
[Federal Register Volume 78, Number 99 (Wednesday, May 22, 2013)]
[Notices]
[Pages 30313-30317]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-12124]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-0502]


Standardizing and Evaluating Risk Evaluation and Mitigation 
Strategies; Notice of Public Meeting; Request for Comments

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 2-day 
public meeting to obtain input on issues and challenges associated with 
the standardization and assessment of risk evaluation and mitigation 
strategies (REMS) for drug and biological products. As part of the 
reauthorization of the Prescription Drug User Fee Act (PDUFA), FDA has 
committed to standardizing REMS to better integrate them into, and 
reduce their burden to, the existing and evolving health care system. 
As part of the PDUFA commitments, FDA will also seek to develop 
evidence-based methodologies for assessing the effectiveness of REMS.
    To obtain input from stakeholders about REMS standardization and 
evaluation, FDA will hold a public meeting to give stakeholders, 
including health care providers, prescribers, patients, pharmacists, 
distributors, drug manufacturers, vendors, researchers, standards 
development organizations, and the public an opportunity to provide 
input on ways to standardize and assess REMS.

DATES: The meeting will be held on July 25 and 26, 2013, from 8:30 a.m. 
to 4:30 p.m. Individuals who wish to present at the meeting must 
register by July 10, 2013. See section IV of this document for 
information on how to register to speak at the meeting.

ADDRESSES: The public meeting will be held at FDA's White Oak Campus, 
10903 New Hampshire Ave., Building 31 Conference Center, the Great Room 
(Rm. 1503), Silver Spring, MD 20993. Submit electronic comments to 
http://www.regulations.gov. Submit written comments to the Division of 
Dockets Management (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD 20852. Identify each set of 
comments with the corresponding docket number for the public meeting as 
follows: ``Docket No. FDA-2013-N-0502, ``Standardization and Evaluation 
of Risk Evaluation and Mitigation Strategies, Public Meeting.''

FOR FURTHER INFORMATION CONTACT: Adam Kroetsch, Food and Drug 
Administration, Center for Drug Evaluation and Research, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 1192, Silver Spring, MD 20993, 301-796-
3842, FAX: 301-847-8443, email: REMS_Standardization@fda.hhs.gov.

I. Background

    This meeting builds upon prior stakeholder feedback on and input 
into the design, implementation, and assessment of REMS. In July 2010, 
FDA held a public meeting to obtain input on issues associated with the 
development and implementation of REMS. In June 2012, FDA held a public 
workshop to discuss survey methodologies and instruments that can be 
used to evaluate patients' and health care providers' knowledge about 
the risks of drugs marketed with an approved REMS. In addition, the 
Food and Drug Administration Amendments Act of 2007 (Pub. L. 110-85) 
requires FDA to bring, at least annually, one or more drugs with REMS 
with elements to assure safe use (ETASU) before the Drug Safety and 
Risk Management Advisory Committee. FDA also regularly discusses both 
pre- and postapproval REMS with ETASUs with various FDA advisory 
committees in the context of specific applications.
    This meeting also builds on FDA's internal efforts to improve the 
design, implementation and assessment of REMS. In 2011, FDA created the 
REMS Integration Initiative, designed to evaluate and improve its 
implementation of REMS authorities. More information about the REMS 
Integration Initiative can be found at (http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm350852.htm). As part of this 
effort, FDA seeks to improve future REMS assessments and incorporate 
the latest methodologies in the evolving science of risk management. In 
its February 2013 report, ``FDA Lacks Comprehensive Data to Determine 
Whether Risk Evaluation and Mitigation Strategies Improve Drug 
Safety,'' the Department of Health and Human Services Office of the 
Inspector General affirmed the need to identify and implement reliable 
methods to assess the effectiveness of REMS and REMS components. This 
report is available at https://oig.hhs.gov/oei/reports/oei-04-11-00510.pdf.
    This public meeting is intended to meet performance goals included 
in the fifth reauthorization of the Prescription Drug User Fee Act 
(PDUFA V). This reauthorization, part of the Food and Drug 
Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144) 
signed by the President on July 9, 2012, includes a number of 
performance goals and procedures that are documented in the PDUFA V

