures reports for 2000 and 2001,
prepared using American Institutes for Research analysis of Scott-Levin
Prescription Audit Data. OxyContin was ranked 18th in 2000.

Table 2: Total OxyContin Sales and Prescriptions for 1996 through 2002
with Percentage Increases from Year to Year

                                   Percentage      Number of       Percentage 
            Year            Sales      increase  prescriptions       increase 
            1996      $44,790,000           N/A          316,786          N/A 
            1997      125,464,000           180          924,375 
            1998      286,486,000           128    1,910,944     
            1999      555,239,000            94    3,504,827     
            2000      981,643,000            77    5,932,981     
            2001  1,354,717,000              38    7,183,327     
            2002  1,536,816,000              13    7,234,204     

Sources: Purdue and IMS Health.

Legend: N/A = not applicable.

Note: GAO analysis of OxyContin sales and prescription data from Purdue
and IMS Health, which includes data from all 50 states and the District of
Columbia. Sales include combined retail and nonretail sales in drugstores,
hospitals, and long-term-care facilities from the IMS Health U.S. National
Sales database. Prescriptions include retail pharmacy, long-term-care, and
mail-order prescriptions from IMS Health's National Prescriptions Audit.

    History of Prescription Drug Abuse in Some States May Have Predisposed Them
    to Problems with OxyContin

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.44

According to a 2001 HIDTA report,45 the Appalachian region, which
encompasses parts of Kentucky, Tennessee, Virginia, and West Virginia,

44In making a designation, ONDCP considers whether the geographic area is
a center of drug production, manufacturing, importation, or distribution;
whether state and local law enforcement agencies have committed resources
to respond aggressively to the drug trafficking problem; whether drug
activities in the area are having a harmful impact on other areas of the
country; and whether a significant increase in federal resources is
necessary to respond to the area's drug-related activities.

45Appalachia High Intensity Drug Trafficking Area Task Force, The
OxyContin Threat in Appalachia (London, Ky.: August 2001).

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.

    Limitations on Abuse and Diversion Data Prevent Assessment of the
    Relationship with OxyContin's Availability

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.46
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."47

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.48 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.49 OxyContin is
the most abused single-entity prescription product according to those DEA
state and divisional offices that report OxyContin abuse.

46The reliability of the data collected depends on whether the emergency
room patient visit was reported as drug related, whether the patient
reported taking a particular drug, and whether the emergency room
physician indicated a drug's brand name in the patient's medical record.

47See app. III for more details on the abuse and diversion databases DEA
uses.

48The 15 states are Alabama, Arizona, Colorado, Connecticut, Florida,
Louisiana, Massachusetts, Mississippi, Missouri, New Jersey, North
Carolina, South Carolina, Texas, Washington, and Wisconsin.

49Hydrocodone products, such as Anexsia, Hycodan, Lorcet, Lortab, and
Vicodin, remain among the most abused and diverted scheduled prescription
drugs nationally.

  Federal and State Agencies and Purdue Have Taken Actions to Prevent Abuse and
  Diversion of OxyContin

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.

    Reports of Abuse and Diversion Led to Label Changes and Other Actions by FDA

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."

Table 3: Selected Language Approved by FDA in Warning Sections of
OxyContin Labels, 1995 and 2001

Warning label in 1995 Black box warning in 2001

"Warning:

OxyContin Tablets are to be swallowed whole, and are not to be broken,
chewed, or crushed. Taking broken, chewed, or crushed OxyContin Tablets
could lead to the rapid release and absorption of a potentially toxic dose
of oxycodone."

"Warning: OxyContin is an opioid agonist and a Schedule II controlled
substance with an abuse liability similar to morphine."

"OxyContin Tablets are to be swallowed whole and are not to be broken,
chewed, or crushed. Taking broken, chewed, or crushed OxyContin Tablets
leads to rapid release and absorption of a potentially fatal dose of
oxycodone." (emphasis added)

Source: FDA-approved label for Purdue's OxyContin.

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.

Table 4: Selected Language Approved by FDA in the Indication Sections of
OxyContin Labels, 1995 and 2001

Indication in 1995 Black box indication change in 2001

"OxyContin Tablets are a controlled-release "OxyContin Tablets are a
controlled-release oral formulation of oxycodone hydrochloride oral
formulation of oxycodone hydrochloride indicated for the management of
moderate-indicated for the management of moderateto-severe pain where use
of an opioid to-severe pain when a continuous, analgesic is appropriate
for more than a few around-the-clock analgesic is needed days." for an
extended period of time."

