[Federal Register Volume 75, Number 116 (Thursday, June 17, 2010)]
[Notices]
[Pages 34453-34456]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-14547]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket Nos. FDA-2010-N-0284 and FDA-2009-D-0461]


Risk Evaluation and Mitigation Strategies; Notice of Public 
Meeting; Reopening of Comment Period

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting; reopening of comment period.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a 2-day 
public meeting to obtain input on issues and challenges associated with 
the development and implementation of risk evaluation and mitigation 
strategies (REMS) for drugs and biological products. As FDA has taken 
steps to implement the REMS provisions of the Federal Food, Drug, and 
Cosmetic Act (FDCA), some stakeholders have raised concerns about the 
impact of various REMS, and the growing number of REMS on the health 
care system, as well as on individual prescribers, pharmacists, 
distributors, and other affected stakeholders. To obtain public input 
about the REMS program and its impact, and to gather additional input 
on a draft guidance for industry issued on October 1, 2009 entitled 
``Format and Content of Proposed Risk Evaluation and Mitigation 
Strategies (REMS), REMS Assessments, and Proposed REMS Modifications,'' 
FDA has decided to hold this public meeting. FDA wishes to give a wide 
range of stakeholders the opportunity to provide input in this area, 
and will take the information it obtains from the meeting into account 
in its implementation of the REMS program and in the development of the 
final guidance and future REMS guidances.

DATES: The meeting will be held on July 27 and 28, 2010, from 8:30 a.m. 
to 4:30 p.m. Individuals who wish to present at the meeting must 
register by July 6, 2010. The comment period for the draft guidance for 
industry on ``Format and Content of Proposed Risk Evaluation and 
Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS 
Modifications'' has been reopened until August 31, 2010.

ADDRESSES: The public meeting will be held at FDA's White Oak Campus, 
10903 New Hampshire Ave., Bldg. 31, rm. 1503, Silver Spring, MD 20993. 
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. Identify each set of comments with the 
corresponding docket number for either the public meeting or the draft 
guidance as follows: Docket No. FDA-2010-N-0284, ``Risk Assessment and 
Mitigation Strategies; Public Meeting,'' and Docket No. FDA-2009-D-
0461, Draft guidance for industry on ``Format and Content of Proposed 
Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and 
Proposed REMS Modifications.''

FOR FURTHER INFORMATION CONTACT: Kristen Everett, Food and Drug 
Administration, Center for Drug Evaluation and Research, 10903 New 
Hampshire Ave., Bldg. 51, rm. 6228, Silver Spring, MD 20993, 301-796-
0453, FAX: 301-847-8440, Email: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    On September 27, 2007, the President signed into law the Food and 
Drug Administration Amendments Act of 2007 (FDAAA) (Public Law 110-85). 
Title IX, subtitle A, section 901 of FDAAA created new section 505-1 of 
the FDCA, which authorizes FDA to require persons submitting new drug 
applications (NDAs) or abbreviated new drug applications (ANDAs) for 
prescription products, or biologics license applications (BLAs), to 
submit and implement a REMS if FDA determines that a REMS is necessary 
to ensure the benefits of a drug outweigh the risks of the drug. To 
require a REMS for an already approved drug, FDA must have new safety 
information as defined in the statute.
    FDAAA specifies the criteria FDA must consider in determining when 
to require a REMS, the elements of a REMS that FDA must and may 
require, and additional considerations when requiring a REMS with 
elements to assure safe use. FDAAA also contains provisions that are 
specifically directed to REMS for ANDAs and describes enforcement 
actions for failure to comply with REMS. FDAAA contains provisions that 
require the FDA to seek input from patients, physicians, pharmacists, 
and other health care providers about how the elements to assure safe 
use may be standardized to (1) not be unduly burdensome on patient 
access to the drug and (2) to the extent practicable, minimize the 
burden on the health care delivery system. A webinar will be available 
on the agency's Web site at http://www.fda.gov/Drugs/NewsEvents/ucm210201.htm 2 weeks before the meeting, describing in more detail the 
statutory requirements for REMS.

