[Federal Register Volume 74, Number 74 (Monday, April 20, 2009)]
[Notices]
[Pages 17967-17970]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-8992]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2009-N-0143]


Risk Evaluation and Mitigation Strategies for Certain Opioid 
Drugs; Notice of Public Meeting

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting; request for comments.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a public 
meeting to obtain input on developing Risk Evaluation and Mitigation 
Strategies (REMS) for certain opioid drugs. The REMS would be intended 
to ensure that the benefits of these drugs continue to outweigh certain 
risks. The agency has long been concerned about adverse events 
associated with this class of drug and has taken steps in cooperation 
with drug manufacturers to address these risks. We intend to use the 
agency's REMS authority under the Food and Drug Administration 
Amendments Act of 2007 (FDAAA) to mitigate the risks of these drugs. 
The purpose of the public meeting is to receive information and 
comments on this topic.

DATES: The public meeting will be held on May 27 and 28, 2009, from 8 
a.m. to 5 p.m. Register to attend the meeting by May 15, 2009. See 
section III of this document for information on how to register or make 
an oral presentation at the meeting. Written or electronic comments 
will be accepted until June 30, 2009.

ADDRESSES: The public meeting will be held at the Hilton Washington, DC 
North/Gaithersburg Hotel, 620 Perry Pkwy., Gaithersburg, MD 20877. 
Submit written comments to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061. 
Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov. All comments should be identified with the docket 
number found in brackets in the heading of this document. Transcripts 
of the meeting will be available for review at the Division of Dockets 
Management and on the Internet at http://www.regulations.gov 
approximately 30 days after the meeting.

FOR FURTHER INFORMATION CONTACT: Theresa (Terry) Martin, Center for 
Drug Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 6184, Silver Spring, MD 20993-0002, 301-
796-3448, FAX: 301-847-8752, or Anne Henig, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg 51, rm. 6176, Silver Spring, MD 20993-0002, 301-796-3442, FAX: 
301-847-8753, email: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    FDAAA (Public Law 110-85) created section 505-1 of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355-1). Under section 
505-1 of the act,

[[Page 17968]]

FDA may require a REMS when FDA determines that a REMS is necessary to 
ensure the benefits of a drug outweigh the risks associated with the 
drug. On February 6, 2009, FDA sent letters to manufacturers of certain 
opioid drug products, indicating that these drugs will be required to 
have a REMS to ensure that the benefits of the drugs continue to 
outweigh the risks. An example of the text of these letters is 
available on the agency's Web site at http://www.fda.gov/cder/drug/infopage/opioids/meeting_template.pdf. A table of opioid products that 
may be required to have REMS is also available on the agency's Web site 
at http://www.fda.gov/cder/drug/infopage/opioids/Opioid_Products_chart.htm. Copies of these documents may also be requested from Terry 
Martin or Anne Henig (see FOR FURTHER INFORMATION CONTACT).
    The affected opioid drugs include brand name and generic products 
and are formulated with the following active ingredients: Fentanyl, 
hydromorphone, methadone, morphine, oxycodone, and oxymorphone. The 
REMS would be intended to ensure that the benefits of these drugs 
continue to outweigh the risks associated with: (1) Use of high doses 
of long acting opioids and extended release opioid products in non-
opioid tolerant and inappropriately selected individuals; (2) abuse; 
(3) misuse; and (4) overdose, both accidental and intentional. REMS for 
opioids would likely include elements to assure safe use to ensure that 
prescribers, dispensers, and patients are aware of and understand the 
risks and how these products should be used. The purpose of this 
meeting is to examine specific features of REMS for these drugs and 
provide interested persons an opportunity to comment. The meeting will 
also address issues associated with creating and implementing the REMS 
and evaluating its effectiveness.