                                (emphasis added)

Source: FDA-approved label for Purdue's OxyContin.

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.50 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.

DEA Developed an Action In April 2001, DEA developed a national action
plan to deter abuse and Plan to Deter OxyContin diversion of OxyContin.
According to DEA officials, this marked the first Abuse and Diversion 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

50See www.fda.gov/cder/drug/infopage/oxycontin/default.htm.

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.

    State Agencies Have Responded to Reports of OxyContin Abuse and Diversion

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.51 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.

    Purdue Is Implementing a Risk Management Plan for OxyContin

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 2001.52 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

51The Kentucky guidelines for the use of controlled substances in pain
treatment provide that (1) a complete medical history and examination be
conducted and documented in patient medical records, (2) a written
treatment plan state objectives for determining treatment success, (3) the
risks and benefits of the use of controlled substances be discussed by
physician and patient, (4) periodic review of the course of treatment be
conducted, (5) consultation or referral to an expert in pain management be
considered for patients who are at risk for substance abuse, (6) patient's
medical record be kept accurate and complete, and (7) physicians be in
compliance with applicable federal and state controlled substance laws and
regulations.

52Amended versions of Purdue's risk management plan for OxyContin were
submitted to FDA for review in April 2002 and in March 2003.

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.53 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

53RADARS will collect information on brand-name and generic versions of
buprenorphine, fentanyl, hydrocodone, hydromorphone, oxycodone, morphine,
and methadone. Benzodiazepine is scheduled to be added to RADARS in late
2003.

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
160milligram 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.

Conclusions 	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.

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.

  Recommendation for Executive Action

  Agency and Purdue Comments and Our Evaluation

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, morphinebased
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
EURcontents earlier, we plan no further distribution until 30 days after
its issue EURdate. At that time, we will send copies of this report to the
Commissioner EURof Food and Drugs, the Administrator of the Drug
Enforcement EURAdministration, Purdue, and the other pharmaceutical
companies whose EURdrugs we examined. We will also make copies available
to others upon EURrequest. In addition, the report will be available at no
charge on the GAO EURWeb site at http://www.gao.gov. EUR

If you or your staffs have any questions about this report, please call me
atEUR(202) 512-7119 or John Hansen at (202) 512-7105. Major contributors
to EURthis report were George Bogart, Darryl Joyce, Roseanne Price, and
OpalEURWinebrenner. EUR

Marcia Crosse EURDirector, Health Care-Public Health EUR

and Military Health Care Issues EUR

                       Appendix I: Scope and Methodology

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

Appendix I: Scope and Methodology

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.

Appendix II: Summary of FDA Changes to the Original Approved OxyContin Label

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.

Table 5: FDA Changes to the Original OxyContin Label Made from June 1996
through July 2001

Summary of FDA changes to original
OxyContin label in 2001 Language in OxyContin label approved in 2001

Black box warning was added to stress the opioid nature of oxycodone and
risks for abuse and diversion of the drug.

"WARNING:

OxyContin is an opioid agonist and a Schedule II controlled substance with
an abuse liability similar to morphine.

Oxycodone can be abused in a manner similar to other opioid agonists,
legal or illicit. This should be considered when prescribing or dispensing
OxyContin in situations where the physician or pharmacist is concerned
about an increased risk of misuse, abuse, or diversion.

OxyContin Tablets are a controlled-release oral formulation of oxycodone
hydrochloride indicated for the management of moderate to severe pain when
a continuous, around-the-clock analgesic is needed for an extended period
of time.

OxyContin Tablets are NOT intended for use as a prn analgesic. OxyContin
80 mg and 160 mg Tablets ARE FOR USE IN OPIOID-TOLERANT PATIENTS ONLY.
These tablet strengths may cause fatal respiratory depression when
administered to patients not previously exposed to opioids. OxyContin
TABLETS ARE TO BE SWALLOWED WHOLE AND ARE NOT TO BE BROKEN, CHEWED, OR
CRUSHED. TAKING BROKEN, CHEWED, OR CRUSHED OxyContin TABLETS LEADS TO
RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF OXYCODONE."