II. REMS Draft Guidance and Comment Period

    FDA has been implementing the REMS FDAAA provisions for more than 2 
years. On October 1, 2009, the Agency published in the Federal Register 
(74 FR 80801) a notice of availability of a draft guidance for industry 
entitled, ``Format and Content of Proposed Risk Evaluation and 
Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS 
Modifications.'' Although comments on Agency guidances are welcome at 
any time (see 21 CFR 10.115(g)(5)), to ensure that comments could be 
considered as the Agency worked on the final version of the guidance, 
interested persons were invited to comment on the draft guidance by 
December 30, 2009. The draft guidance provides information

[[Page 34454]]

regarding FDA's current thinking on the format and content that should 
be used for submissions of proposed REMS, including the availability of 
templates for REMS and REMS supporting documents. It also includes 
preliminary information on the content of assessments and proposed 
modifications to approved REMS.
    In comments on the guidance, as well as in various other contexts, 
stakeholders have raised concerns with the Agency about the use of 
REMS, and the impact of both the variety of REMS and the growing number 
of REMS on the health care system and on affected prescribers, 
pharmacists, distributors, patients, and other affected stakeholders. 
For example, some stakeholders have expressed concern regarding the 
cumulative burden of REMS on the health care delivery system. Others 
have raised concerns about prescribers' and pharmacists' costs of 
implementing REMS, and some have raised questions about the impact of 
REMS on patient access to therapies. FDA has decided to hold a public 
meeting to hear from stakeholders about their opinions on how REMS are 
working, and the effects of REMS on prescribers, pharmacists, 
distributors, patients, and other stakeholders, and on the overall 
health care system. At the same time, FDA is reopening the comment 
period on the draft guidance for industry on ``Format and Content of 
Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS 
Assessments, and Proposed REMS Modifications'' until August 31, 2010. 
FDA will take into account the input it receives through comments and 
at the public meeting in its implementation of the FDAAA REMS 
provisions when it finalizes the above guidance, and in the development 
of future guidances regarding REMS for drugs and biological products.

III. FDA Actions Under FDAAA

    Section 901 of FDAAA became effective March 25, 2008. Between March 
25, 2008, and March 25, 2010, FDA approved 110 new REMS for NDAs and 
BLAs, and two deemed REMS.\1\ Table 1 shows the various types of 
approved REMS.
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    \1\ Section 909 of FDAAA provides that drugs approved with 
elements to assure safe use before FDAAA was enacted were deemed to 
have REMS. Sponsors of these products were required to submit 
proposed REMS by September 21, 2008.

Table 1. New REMS Approved Between March 25, 2008, and March 25, 2010\1\
------------------------------------------------------------------------
 REMS Elements (in addition to a timetable
 for submission of assessments of the REMS)          No. Approved
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Medication Guide (MG) Only                   75
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Communication plan (CP) alone or with a MG   25
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Elements to assure safe use alone or with    10
 CP and/or MG
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Total new REMS approved                      110
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\1\ ``New REMS'' means REMS approved since FDAAA took effect for drugs
  that did not previously have risk management plans in place.