A. Opioids

    Opioid drugs have effects similar or identical to those of opiates 
produced naturally in the opium poppy. On the molecular level, they act 
at protein sites called opioid receptors, which are found in the brain, 
spinal cord, gastrointestinal tract, peripheral nerve terminals, and 
other peripheral sites. The actions of these drugs at certain opioid 
receptors in the brain, spinal cord, and other sites can effectively 
block the transmission of pain messages to the brain. Opioid drugs 
currently marketed in the United States for pain relief include 
products formulated with active ingredients such as fentanyl, 
hydromorphone, methadone, morphine, oxycodone, and oxymorphone. 
Individual patients respond differently to different opioid drug 
substances, and some patients develop tolerance to the effects of a 
particular opioid after chronic exposure. Physicians use a technique 
known as ``opioid rotation'' whereby they switch a patient from one 
opioid to another if the patient develops tolerance to the drug's 
analgesic effects and cannot get adequate pain relief from any single 
drug.
    Some opioids are naturally long acting; others are incorporated 
into extended release formulations. Long acting opioids and extended 
release opioid formulations are often useful for the management of 
persistent, moderate to severe pain in patients requiring continuous, 
around-the-clock pain relief for an extended period of time. Long 
acting products allow these patients to have their pain controlled for 
long periods of time without the need for another dose and to 
significantly reduce the number of tablets the patient must take each 
day. Therefore, having long acting opioids and extended release opioid 
formulations available provides important pain relief options for 
patients who require management of persistent, moderate to severe pain.
    The expected duration of treatment with long acting opioids and 
extended release opioid formulations ranges from a few weeks to months 
or longer. In some cases, moderate to severe pain requiring continuous, 
around-the-clock opioid therapy is associated with a serious condition 
that is unlikely to improve.
    These types of opioids are widely prescribed, posing challenges for 
the development of REMS for these products. Long acting and extended 
release opioid formulations were used by nearly 4 million patients in 
the United States in 2007. Physicians who prescribe and administer long 
acting and extended release opioid drugs practice in a wide variety of 
areas including family practice, anesthesiology, internal medicine, 
orthopedic surgery, physiatry, neurology, rheumatology, oncology, and 
other areas. A REMS, to adequately manage the risks of these products 
without unduly burdening the health care system or reducing patient 
access to these medications, must be carefully designed.

B. Adverse Events Associated With Opioids

    The most serious of the known adverse events associated with opioid 
pain relievers are: Respiratory depression, central nervous system 
depression, addiction, and death. Adverse events are associated with 
improper dosing, indication, and patient selection, as well as with 
abuse and addiction. For example, some products and doses are indicated 
only for the management of persistent moderate to severe pain in 
patients who have demonstrated opioid tolerance. Use of these products 
in non-opioid-tolerant patients may result in fatal respiratory 
depression. In other cases, when extended release products are 
intentionally crushed or dissolved, the controlled-release mechanism 
may be defeated, allowing a large dose to be taken at once. This 
presents a risk of fatal overdose, particularly in individuals who are 
not tolerant to opioids.

C. Efforts to Address the Risks of Opioid Use

    FDA and drug manufacturers have taken steps to decrease abuse and 
misuse of long acting opioids and extended release opioids while 
seeking to ensure that they remain available for patients who suffer 
daily from chronic pain. Since 2001, FDA has required boxed warnings, 
the agency's strongest warning, on the labeling of long acting opioid 
drugs to educate physicians and patients on the risks and proper uses 
of these products. The agency has also required risk management plans 
for many of these products. These plans have incorporated educational 
programs for prescribers, pharmacists, and patients, and surveillance 
systems to monitor for signals of increasing abuse, misuse, and 
diversion, as well as plans for intervention when these signals are 
noted. In addition, drug manufacturers have sought to incorporate 
features into their products intended to deter abuse. For example, the 
active ingredient may be incorporated into a matrix from which it 
cannot easily be extracted or that is not easily ground into powder. In 
other cases, an opioid antagonist is sequestered in the inner core of 
an extended release tablet, designed to be released if the tablet is 
crushed or dissolved.

D. REMS for Long Acting and Extended Release Opioids

    Despite existing efforts to address the risks associated with 
opioid drugs, misuse and abuse are increasing. Data from multiple 
sources, including the Centers for Disease Control (CDC) and the 
Substance Abuse and Mental Health Services Administration (SAMHSA), 
indicate increasing misuse and abuse of prescription opioid analgesic 
medications over the past decade. For example, SAMHSA's National Survey 
on Drug Use and Health estimates that

[[Page 17969]]