Clinical pharmacology "CLINICAL PHARMACOLOGY

-Provides a pharmacological description of Oxycodone is a pure agonist
opioid whose principal therapeutic action is oxycodone as a pure opioid
agonist whose principal analgesia. Other members of the class known as
opioid agonists include action is analgesia. substances such as morphine,
hydromorphone, fentanyl, codeine, and -Identifies other members of the
opioid agonist hydrocodone. Pharmacological effects of opioid agonists
include anxiolysis, class, such as morphine, hydromorphone, fentanyl,
euphoria, feelings of relaxation, respiratory depression, constipation,
miosis, and hydrocodone. and cough suppression, as well as analgesia. Like
all pure opioid agonist

analgesics, with increasing doses there is increasing analgesia, unlike
with -Describes the pharmacological properties of mixed
agonist/antagonists or non-opioid analgesics, where there is a limit to
the opioids in general (anxiolysis, euphoria, feelings of analgesic effect
with increasing doses. With pure opioid agonist analgesics, relaxation,
respiratory depression, constipation, there is no defined maximum dose;
the ceiling to analgesic effectiveness is miosis, cough suppression, and
analgesia). imposed only by side effects, the more serious of which may
include

-Describes respiratory depression as one of the somnolence and respiratory
depression."
most serious side effects of opioids that could lead
to overdose or death.

Appendix II: Summary of FDA Changes to the Original Approved OxyContin
Label

Summary of FDA changes to original
OxyContin label in 2001 Language in OxyContin label approved in 2001

Misuse, abuse, and diversion of opioids

A subsection on misuse, abuse and diversion was added to the WARNINGS
section of the label.

-Characterizes oxycodone as an opioid agonist of the morphine-type and
stresses that opioid agonists are sought by drug abusers and people with
addiction disorders and are subject to diversion.

-Makes clear that oxycodone can be abused in a manner similar to other
opioid agonists, legal or illicit, and that physicians and pharmacists
should be aware of and alert to risk of misuse, abuse, and diversion when
prescribing or dispensing oxycodone.

-Modifies original label statement that iatrogenic addiction (addiction
induced inadvertently by a physician or a physician's treatment) is rare
if opioids were legitimately used in the management of pain to state that
data are not available to establish the true incidence of addiction in
chronic patients.

"Misuse, Abuse and Diversion of Opioids

Oxycodone is an opioid agonist of the morphine-type. Such drugs are sought
by drug abusers and people with addiction disorders and are subject to
criminal diversion.

Oxycodone can be abused in a manner similar to other opioid agonists,
legal or illicit. This should be considered when prescribing or dispensing
OxyContin in situations where the physician or pharmacist is concerned
about an increased risk of misuse, abuse, or diversion.

OxyContin has been reported as being abused by crushing, chewing,
snorting, or injecting the dissolved product. These practices will result
in the uncontrolled delivery of the opioid and pose a significant risk to
the abuser that could result in overdose and death (see WARNINGS and DRUG
ABUSE AND ADDICTION).

Concerns about abuse, addiction, and diversion should not prevent the
proper management of pain. The development of addiction to opioid
analgesics in properly managed patients with pain has been reported to be
rare. However, data are not available to establish the true incidence of
addiction in chronic pain patients.

Healthcare professionals should contact their State Professional Licensing
Board, or State Controlled Substances Authority for information on how to
prevent and detect abuse of this product."

  Appendix II: Summary of FDA Changes to the Original Approved OxyContin Label

Summary of FDA changes to original
OxyContin label in 2001 Language in OxyContin label approved in 2001

Drug abuse and addiction

-Emphasizes that the abuse potential of oxycodone is equivalent to that of
morphine.

-Describes the controlled status of OxyContin and emphasizes that, like
morphine and other opioids used in analgesia, oxycodone can be abused and
is subject to criminal diversion.

-Stresses proper prescribing practices, dispensing, and storage.

-Deletes statement that delayed absorption of OxyContin was believed to
reduce the abuse liability of the drug.

-Stresses the risks associated with parenteral injection of OxyContin and
reiterates the original label's description of drug addiction and
"drugseeking" behaviors commonly in addicts and abusers.

"DRUG ABUSE AND ADDICTION

OxyContin is a mu-agonist with an abuse liability similar to morphine and
is a Schedule II controlled substance. Oxycodone, like morphine and other
opioids used in analgesia, can be abused and is subject to criminal
diversion.