    As shown in Table 1, 68 percent of the newly approved REMS 
contained only a Medication Guide and a timetable for submission of 
assessments of the REMS (the only element required in all REMS). Before 
FDAAA, a drug with only a Medication Guide would not have been 
considered to have a risk management plan. Instead, Medication Guides 
were considered part of labeling.
    Less than 10 percent of the new REMS contain elements to assure 
safe use; however, these new REMS are in addition to the 16 previously 
approved risk management plans with elements to assure safe use that 
have been deemed to be REMS.
    In each case where a REMS was required, FDA made the finding that a 
REMS was necessary to ensure that the benefits of the drug outweighed 
the risks. In the case of REMS with elements to assure safe use, the 
types of REMS that place the greatest burden on participants in the 
program and on the health care system, FDA determined that without 
these elements to assure safe use, the drug could not be approved, or 
if previously approved, would need to be withdrawn from the market. It 
is these types of REMS that seem to be of most concern to stakeholders 
who have communicated concerns about the REMS program.
    Most of the REMS with elements to assure safe use require 
prescriber education and certification about the specific risks of the 
drug covered by the REMS and the drug's appropriate use. In some cases, 
prescribers are required to counsel patients about the risks of the 
drug. They also may be required to enroll patients in the REMS, and 
they may be asked to have the patient sign a prescriber/patient 
agreement. All of these actions are intended to promote informed, 
appropriate prescribing of the particular drug, and provide information 
to the patient about the risks and appropriate use of the drug. 
However, FDA has heard from prescribers who are concerned about having 
to enroll in many different programs, obtain different certifications, 
and comply with various requirements for counseling their patients. 
They are concerned that these restrictive programs interfere with the 
practice of medicine and are costly to implement without any 
reimbursement for the costs incurred. Patients have expressed the 
concern individually and through patient advocacy groups that 
prescribers may refuse to participate in the REMS, so they may be 
deprived of access to necessary drugs.
    Many of the REMS with elements to assure safe use require 
pharmacists or pharmacies to be certified, and in several REMS with 
elements to assure safe use, pharmacists are required to determine 
whether the prescription presented by the patient was written by a 
certified prescriber or whether the patient is authorized to receive 
the drug. Sometimes pharmacists are also provided educational materials 
so that they can counsel patients on the safe and appropriate use of 
the drug. FDA has heard from pharmacy organizations that complying with 
these requirements can cause a disruption in usual workflow, and these 
organizations have expressed concern that there is no additional 
compensation for pharmacists complying with REMS requirements. In 
addition, pharmacists have said that the multiplicity of programs 
requiring separate enrollment and certification are unduly burdensome 
on the pharmacy, as is the lack of a single source for information on 
all REMS requirements.
    In some REMS, to help ensure that the REMS is appropriately 
implemented, the sponsor will elect to distribute only through a 
central pharmacy or pharmacies that agree to abide by the terms of the 
REMS. Some health care organizations have expressed the concern that 
these arrangements disrupt their ability to provide drugs to patients 
in their system, and are anticompetitive in nature. (See the citizen 
petition filed under 21 CFR 10.30 by Kaiser Foundation Health Plan, 
Inc., Docket No. FDA-2009-P-0602, available on the Internet at http://www.regulations.gov.)
    A few REMS with elements to assure safe use require that drugs be 
dispensed only in particular settings, such as hospitals. Some require 
patients to be monitored for the development of undesirable reactions 
to the drug or, in the case of drugs that can adversely affect a fetus, 
require pregnancy testing to prevent fetal exposure to the drug. 
Stakeholders have expressed concerns

[[Page 34455]]

about these types of restrictions, citing burden and cost.
    Several of the REMS with elements to assure safe use require that 
the drug be dispensed only with documentation of conditions to assure 
safe use. For example, patient enrollment may be required in a program 
designed to make sure the patient is educated about the risks of the 
drug, the importance of follow-up, monitoring, if applicable, and 
reporting of adverse events. Stakeholders have raised concerns about 
the effect of such restrictions on patient access to medications and 
about the costs to prescribers and pharmacists to implement such a 
program.
    All REMS include a timetable for submission of assessments. The 
timing for assessments is at a minimum 18 months, 3 years, and 7 years, 
but for drugs that have REMS with elements to assure safe use, the 
assessments can be more frequent. Sponsors must assess the REMS and 
determine whether the goals of the REMS are being met. REMS assessment 
reports generally summarize surveys of patients and prescribers, data 
on compliance with the REMS processes, drug use, and information on 
certain outcomes.
    Because FDA regulates the holders of approved applications to 
market drugs, the REMS requirements are imposed on sponsors, not 
directly on other participants in the health care system. Thus, 
sponsors must establish the education and certification programs and 
the monitoring systems, and implement the REMS requirements. Yet 
sponsors do not control the other participants in the health care 
system, and it may be difficult to get the participants to comply with 
the REMS requirements. Furthermore, because in most cases the REMS 
programs are established by individual sponsors and are tailored to the 
characteristics of the drug, the population using the drug, and the way 
the drug is prescribed and distributed, it can be difficult to 
standardize the elements of REMS to reduce their burden. Finally, it 
may be difficult to determine whether a REMS is working effectively 
and, if so, which specific elements of the REMS are working well.
    As FDA continues to require and approve REMS for drugs, it is 
important to hear more from stakeholders about their concerns. 
Therefore, FDA has decided to hold this public meeting.