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Commitment Letter. (See ``PDUFA Reauthorization Performance Goals and 
Procedures Fiscal Years 2013 Through 2017,'' which is available at 
http://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm270412.pdf.)
    FDA developed the performance goals and procedures for PDUFA V in 
consultation with drug industry representatives, patient and consumer 
advocates, health care professionals, and other public stakeholders 
from July 2010 through May 2011. Title XI of the letter, ``Enhancement 
and Modernization of the FDA Drug Safety System,'' states that FDA user 
fees will be used to enhance REMS by measuring the effectiveness of 
REMS and evaluating, with stakeholder input, appropriate ways to better 
integrate them into the existing and evolving health care system. (See 
``PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 
2013 through 2017'' at http://www.fda.gov/downloads/ForIndustry/
UserFees/PrescriptionDrugUserFee/UCM270412.pdf).
    Toward that end, the PDUFA V Commitment Letter identified a number 
of specific goals, including holding one or more public meetings to 
explore strategies to standardize REMS and reduce the burden of 
implementing REMS on practitioners, patients, and others in various 
health care settings and on methodologies for assessing whether REMS 
are mitigating the risks they purport to mitigate and for assessing the 
effectiveness and impact of REMS, including methods for assessing the 
effect on patient access, individual practitioners, and the overall 
burden on the health care delivery system. FDA also committed to 
issuing a report of its findings regarding standardizing REMS; the 
report will identify priority projects in four areas (pharmacy systems, 
prescriber education, providing benefit/risk information to patients, 
and practice settings). FDA also committed to issuing guidance on 
methodologies for assessing REMS, specifically, methodologies for 
determining whether a specific REMS with ETASU is commensurate with the 
specific serious risk listed in the labeling of the drug and 
considering the observed risk, not unduly burdensome on patient access 
to the drug. For details on specific FDA commitments, see the PDUFA 
Reauthorization Performance Goals and Procedures Fiscal Years 2013 
Through 2017, Section XI, ``Enhancement and Modernization of the FDA 
Drug Safety System,'' Parts A2, A3, which is available at http://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm270412.pdf.

II. Purpose and Scope of Meeting

    The purpose of this public meeting is to obtain feedback from 
stakeholders on: (1) Issues and challenges associated with 
standardizing and assessing REMS for drug and biological products and 
(2) identifying potential projects that will help standardize REMS and 
integrate them into the health care delivery system. FDA is seeking 
information and comments from a broad range of stakeholders, including 
interested health care providers, prescribers, patients, pharmacists, 
distributors, drug manufacturers, vendors, researchers, standards 
development organizations, and the public.
    To promote greater standardization and improved assessment of REMS, 
FDA is seeking feedback on how to reduce any unnecessary variation in 
REMS and, in the process, to make REMS elements and associated tools 
less burdensome to stakeholders, better integrated into the health care 
system, more effective, and easier to assess. FDA recognizes that the 
REMS elements and associated tools found in existing REMS programs have 
varied. In some cases, these variations are appropriate, because REMS 
are designed to address specific risks posed by particular drugs in a 
wide range of patient populations and health care settings. However, 
FDA may be able to establish standards to reduce unnecessary variation 
and to make REMS more predictable and simpler to understand, implement, 
and measure. The establishment of standards also presents the 
opportunity to improve upon the design of REMS elements and associated 
tools and assessment methodologies in the future.
    After this meeting, FDA will issue a report to the public that 
identifies REMS standardization projects in the four areas specified in 
the PDUFA V commitment letter: Prescriber education, pharmacy systems, 
practice settings, and providing benefit/risk information to patients. 
FDA welcomes stakeholder input to help identify high-quality projects 
that could offer FDA and stakeholders the opportunity to develop, test, 
and implement new approaches to standardizing REMS and integrating them 
into the health care system. The scope of such projects might include 
research studies, demonstration projects, and the development of new 
REMS tools using, for example, emerging information technologies or 
existing controls in the health care system. These projects might be 
carried out by FDA alone or in collaboration with stakeholders and 
outside experts.