11 million Americans over the age of 12, or 4.7 percent of that 
population, took pain relievers for nonmedical use in 2002. That number 
increased to 12.5 million, or 5.0 percent of the population over 12, in 
2007. Likewise, data compiled by SAMHSA show a significant increase 
from 2000 to 2006 in admissions to substance abuse treatment services 
for individuals abusing opioid analgesics. Much of this misuse has 
involved the extended release opioid analgesics and methadone. To 
address this public health problem, the agency has indicated it will 
require REMS for certain opioid products.
    Section 505-1 of the act authorizes FDA to require persons 
submitting certain drug approval applications to submit a proposed REMS 
as part of the application. FDA may require a REMS when FDA determines 
that a REMS is necessary to ensure the benefits of the drug outweigh 
the risks associated with the drug. Section 505-1 of the act also 
authorizes FDA to require holders of certain drug applications approved 
without a REMS to submit a proposed REMS if the agency becomes aware of 
new safety information and makes a determination that a REMS is 
necessary to ensure the benefits of the drug outweigh the risks. Once 
FDA notifies the holder of an approved covered application that a REMS 
is necessary, the holder must submit a proposed REMS within 120 days, 
or within such other reasonable time as FDA requires.
    Every REMS must include a timetable for the submission of 
assessments of the REMS. A REMS may also include a Medication Guide (as 
provided in 21 CFR part 208), a patient package insert, a communication 
plan, and certain ``elements to assure safe use.'' The elements to 
assure safe use must include one or more goals to mitigate a specific 
serious risk listed in the labeling of the drug. These elements may 
include the following requirements:
     Health care providers who prescribe the drug have 
particular training or experience, or are specially certified.
     Pharmacies, practitioners, or health care settings that 
dispense the drug are specially certified.
     The drug is dispensed to patients only in certain health 
care settings.
     The drug is dispensed to patients with evidence of safe 
use conditions, such as laboratory test results.
     Each patient using the drug is subject to certain 
monitoring.
     Each patient using the drug is enrolled in a registry.
    The elements to assure safe use may also include an implementation 
plan, whereby the applicant monitors, evaluates, and works to improve 
the implementation of certain of these elements. FDAAA states that when 
elements to assure safe use are required for a drug that is also 
marketed in one or more generic forms, the pioneer drug and the 
generic(s) shall use a single, shared system unless the generic 
applicant obtains a waiver in accordance with statutory criteria. A 
waiver may be granted if the burden of creating a single, shared system 
outweighs the benefits of a single, shared system or if an aspect of 
the elements to assure safe use is entitled to protection as a trade 
secret or is protected by a patent for which the generic applicant has 
unsuccessfully sought a license (section 505-1(i)(1) of the act).
    We are mindful of the provisions in FDAAA that state the elements 
to assure safe use must be, among other things, commensurate with the 
specific serious risk listed in the labeling of the drug, not be unduly 
burdensome on patient access to the drug, and be designed to be 
compatible with established distribution, procurement, and dispensing 
systems (section 505-1(f)(2) of the act). Marketed opioid products 
include both innovator and generic drugs. FDAAA requires, with limited 
exception, that innovator and generic drugs use a single, shared system 
for a REMS that contains elements to assure safe use. Putting together 
a workable system will involve innovator and generic sponsors working 
together to develop a single, shared system.

II. Scope of Meeting

    FDA is holding this public meeting to allow affected sponsors and 
other interested persons to present comments and information on what a 
REMS should look like for these products, how to minimize the burden on 
the health care community and patients while achieving the objective of 
ensuring that the benefits of these drugs continue to outweigh the 
risks, and how FDA should evaluate the REMS to determine whether it is 
achieving these objectives.
    FDA is interested in obtaining information and public comment on 
the following issues:

A. Elements of the REMS

    1. FDA believes that one key element to assure safe use for these 
products will be prescriber certifications to ensure prescribers are 
educated about the risks of these products and proper patient 
selection, and the importance of counseling patients on the safe and 
appropriate use of their prescription medication. Please comment on 
what type of education should be provided to prescribers and how this 
certification should be administered (e.g., through state Medical 
Boards, DEA (Drug Enforcement Agency), other Federal or state systems, 
or privately, through a contractor established to administer the REMS). 
Some combination of administration could also be considered.
    2. FDA believes that another key element to assure safe use for 
these products will be certifications of pharmacists, prescribers, and 
other health care providers or institutions that dispense or directly 
administer covered opioid products to ensure these representatives of 
the health care system also are educated about the risks of these 
products and the importance of counseling patients on the safe and 
appropriate use of their prescription medication. These representatives 
of the health care system could be asked to check that the prescriber 
has obtained the certification necessary to prescribe these products. 
Please comment on what type of education should be provided to 
pharmacists and other health care providers who dispense or directly 
administer covered products and how this certification should be 
administered (e.g., through state Boards of Pharmacy, DEA, other 
Federal or state systems, or privately, through a contractor 
established to administer the REMS). Some combination of administration 
could also be considered.
    3. FDA believes patient education, in conjunction with a 
prescriber-patient agreement, is another key element of the REMS. What 
education should be provided to patients, and should the system be 
designed to ensure such education is provided? For example, other REMS 
programs require prescriber-patient agreements that patients sign 
before receiving a prescription to acknowledge that they have been 
advised about the risks and appropriate use of the products and 
received a Medication Guide or other appropriate patient information. 
Is such a system necessary for opioid products?
    4. Are other REMS elements necessary to support the safe use of 
approved opioids? A list of possible REMS elements is provided in 
section I.D of this document.