IV. Purpose and Scope of Meeting

    The purpose of this meeting is to receive information and comments 
on issues with REMS from a broad group of stakeholders including 
interested prescribers, pharmacists, patients, third party payers, 
application holders, and the public.
    Although any comments are welcome, FDA is particularly interested 
in obtaining information and public comment on the following issues:

A. Requirement for a REMS

    In each case where a REMS was required, FDA made the statutorily 
required finding that a REMS was necessary to ensure that the benefits 
of the drug outweighed the risks. Section 505-1 lists the factors FDA 
must consider in determining whether to require a REMS as follows:
     The estimated size of the population likely to use the 
drug
     The seriousness of the disease or condition that is to be 
treated with the drug
     The expected benefit of the drug with respect to the 
disease or condition
     The expected or actual duration of treatment with the drug
     The seriousness of any known or potential adverse events 
that may be related to the drug and the background incidence of such 
events in the population likely to use the drug
     Whether the drug is a new molecular entity
    In addition, for REMS with elements to assure safe use, the 
elements to assure safe use must:
     Be commensurate with the specific serious risk listed in 
the labeling of the drug
     Not be unduly burdensome on patient access to the drug, 
considering the risk and, in particular, patients with serious or life-
threatening diseases or conditions and patients who have difficulty 
accessing health care (such as patients in rural or medically 
underserved areas)
     To the extent practicable, conform with elements to assure 
safe use for other drugs with similar serious risks, and
     Be designed to be compatible with established 
distribution, procurement, and dispensing systems for drug.
    1. How should these factors be evaluated individually and in 
relation to each other to determine whether a REMS is appropriate?
    2. How should the factors be evaluated individually and in relation 
to each other to determine what type of REMS is appropriate (i.e., what 
elements should be included in the REMS: Medication Guide, 
communication plan, elements to assure safe use, implementation 
system)?
    3. Are there other factors that FDA should consider besides the 
statutorily enumerated factors in deciding whether to require a REMS, 
and if FDA believes a REMS is necessary, what type of REMS should be 
required?

B. Establishing the Goals of A REMS

    1. When FDA requires a REMS, how should the goals be expressed? For 
example:
    a. Should the goal be to reduce the risk to zero (e.g., zero fetal 
exposures or cases of agranulocytosis), even if it is recognized as an 
aspirational and not an achievable goal?
    b. Should the goal be expressed in terms of risk reduction either 
to some minimum level (e.g., not more than 100 fetal exposures) or as 
compared to a baseline, assuming there is a known baseline from which 
risk reduction can be measured (e.g., reduce fetal exposures by 90 
percent)?
    c. What factors should FDA consider in establishing the goals of a 
REMS?
    d. What criteria might be considered for modifying a REMS 
(increasing or decreasing elements, or eliminating it all together)?

C. Issues Regarding Elements to Assure Safe Use

    1. Is there evidence that REMS with elements to assure safe use 
have adversely affected appropriate patient access to approved drugs?
    a. What features of a REMS with elements to assure safe use are 
most likely to adversely affect appropriate patient access to approved 
drugs?
    b. What design features or safeguards could be incorporated into 
elements to assure safe use to reduce any negative impact on 
appropriate patient access?
    2. Is there evidence that REMS with elements to assure safe use 
have improved patient safety?
    3. Is there evidence that REMS with elements to assure safe use 
have adversely affected patient safety?
    4. How have REMS with elements to assure safe use affected the 
health care delivery system?
    a. What features of a REMS with elements to assure safe use are 
most likely to adversely affect the health care delivery system?
    b. What design features could be incorporated into elements to 
assure safe use to reduce any negative impact on the health care 
delivery system? For example, can training and certification of health 
care providers be streamlined? If so, how?
    c. How should REMS with elements to assure safe use be made 
compatible with established distribution systems so as to minimize the 
burden on the health care delivery system?
    5. Some REMS are implemented by distribution of drugs through a 
central pharmacy system, and some are