III. Scope of Public Input Requested

    FDA is particularly interested in obtaining information and public 
comment on the following areas:

A. Prescriber-Directed REMS Tools

    REMS programs use a number of tools to educate prescribers and/or 
ensure that they carry out REMS requirements, including screening, 
monitoring, and counseling patients. These tools have included risk 
communications to prescribers, prescriber training, and instruments to 
help prescribers prescribe the drug safely--for example, counseling 
guides and checklists.
    1. Many REMS with elements to assure safe use provide for 
prescriber training on the risks of the drug and how to use the drug 
safely. In some REMS, the completion of this training is required 
before a person can become a certified prescriber of the drug. Sponsors 
provide REMS training in a variety of formats, including in-person, 
online, and through printed materials. FDA is interested in input on 
which formats and training approaches are most effective for prescriber 
training; how frequently prescribers should be asked to take REMS 
training and whether a single training is sufficient; what additional 
tools could be used to reinforce what prescribers learn during the 
training and help them apply what they have learned; and how REMS 
training could be incorporated into continuing medical education 
programs.
    2. Prescriber training often includes knowledge assessments that 
prescribers must successfully complete as part of the training. These 
knowledge assessments, which typically take the form of multiple-choice 
questions, are designed to ensure that the prescriber understands the 
training material; they also serve to reinforce key messages from the 
training. (Knowledge assessments should not be confused with the 
surveys of knowledge that drug manufacturers may conduct as part of 
their REMS assessments.) FDA is interested in input on when knowledge 
assessments should be included in REMS and whether they should be 
included in all REMS that include prescriber training. In addition, FDA 
requests input on how knowledge assessments can be designed to ensure 
accurate measurement of prescribers' knowledge and how knowledge 
assessments can be designed to measure or predict prescribers' ability 
to apply what they have learned in their practice.
    3. Once prescribers have met all requirements for certification 
under the

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REMS (e.g., completed training), they generally must complete an 
enrollment form to be recognized as certified and able to prescribe the 
drug. Generally, by completing, signing, and submitting the enrollment 
form, prescribers acknowledge their understanding of the drug's risks 
and the REMS requirements. In some REMS, the enrollment form also is 
used to share information about the risks of the drug and how to use 
the drug safely. FDA is interested in stakeholder input on whether the 
information and agreements included in current REMS prescriber 
enrollment forms are presented in a way that is easy for prescribers to 
understand. Also, what, if anything, should be done to standardize, 
simplify, or streamline prescriber enrollment forms and the overall 
prescriber enrollment process?
    4. What else can be done to improve the effectiveness of existing 
prescriber-directed REMS tools, to standardize them, to reduce their 
burden, and/or to better integrate them into the health care delivery 
system?
    5. What tools and technologies not currently used in REMS could be 
incorporated into REMS to help educate prescribers and ensure that they 
carry out REMS requirements? What evidence exists to support the 
effectiveness of these tools and technologies?
    6. What projects could be carried out to standardize the provision 
of prescriber education in REMS?
    7. What projects could be carried out to better integrate REMS into 
prescriber practice settings?
    8. What methodologies exist or might be developed to assess the 
effectiveness of prescriber-directed REMS tools, the tools' burden on 
the health care delivery system, and the effect of these tools on 
patient access?

B. Patient-Directed REMS Tools

    REMS programs may use a number of tools to educate and counsel 
patients, provide patients with information about the risks of the 
drug, and help to ensure that patients use the drug safely. These tools 
may include patient enrollment in the REMS, patient monitoring, 
counseling by health care professionals, Medication Guides, and other 
patient-directed educational materials.
    1. REMS use a range of written materials to help educate and 
counsel patients, including Medication Guides. In some cases, health 
care practitioners give these materials to patients to read on their 
own, and in other cases health care providers are asked to review these 
materials with patients and use them in patient counseling.
    2. In REMS that include patient education, what would make written 
educational materials more effective? What other materials, tools, and 
technologies, (e.g., reference materials, checklists, smartphone 
applications) might be used to help educate patients and reinforce what 
they have learned?
    3. How could the provision of information to patients be 
standardized, and what are the most efficient ways of providing 
information to patients given the variety of patient information needs 
and learning styles?
    4. In many REMS, patients receive counseling that may include a 
discussion of the benefits and risks of the drug as well as 
instructions on how to use the drug safely. In the majority of such 
REMS, prescribers are called upon to counsel patients, but other health 
care practitioners, including pharmacists and nurses, may also play a 
role in counseling patients. What are ways to improve current REMS 
approach to counseling patients? How should the timing and frequency of 
patient counseling be determined? Under what circumstances is it 
appropriate for prescribers to provide patient counseling in a REMS, 
when should other providers play a role in counseling patients in a 
REMS, and how can patient counseling in REMS be integrated into 
pharmacists' existing medication therapy management practices?
    5. Many REMS with elements to assure safe use include prescriber-
patient agreements. These agreements are used to document that an 
informed discussion of the drug's benefits and risks took place and 
that the patient understood the risks. Prescriber-patient agreements 
may also support patient counseling by providing information for 
prescribers to review with patients. Some REMS require that these 
agreements be signed by the prescriber and patient and submitted to the 
drug manufacturer. Are the information and agreements included in 
prescriber-patient agreements presented in a way that is easy for 
patients to understand and act upon? What, if anything, should be done 
to standardize, simplify, or streamline prescriber-patient agreement 
forms and the overall agreement process?
    6. What else can be done to improve the effectiveness of existing 
patient-directed tools, to standardize them, to reduce their burden, 
and/or to better integrate them into the existing and evolving health 
care delivery system?
    7. What tools and technologies not currently used in REMS could be 
incorporated into REMS to help counsel patients, to provide them with 
information on the risks of the drug, and to ensure that they use the 
drug safely? What evidence exists to support the effectiveness of these 
tools and technologies?
    8. What projects could be carried out to standardize the provision 
of benefit-risk information to patients?
    9. What methodologies exist or might be developed to assess the 
effectiveness of patient-directed REMS tools, the tools' burden on the 
health care delivery system, and the effect of these tools on patient 
access?

