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STATEMENT
BY
JOHN K. JENKINS, M.D.
DIRECTOR, OFFICE OF NEW DRUGS
CENTER FOR DRUG EVALUATION AND
RESEARCH
FOOD AND DRUG ADMINISTRATION, HHS
FOR THE HEARING ON
OXYCONTIN: BALANCING RISKS AND
BENEFITS
BEFORE THE
U.S. SENATE
COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS
FEBRUARY 12, 2002
RELEASE
ONLY UPON DELIVERY
INTRODUCTION
Mr. Chairman and Members of
the Committee, I am John K. Jenkins, M.D., Director, Office
of New Drugs, Center for Drug Evaluation and Research (CDER),
Food and Drug Administration (FDA or the Agency). I appreciate
the opportunity to talk about the drug OxyContin and the
steps that FDA has taken in an effort to decrease abuse
and misuse of this product while assuring that this drug
is used properly and remains available for patients who
suffer daily from chronic moderate to severe pain.
Let me assure you that the
Agency has taken reports of abuse and misuse of OxyContin
very seriously and we have implemented aggressive steps
in response to these reports. FDA has worked closely with
the manufacturer of OxyContin, Purdue Pharma L.P., to strengthen
the warnings and precautions sections of the approved labeling
for OxyContin in order to educate physicians, other healthcare
professionals, and patients regarding the serious, and potentially
fatal, risks of abuse and misuse of this product. FDA has
also worked with Purdue Pharma to modify the approved labeling
for OxyContin to emphasize that it is approved for the treatment
of moderate to severe pain in patients who require around-the-clock
narcotics for an extended period of time. FDA also has worked
closely with the Drug Enforcement Administration (DEA) to
address their concerns regarding abuse, misuse, and illegal
diversion of OxyContin.
In order to help you to better
understand FDA's actions, I would like to give you a brief
overview of the process FDA followed in approving OxyContin
and FDA's activities related to regulation of the promotion
and marketing of OxyContin.
BACKGROUND
OxyContin is a narcotic drug
that was approved by FDA for
the treatment of moderate to severe pain on December 12,
1995. OxyContin contains
oxycodone HCl, an opioid agonist with an addiction potential
similar to that of morphine. Opioid agonists are substances
that act by attaching to specific proteins called opioid
receptors, which are found in the brain, spinal cord, and
gastrointestinal tract. When these drugs attach to certain
opioid receptors in the brain and spinal cord they can effectively
block the transmission of pain messages to the brain.
OxyContin is formulated to release oxycodone HCl
in a slow and steady manner following oral ingestion. OxyContin
is the only currently marketed FDA approved controlled-release
formulation of oxycodone. The drug substance oxycodone,
however, has been marketed in the U.S. for many decades
and is available in a wide variety of immediate release
and combination dosage forms.
Oxycodone,
like morphine and other opioid agonists, has a high potential
for abuse. OxyContin was
specifically developed as a controlled release formulation
by Purdue Pharma to allow for up to 12 hours of relief from
moderate to severe pain. This dosage form allows patients
with chronic moderate to severe pain to have their pain
controlled for long periods of time without the need for
another dose of medication and significantly reduces the
number of tablets the patient must take each day.
When used properly, the OxyContin
tablet must be taken whole and only by mouth. If the tablet
is crushed, the controlled-release mechanism is defeated
and the oxycodone contained in the tablet is all released
at once. If the contents of an OxyContin tablet are injected
intravenously or snorted into the nostrils a potentially
lethal dose of oxycodone is released immediately. The risk
of death due to abuse of OxyContin in this manner is particularly
high in individuals who are not tolerant to opioids.
Oxycodone, the active ingredient
in OxyContin, is a controlled substance in Schedule II of
the Controlled Substances Act (CSA), 21 U.S.C. �801 et seq.
which is administered by the DEA. Schedule II provides the
maximum amount of control possible under the CSA for approved
drug products. Schedule I drugs are considered to have no
recognized medical purpose and are illegal in the U.S. outside
of FDA approved research.
FDA
DRUG APPROVAL PROCESS
Before any drug is approved
for marketing in the U.S., FDA must decide--as quickly as
a thorough evaluation allows--whether the studies submitted
by the drug's sponsor (usually the manufacturer) have adequately
demonstrated that the drug is safe and effective under the
conditions of use in the drug's labeling. It is important
to realize; however, that no drug is absolutely safe. There
is always some risk of adverse reactions with drugs. FDA's
approval decisions, therefore, always involve an assessment
of the benefits and the risks for a particular product.
When the benefits of a drug are thought to outweigh the
risks, and if the labeling instructions allow for safe and
effective use, FDA considers a drug safe for approval and
marketing.
OxyContin was reviewed by
FDA and was approved for treatment of moderate to severe
pain based on two clinical trials that demonstrated that
it was safe and effective for this use. Prior to approval,
FDA evaluated the benefits and risks of use of OxyContin
for treatment of moderate to severe pain and determined
that the drug was appropriate for use in
this population when used according to the approved labeling.