[[Page 34456]]

implemented through a retail pharmacy system.
    a. What are the advantages and disadvantages of the various models 
of drug distribution under a REMS?
    b. Should sponsors be permitted to choose the drug distribution 
system they prefer to manage the risks, or should a common distribution 
system be employed for REMS?
    6. Can implementation of elements to assure safe use be 
standardized (e.g., could uniform systems for providing prescriber and 
pharmacist education or certification be developed)?
    a. Is there a preferred way to standardize the elements to assure 
safe use (e.g., based on the nature of the risk, across a class of 
drugs with common risks, or around certain elements such as prescriber 
education or pharmacy certification)?
    b. What are the advantages and disadvantages of standardizing the 
way elements to assure safe use are implemented on:
    i. Patient safety?
    ii. Patient access?

D. Evaluating the Effectiveness of REMS

    1. How should REMS be monitored and assessed to determine their 
effectiveness, considering the different types of REMS elements (e.g., 
Medication Guides, communication plans, elements to assure safe use)?
    2. How should the overall burden on the health care system of a 
REMS with elements to assure safe use be monitored and assessed, 
considering the different types of elements to assure safe use (e.g., 
training or certification of prescribers and pharmacists, 
implementation of patient registries)?
    3. Should metrics for determining the effectiveness of a REMS be 
specified at the time the REMS is approved? How should the appropriate 
metrics be determined?
    4. Are surveys the optimal method to assess patient and health care 
provider understanding of the serious risks and safe use of the drug? 
Are there alternative methods that should be considered?

E. Effects of REMS on Generic Drugs

    1. Section 505-1(f)(8) states that no holder of an approved 
application shall use any element to assure safe use required by the 
Secretary to block or delay approval of an application under section 
505(b)(2) or (j) or to prevent application of an element to assure safe 
use to a drug that is the subject of an abbreviated new drug 
application. What steps should FDA take to ensure that REMS are not 
used to block or delay generic competition?
    2. FDAAA requires that innovator and generic sponsors use a single 
shared system to provide a REMS with elements to assure safe use, 
unless a waiver is granted. What design or process features should be 
taken into account when designing an innovator REMS to facilitate use 
of a single shared system when generics are approved?

F. Protection of Patient Information

    1. Some REMS with elements to assure safe use require enrollment of 
patients and health care providers in a program, or require a patient 
registry as a condition of prescribing or dispensing a drug.
    a. What, if any, privacy concerns are raised by these programs?
    b. Does enrollment in a REMS program or a patient registry without 
requiring a specific collection of health information raise the same 
privacy concerns?
    2. What steps should FDA take to reduce concerns about patient 
privacy when REMS with such elements to assure safe use are determined 
to be necessary to ensure the benefits of a drug outweigh its risks?

V. Attendance and Registration

    The FDA Conference Center at the White Oak location is a Federal 
facility with security procedures and limited seating. Attendance is 
free and will be on a first come, first served basis. Individuals who 
wish to present at the public meeting must register by email to 
[email protected] on or before June 30, 2010, and provide 
complete contact information, including name, title, affiliation, 
address, email, and phone number. In section IV of this document, FDA 
has included questions for comment. You should identify by number each 
question you wish to address in your presentation, so that FDA can 
consider that in organizing the presentations. FDA will do its best to 
accommodate requests to speak, and will determine the amount of time 
allotted to each presenter and the approximate time that each oral 
presentation is scheduled to begin. An agenda will be available 
approximately 2 weeks before the meeting on the Agency Web site at 
http://www.fda.gov/Drugs/NewsEvents/ucm210201.htm.
    If you need special accommodations because of disability, please 
contact Kristen Everett (see FOR FURTHER INFORMATION CONTACT) at least 
7 days before the meeting.
    A live Web cast of this meeting will be available on the Agency Web 
site at http://www.fda.gov/Drugs/NewsEvents/ucm210201.htm on the day of 
the meeting. A video record of the meeting will be available at the 
same Web address for 1 year.

VI. 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 August 31, 2010. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday.

VII. 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: June 11, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-14547 Filed 6-11-10; 4:15 pm]
BILLING CODE 4160-01-S