B. System Issues

    1. How restrictive a system should be designed? For example, in 
some previously approved risk management systems, covered drugs are 
provided only when prescribers, pharmacists, and patients are all 
enrolled in a program designed to ensure that all understand the risks 
and appropriate use of the

[[Page 17970]]

products. Such systems have been put in place for drugs that are or are 
suspected to be teratogenic, and the programs are designed to ensure 
patients are not pregnant and will not become pregnant while taking the 
drug. Such systems create burdens on patients and the health care 
system. Is such a system necessary for opioids? How would such a 
program be implemented given the number of patients, prescribers, and 
other health care providers involved in their use?
    2. Should the REMS include controls on distributors who distribute 
products to pharmacies and other health care providers? What controls 
are necessary, and how can they be efficiently provided without being 
unduly burdensome on the health care system?
    3. What existing systems (for example, in pharmacies) already exist 
that could be used to implement a REMS? For example, could patient 
information be provided through existing pharmacy systems to patients? 
Are there systems for providing education to prescribers that could be 
used to provide the educational component of a REMS?
    4. FDAAA requires that innovator and generic application holders 
use a single, shared system to provide a REMS with elements to assure 
safe use. What obstacles need to be addressed before such a system 
could be developed?
    5. What metrics should be used to assess the success of the REMS? 
Please comment on the metrics that should be applied to measure the 
success of each of the components of the REMS (e.g., educational 
requirements) as well as metrics to assess the impact of the overall 
REMS on decreasing abuse and misuse of long acting opioids and extended 
release opioids while seeking to ensure that they remain available for 
patients who suffer daily from chronic pain.

III. Attendance and Registration

    Register via email to [email protected] by providing complete 
contact information for each attendee (including name, title, 
affiliation, address, email address, and phone number(s)) by May 15, 
2009. Registration is free and will be on a first-come, first-served 
basis. Early registration is recommended because seating is limited. 
Please send no more than two individuals from your organization. 
Registration on the first day of the meeting will be provided on a 
space available basis beginning at 8 a.m.
    If you wish to make an oral presentation at the meeting, you must 
indicate this at the time of registration. FDA has included questions 
for comment in section II of this document. You should also identify by 
number each question you wish to address in your presentation. FDA will 
do its best to accommodate requests to speak. Individuals and 
organizations with common interests are urged to consolidate or 
coordinate their presentations, and to request time for a joint 
presentation. FDA will determine the amount of time allotted to each 
presenter and the approximate time that each oral presentation is 
scheduled to begin. If you need special accommodations because of 
disability, please e-mail [email protected] at least 7 days before 
the meeting.

IV. Comments

    Regardless of attendance at the public meeting, interested persons 
may submit written or electronic comments to the Division of Dockets 
Management (see ADDRESSES). Submit a single copy of electronic comments 
or two paper copies of any mailed comments, except that individuals may 
submit one paper copy. Comments are to be identified with the docket 
number found in brackets in the heading of this document. To ensure 
consideration, submit comments by June 30, 2009. Received comments may 
be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday.

V. Transcripts

    Transcripts of the meeting will be available for review at the 
Division of Dockets Management and on the Internet at http://www.regulations.gov approximately 30 days after the meeting. A 
transcript will also be made available in either hard copy or on CD-
ROM, upon submission of a Freedom of Information request. Written 
requests are to be sent to Division of Freedom of Information (HFI-35), 
Office of Management Programs, Food and Drug Administration, 5600 
Fishers Lane, rm. 6-30, Rockville, MD 20857.

    Dated: April 14, 2009.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E9-8992 Filed 4-17-09; 8:45 am]
BILLING CODE 4160-01-S