Drug addiction is characterized by compulsive use, use for non-medical
purposes, and continued use despite harm or risk of harm. Drug addiction
is a treatable disease, utilizing a multi-disciplinary approach, but
relapse is common.

"Drug-seeking" behavior is very common in addicts and drug abusers.
Drugseeking tactics include emergency calls or visits near the end of
office hours, refusal to undergo appropriate examination, testing or
referral, repeated "loss" of prescriptions, tampering with prescriptions,
and reluctance to provide prior medical records or contact information for
other treating physician(s). "Doctor shopping" to obtain additional
prescriptions is common among drug abusers and people suffering from
untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and
tolerance. Physicians should be aware that addiction may not be
accompanied by concurrent tolerance and symptoms of physical dependence in
all addicts. In addition, abuse of opioids can occur in the absence of
true addiction and is characterized by misuse for non-medical purposes,
often in combination with other psychoactive substances. OxyContin, like
other opioids, has been diverted for non-medical use. Careful record
keeping of prescribing information, including quantity, frequency, and
renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic
reevaluation of therapy, and proper dispensing and storage are appropriate
measures that help to limit abuse of opioid drugs.

OxyContin consists of a dual-polymer matrix, intended for oral use only.
Abuse of the crushed tablet poses a hazard of overdose and death. This
risk is increased with concurrent abuse of alcohol and other substances.
With parenteral abuse, the tablet excipients, especially talc, can be
expected to result in local tissue necrosis, infection, pulmonary
granulomas, and increased risk of enocarditis and valvular heart injury.
Parenteral drug abuse is commonly associated with transmission of
infectious disease such as hepatitis and HIV."

Safety and handling "SAFETY AND HANDLING

-Emphasizes the controlled status of OxyContin. OxyContin Tablets are
solid dosage forms that contain oxycodone which is a
-Alerts health care professionals that OxyContin controlled substance.
Like morphine, oxycodone is controlled under Schedule II

could be a target for theft and diversion and of the Controlled Substances
Act.
instructs that they should contact their State OxyContin has been targeted
for theft and diversion by criminals. Healthcare
Professional Licensing Board or State Controlled professionals should
contact their State Professional Licensing Board or State
Substances Authority for information on how to Controlled Substances
Authority for information on how to prevent and detect
prevent and detect abuse or diversion of the abuse or diversion of this
product."
product.

               Source: FDA-approved label for Purdue's OxyContin.

Appendix III: Databases Used to Monitor Abuse and Diversion of OxyContin and Its
Active Ingredient Oxycodone

  DAWN Data

NFLIS Data

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).1 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.2

SAMHSA operates the DAWN system, which estimates national drugrelated
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.

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,

1Other databases used by DEA to assess changes in drug abuse and diversion
include the Drug Early Warning System, the Drug and Alcohol Services
Information System, the Treatment Episode Data Set, the National Survey of
Substance Abuse Treatment Services, the Uniform Facility Data Set, the
Poison Control Center Data or Toxic Exposure Surveillance System, the
Automation of Reports and Consolidated Ordering System, the DEA Theft
System, and the DEA Field Reports and Investigative Teletypes.

2The National Institute on Drug Abuse is part of the National Institutes
of Health within the Department of Health and Human Services.

Appendix III: Databases Used to Monitor Abuse and Diversion of OxyContin
and Its Active Ingredient Oxycodone

  STRIDE Data

National Survey on Drug Use and Health Data

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.

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.

The National Survey on Drug Use and Health, another SAMHSA database, is
used to develop national and state estimates of trends in drug
consumption.3 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.

Monitoring the Future 	The Monitoring the Future Survey, funded by the
National Institute on Drug Abuse and conducted by the University of
Michigan, annually

Survey Data 	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.

3Self-reporting individuals are interviewed regarding their illicit drug
use over three periods-within the last 30 days, during the past year, and
during their lifetime. The survey data are limited, as it is not possible
to determine specifically which year respondents may have used a drug
illicitly, because they are asked both whether they have ever used the
drug illicitly in their lifetime and whether they have used it during the
past year.

Appendix IV: Comments from the Food and Drug Administration

Appendix IV: Comments from the Food and Drug Administration

Appendix IV: Comments from the Food and Drug Administration

                Page 56 GAO-04-110 OxyContin Abuse and Diversion

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