C. REMS Tools in Drug Dispensing Settings

    Drug dispensing settings, such as prescribers' offices, hospitals, 
pharmacies (e.g., specialty, retail, and mail-order), integrated health 
care delivery systems, and infusion centers, often play a significant 
role in REMS. This is a challenging area to address because of the wide 
range of health care settings involved and because dispensers are 
frequently called upon to coordinate care across a range of health care 
settings and practitioners and to reinforce the tools that have been 
used by other health care practitioners. Specific dispensing settings 
may be required to obtain certification under a REMS, and, like 
prescribers, the health care practitioners who dispense a drug 
(authorized dispensers) may be required to complete training, counsel 
patients, and provide patients with educational materials, including 
Medication Guides. In addition, dispensers may be required to document 
that certain safe-use conditions are met before dispensing (e.g., by 
ordering/checking lab tests or completing a form or checklist).
    Many REMS with elements to assure safe use require that specific 
health care settings be certified to be able to dispense the drug. To 
certify the health care setting, REMS typically require a 
representative of that health care setting to agree that the health 
care setting will meet all REMS requirements, including the completion 
of any necessary training.
    1. Under what circumstances should individual practitioners within 
a health care setting (e.g., pharmacists, as opposed to pharmacies) be 
certified, instead of the health care setting? How could this 
effectively be accomplished while minimizing the burden on the health 
care system?
    2. In most REMS that include dispenser certification, each 
dispensing site is certified individually. Under what circumstances 
would it be appropriate to use a single certification for a health care 
setting with multiple dispensing sites such as a pharmacy

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chain, an integrated health care system, or a hospital system?
    3. In what ways can the implementation of REMS tools in different 
dispensing settings be standardized, and under what circumstances might 
the implementation approach need to vary to accommodate the different 
types of dispensing settings that can be part of a REMS?
    4. What obstacles have made it difficult for authorized dispensers 
to obtain drugs under existing REMS, and how can these be overcome?
    5. How can REMS be made more compatible with existing systems for 
the procurement and distribution of drugs? How can REMS be integrated 
into any future electronic track and trace systems?
    6. What else can be done to improve the effectiveness of existing 
REMS tools in drug dispensing settings, to standardize them, to reduce 
their burden, and/or to better integrate them into the existing and 
evolving health care delivery system?
    7. What tools and technologies not currently used in REMS could be 
incorporated into REMS to help train and certify authorized dispensers, 
ensure that only certified dispensers can obtain the drug, and ensure 
that any safe-use conditions are met before a drug is dispensed? What 
evidence exists to support the effectiveness of these tools and 
technologies?
    8. What projects could be carried out to integrate REMS tools into 
pharmacy systems?
    9. What projects could be carried out to integrate REMS tools into 
other drug dispensing settings, such as hospitals, pharmacies, long-
term care facilities, and integrated health care delivery systems?
    10. What methodologies exist or might be developed to assess the 
effectiveness of REMS tools across the range of dispensing settings, 
the tools' burden on the health care delivery system, and the effect of 
these tools on patient access?