During the approval process
of OxyContin, as with all drugs that are active in the brain,
FDA assessed its potential for abuse and misuse. Abuse liability
assessments are based on a composite profile of the drug's
chemistry, pharmacology, clinical manifestations, similarity
to other drugs in a class, and the potential for public
health risks following introduction of the drug to the general
population. At the time of approval, the abuse potential
for OxyContin was considered by FDA to be no greater than
for other Schedule II opioid analgesics that were already
marketed in the U.S. Based on the information available
to FDA at the time of its approval, including the record
of other modified release Schedule II opioids, the widespread
abuse and misuse of OxyContin that has been reported over
the past few years was not predicted. In fact, at the time
of its approval, FDA believed that the controlled-release
characteristics of the OxyContin formulation would result
in less abuse potential since, when taken properly, the
drug would be absorbed slowly and there would not be an
immediate "rush" or high that would promote abuse. In part,
FDA based its judgment of the abuse potential for OxyContin
on the prior marketing history of MS-Contin, a controlled-release
formulation of morphine that had been marketed in the U.S.
by Purdue Pharma without significant reports of abuse and
misuse for many years. At the time of OxyContin's approval,
FDA was aware that crushing the controlled-release tablet
followed by intravenous injection of the tablet's contents
could result in a lethal overdose. A warning against such
practice was included in the approved labeling. FDA did
not anticipate, however, nor did anyone suggest, that crushing
the controlled-release capsule followed by intravenous injection
or snorting would become widespread and lead to a high level
of abuse.
FDA ACTIONS
Labeling changes
In July 2001, Purdue Pharma,
working in cooperation with FDA, significantly strengthened
the warnings and precautions sections
in the labeling for OxyContin. The labeling for OxyContin
now includes a "black box" warning, the strongest warning
for an FDA approved product, which warns patients and physicians
of the potentially lethal consequences of crushing the controlled-release
tablets and injecting or snorting the contents. The indication
for use was clarified to reflect that it is approved for
the treatment of moderate to severe pain in patients who
require around the clock narcotics for an extended period
of time.
To
help in the effort to curb abuse and misuse of OxyContin,
FDA has worked with Purdue Pharma to implement other specific
changes in the OxyContin labeling. The
new labeling is intended to highlight to physicians, other
health care professionals, and patients that OxyContin should
be used for the treatment of moderate to severe pain in
patients who require around the clock narcotics for an extended
period of time. As part of the labeling changes, a patient
instruction sheet was added, which contains information
to assist patients in the proper use of OxyContin. These
labeling changes are an effort to educate pharmacists, other
health professionals, and the general public regarding just
how important it is to use this drug properly. The new warnings
are intended to lessen the chance that OxyContin
will be prescribed inappropriately for
pain of lesser severity than the approved use or for
other disorders or conditions inappropriate for
a Schedule II narcotic.
FDA has developed a patient-information page on its website
(www.fda.gov/cder/drug/infopage/oxycontin/default.htm).
This site provides important information to patients regarding
how to safely use OxyContin, urges patients to keep their
supply of OxyContin in a secure location, and instructs
patients to destroy unneeded tablets.
As part of a longer-term strategy
to address the current reports of abuse and misuse of OxyContin,
Purdue Pharma has informed FDA that the company is working
to reformulate OxyContin. The reformulation would add an
opioid antagonist that would counteract the effects of oxycodone,
the active ingredient in OxyContin, if the OxyContin tablet
were crushed into a powder and injected or snorted. FDA
is working actively with Purdue Pharma to evaluate the safety
and effectiveness of such a reformulated product. It must
be noted that such a reformulation is not a simple task
and it could be several years before any new combination
product is developed, tested in clinical trials, and approved
by FDA. It also must be noted that the addition of the opioid
antagonist to OxyContin to deter abuse means that legitimate
patients would be exposed to a drug substance that they
do not need. This could result in adverse reactions in such
legitimate patients. These potential safety issues, and
assurance that the combination tablet retains its effectiveness
in treating moderate to severe pain, must be a part of FDA's
review of a reformulated OxyContin product.
Letters
to health care professionals
There have been numerous reports
of OxyContin diversion
and abuse in several states. Some of these reported cases
have been associated with serious consequences including
death. In an effort to educate health care providers about
these risks, Purdue Pharma has issued a warning in the form
of a "Dear Healthcare Professional" letter. The "Dear Healthcare
Professional" letter was distributed widely to physicians,
pharmacists, and other health professionals. The letter
explains the changes to the labeling, including proper prescribing
information and highlights the problems associated with
the abuse and diversion of OxyContin.
FDA approved indication for
OxyContin
is for
the treatment of patients with moderate to severe pain who
require around-the-clock opioids for
an extended time. An important factor that must be considered
in prescribing OxyContin
is the severity of the pain that is being treated, not simply
the disease causing the painful symptoms.
FDA
continues to recommend that appropriate pain control be
provided to patients who are living with moderate to severe
pain. Although abuse, misuse, and diversion are potential
problems for all opioids,
including OxyContin, they
are a very important part of the medical armamentarium for
the management of pain when used appropriately under the
careful supervision of a physician.