D. Approaches to Standardizing REMS Tools

    Many stakeholders have asked FDA to standardize specific REMS tools 
like stakeholder enrollments, Web sites, and educational materials. 
Standardizing REMS tools will require ongoing collaboration among FDA, 
drug manufacturers, stakeholders, scientific experts, and others. To 
ensure that standardized tools are effective and minimally burdensome, 
they should be developed in an open and inclusive process that 
incorporates the feedback of all relevant stakeholders as well as the 
latest science and best practices from across the health care system. 
To ensure the continued success of these tools, they must be updated 
regularly as best practices evolve.
    1. What opportunities and barriers exist for the development and 
implementation of standardized REMS tools? What are some ways that FDA 
can collaborate with third parties such as standards development 
organizations, industry groups, professional societies, and 
accreditation organizations to develop standardized REMS tools and 
ensure their adoption?
    2. How might health information technologies such as electronic 
health records, pharmacy management systems and electronic prescribing 
systems be used to integrate REMS into existing health care settings? 
What role might health information technologies play in REMS in the 
future? How can these technologies be used to inform practitioners and 
patients about REMS, monitor patients, and document that any safe-use 
conditions are met? Could the integration of REMS into health 
information systems ever reduce or eliminate the need for other REMS 
tools, such as provider education?
    3. Many stakeholders have suggested that a single Web portal should 
be established to act as a repository for standardized REMS tools and 
materials and to serve as a central information or reference source for 
REMS stakeholders. What barriers exist for the development of a single 
REMS Web portal? Who would be responsible for developing and 
maintaining the Web portal, and what role would FDA play?

E. Approaches To Assessing the Impact of REMS

    Drug manufacturers are required to submit assessments of their REMS 
on a regular basis. To date, these assessments have tried to evaluate 
the effectiveness of the REMS by measuring the frequency of adverse 
outcomes of interest, the knowledge of stakeholders, and the compliance 
of stakeholders with certain REMS requirements. To accomplish this, 
drug manufacturers have relied on spontaneous adverse event reporting, 
knowledge surveys, and systems that track stakeholder completion of 
certain activities, such as enrollment and documentation of safe use 
conditions. To improve how REMS are assessed, FDA is considering 
additional areas for measurement and additional methods to measure the 
impact of REMS.
    1. Should FDA routinely ask sponsors to assess the overall impact 
of their REMS on prescriber, dispenser, and patient burden, and/or 
access to the drug? If so, how could drug manufacturers assess the REMS 
impact on access and burden?
    2. What methods might be used to separate the impact of a REMS 
program from that of other related risk management activities? Without 
having a control group, how should FDA interpret and act on REMS 
assessment information?
    3. It is possible to interpret evidence of sustained REMS 
effectiveness to mean that the REMS should be maintained indefinitely, 
but such evidence may also suggest that safe use of the drug is now 
ingrained in the health care system and that the REMS can be modified 
or eliminated. What evidence could help FDA determine whether a drug 
would continue to be used safely if the REMS were modified or released?

IV. 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 on or before July 
10, 2013, through http://remsmeeting.eventbrite.com and provide 
complete contact information, including name, title, affiliation, 
address, email, and phone number. In section III of this document, FDA 
has included questions for comment. You should identify the questions 
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 at http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm351029.htm.
    If you need special accommodations because of disability, please 
contact Adam Kroetsch (see FOR FURTHER INFORMATION CONTACT) at least 7 
days before the meeting.
    A live Web cast of this meeting will be viewable at https://collaboration.fda.gov/remsjuly2013/ on the day of the meeting. A video 
record of the meeting will be available at the same Web address for 1 
year.

V. Comments

    Interested persons may submit either electronic comments regarding 
this document to http://www.regulations.gov

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or written comments to the Division of Dockets Management (see 
ADDRESSES). It is only necessary to send one set of comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. To ensure consideration, submit comment by (see DATES). 
Received comments may be seen in the Division of Dockets Management 
between 9 a.m. and 4 p.m., Monday through Friday, and will be posted to 
the docket at http://www.regulations.gov.

VI. Transcripts

    Please be advised that as soon as a transcript is available, it 
will be accessible at http://www.regulations.gov. It may be viewed at 
the Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD. A 
transcript will also be available in either hardcopy or on CD-ROM, 
after submission of a Freedom of Information request. Written requests 
are to be sent to the Division of Freedom of Information (ELEM-1029), 
Food and Drug Administration, 12420 Parklawn Dr., Element Bldg., 
Rockville, MD 20857.

    Dated: May 16, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-12124 Filed 5-21-13; 8:45 am]
BILLING CODE 4160-01-P