Meeting with other
government agencies and industry
FDA has met with DEA, the
Substance Abuse and Mental Health Services Administration,
the National Institute on Drug Abuse, the Office of National
Drug Control Policy, the Centers for Disease Control and
Prevention and Purdue Pharma, and continue to work collaboratively
sharing information and insights needed to address the problem
of OxyContin abuse and diversion.
Millions of Americans suffer
from some form of chronic pain. The pain can be debilitating
and often prevents those afflicted from working or even
leaving their home. Many medications, including opioids,
play an important role in the treatment of chronic pain.
Opioids, however, often have their use limited by concerns
regarding misuse, addiction, and possible diversion for
non-medical uses. The use of opioid therapy in some patients
has shown extraordinary promise, enabling some to return
to work and to lead a normal life again. FDA is committed
to continuing to work with other government agencies and
sponsors to insure that options are available to patients
with chronic moderate to severe pain, so that in consultation
with their personal physician they can achieve as normal
a life as possible.
Advisory Committee
Meetings
An FDA advisory committee,
a group of non-Agency experts, held a meeting on January
30-31, 2002, to discuss the medical use of opioid analgesics,
appropriate drug development plans to support approval of
opioid analgesics, and strategies to communicate and manage
the risks associated with opioid analgesics, particularly
the risks of abuse of these drugs. Committee members agreed
that opioids are essential for relieving pain and that a
great deal of progress has been made within the last few
years to remove the stigma associated with opioid treatment.
Members suggested that a balanced approach should be taken
to relieve pain for patients and to prevent diversion. They
noted that imposing restrictions on use of opioids could
have substantial likelihood of hurting legitimate patients
and reversing the tremendous progress that has been achieved
in the appropriate treatment of pain.
FDA will
continue to monitor reports of abuse, misuse, and diversion
of OxyContin and other
opioids and will work with other Federal agencies and drug
manufacturers to help ensure that these important drugs
remain available to appropriate patients.
DRUG ADVERTISING
FDA has regulated the advertising
of prescription drugs since 1962, under the Food, Drug,
and Cosmetic (FD&C) Act and its implementing regulations.
The Division of Drug Marketing, Advertising, and Communications
(DDMAC), in CDER, is responsible for regulating prescription
drug advertising and promotion. DDMAC's mission is to protect
the public health by insuring that prescription drug information
is truthful, balanced, and accurately communicated. This
is accomplished through a comprehensive surveillance, enforcement,
and education program, and by fostering optimal communication
of labeling and promotional information to both health care
professionals and consumers.
FDA regulates prescription
drug advertisements and other promotional materials (called
"promotional labeling") disseminated by or on behalf of
the advertised product's manufacturer, packer or distributor
to health care professionals and consumers.
Title 21 of the Code of Federal
Regulations (21 CFR �314.81(b)(3)(i)) requires that advertisements
and promotional labeling be submitted to FDA at the time
of initial dissemination (labeling) and initial publication
(advertisements); a post-marketing submission requirement.
The FD&C Act generally prohibits FDA from requiring
that advertisements be approved prior to their use (see
�502(n)). In other words, FDA's review of promotional materials
is generally intended to occur post hoc - once
the materials have already appeared in public. Accordingly,
any FDA enforcement action that FDA takes is post hoc
as well. Most of FDA's enforcement actions request that
sponsors stop using the violative materials. In some cases,
FDA also asks sponsors to run corrective advertisements
or issue corrective letters to remedy inaccurate product
impressions created by false or misleading materials.
FDA is not aware of any direct-to-consumer
advertising for OxyContin. There is nothing in the FD&C
Act to prohibit such advertising. The advertising and marketing
for OxyContin has been directed only to health care professionals.
It should be noted that the current approved product labeling
for OxyContin contains a "black box" warning. Boxed warnings
are used in labeling to convey serious risks associated
with the use of the drug product. The promotional materials
of drug products with boxed warnings must present these
serious risks in a prominent manner. DDMAC sent a letter
to Purdue Pharma dated May 11, 2000, regarding a journal
advertisement that appeared in the New England Journal
of Medicine that promoted OxyContin in a manner that
was false or misleading. Specifically, the advertisement
implied OxyContin had been studied in all types of arthritis
and can be used as first-line therapy for the treatment
of osteoarthritis, failed to include important limitations
to claims presented from an osteoarthritis study; and promoted
OxyContin in a selected class of patients without presenting
risk information especially applicable to that selected
class of patients. Purdue Pharma agreed to cease dissemination
of this advertisement and this matter was resolved with
the cooperation of the sponsor.
CONCLUSION
The Agency recognizes OxyContin
as a valuable product when used properly. We need to do
all we can to ensure that the prescriptions get to the appropriate
patients and that labeling and promotion are appropriate
for the product. FDA is working closely with the manufacturer
to take appropriate action to curb the misuse and abuse
of OxyContin. In addition, FDA is involved in the strong
interagency effort to address this issue and we are aware
we cannot solve this problem by ourselves.
We share the Committee's interest
and concerns regarding this drug and would be happy to answer
any questions.