[Federal Register Volume 85, Number 215 (Thursday, November 5, 2020)]
[Notices]
[Pages 70639-70643]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-24540]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-N-1845]


Risk Evaluation and Mitigation Strategy Assessment Summary for 
Web Posting; Establishment of a Public Docket; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; establishment of a public docket; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
announcing the establishment of a docket to solicit public comment on a 
proposal to publish a summary of FDA's review of Risk Evaluation and 
Mitigation Strategy (REMS) assessments. The purpose of the docket 
establishment is to increase Agency transparency and promote exchange 
of information regarding the assessment of REMS programs.

DATES: Submit either electronic or written comments by January 4, 2021.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be

[[Page 70640]]

considered. Electronic comments must be submitted on or before January 
4, 2021. The https://www.regulations.gov electronic filing system will 
accept comments until 11:59 p.m. Eastern Time at the end of January 4, 
2021. Comments received by mail/hand delivery/courier (for written/
paper submissions) will be considered timely if they are postmarked or 
the delivery service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2020-N-1845 for ``Risk Evaluation and Mitigation Strategy 
Assessment Summary for Web Posting; Establishment of a Public Docket; 
Request for Comments.'' Received comments, those filed in a timely 
manner (see ADDRESSES), will be placed in the docket and, except for 
those submitted as ``Confidential Submissions,'' publicly viewable at 
https://www.regulations.gov or at the Dockets Management Staff between 
9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Claudia Manzo, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 2418, Silver Spring, MD 20993, 301-796-
0182, Claudia.Manzo@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background

    Section 505-1(g)(3) of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) (21 U.S.C. 355-1) specifies that a REMS assessment shall 
include, with respect to each goal included in the strategy, an 
assessment of the extent to which the approved strategy, including each 
element, is meeting the goal or whether one or more of the goals or 
elements should be modified. Information from a REMS assessment can be 
used to understand whether certain REMS requirements or specific tools 
are effective in mitigating a serious risk.
    Every proposed REMS for a new drug application (NDA) and biologics 
license application (BLA) must have a timetable for submission of REMS 
assessments that fulfills the two parameters below:
     Includes assessments submitted to FDA by the dates that 
are: (1) 18 months after the strategy is initially approved; (2) 3 
years after the strategy is initially approved; and (3) in the seventh 
year after the strategy is so approved, and
     Submitted at a frequency specified in the strategy and can 
be increased or reduced in frequency under certain circumstances and 
eliminated under certain circumstances.
    REMS assessments are also required under the following conditions:
     When the applicant \1\ is submitting a supplemental 
application for a new indication for use
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    \1\ For the purpose of this notice, applicant includes any 
person that holds an application approved under section 505-1 of the 
FD&C Act or a license issued under section 351 of the Public Health 
Service Act (42 U.S.C. 262) for such product, or who submits an NDA, 
an abbreviated new drug application (ANDA), a BLA, or an amendment 
or supplement to an NDA, an ANDA, or a BLA, to obtain FDA approval.
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     When required by the strategy
     Whenever FDA determines that an assessment is needed to 
evaluate whether the strategy should be modified (to ensure the 
benefits of the drug outweigh the risks or to minimize the burden on 
the healthcare delivery system when complying with the strategy)
    Additionally, assessments of approved REMS may be submitted 
voluntarily by the applicant at any time.
    All approved REMS for NDA and BLA products are required to include 
a timetable for submission of assessments of the REMS and applicants 
must submit their REMS Assessment Reports according to this timetable. 
The applicant's REMS Assessment Report is the document that contains 
information generated from the analysis of the metrics outlined in the 
REMS Assessment Plan. The REMS Assessment Plan is a specific plan for 
how the applicant intends to assess the performance of the REMS in 
meeting its risk mitigation goals and objectives. The REMS Assessment 
Plan is outlined in

[[Page 70641]]

the REMS approval letter for NDAs and BLAs and described in detail in 
the REMS Supporting Document.\2\
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    \2\ The REMS Supporting Document provides additional information 
about the REMS, such as the rationale for, and supporting 
information about, the design, implementation, and assessment of the 
REMS.
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    FDA conducts a review of the applicant's REMS Assessment Report to 
determine if the REMS is meeting its goals. These FDA reviews are 
archived in the Agency's electronic archival record system. Some of 
FDA's reviews of applicants' REMS Assessment Reports have been shared 
publicly at FDA advisory committee meetings. An applicant's REMS 
Assessment Report and FDA's review of this report may also be requested 
under the Freedom of Information Act (FOIA); these requests are 
reviewed by FDA staff, and any information exempt from disclosure must 
be redacted prior to fulfilling the FOIA request. An applicant's 
confidential commercial information (CCI), including specific 
information on stakeholder participation in REMS (e.g., number of 
certified prescribers, healthcare settings, or the number of enrolled 
patients), may be redacted from FOIA-released documents following FDA's 
determination that such information is non-public sales and usage 
information. Specific information on stakeholder participation in 
shared system REMS,\3\ however, may be released following FDA's 
determination that such information is aggregate for all the applicants 
in the shared system REMS and is not considered CCI.
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    \3\ A shared system REMS encompasses multiple prescription drug 
products and is developed and implemented jointly by two or more 
applicants.
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    FDA has received feedback from healthcare providers, healthcare 
systems, industry members, researchers, professional organizations, and 
other Federal Agencies, indicating that it would be beneficial to make 
both the applicant's REMS Assessment Report and FDA's review of this 
report available in the public domain for a number of 
purposes.4 5 6 7 8 For example, industry members may 
consider the effectiveness of a particular strategy as they develop a 
new REMS; healthcare providers may have an interest in the assessment 
of a REMS that they participate in; and academics can use the 
information for research purposes.
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    \4\ See The Pink Sheet, After REMS: An Interview With Amgen's 
Paul Seligman; posted July 7, 2014, and available at https://pink.pharmaintelligence.informa.com/PS056230/After-REMS-An-Interview-With-Amgens-Paul-Seligman.
    \5\ Fain, K., K. Nachman, and L. Rutkow, 2015, ``An Analysis of 
FDA's Drug Safety Authorities: Challenges and Opportunities Under a 
New Regulatory Framework,'' Legislation and Public Policy, 17:1-36.
    \6\ See International Society of Pharmacoepidemiology comments 
(Docket No. FDA-2018-D-4628-0006) on the 2019 draft guidance for 
industry ``Risk Evaluation and Mitigation Strategies Assessment: 
Planning and Reporting,'' (84 FR 1153, February 1, 2019) (Docket No. 
FDA-2018-D-4628), available at https://www.fda.gov/media/119790/download. When finalized, this guidance will represent the FDA's 
current thinking on these issues.
    \7\ Id., see Pfizer comments (Docket No. FDA-2018-D-4628-0011).
    \8\ Comments of Tracy Rupp, PharmD, MPH, RD, Senior Fellow at 
the National Center for Health Research, (Docket No. FDA-2013-N-
0502-0069) submitted for Docket No. FDA-2013-N-0502, ``Risk 
Evaluation and Mitigation Strategies: Understanding and Evaluating 
Their Impact on the Health Care Delivery System and Patient 
Access,'' available at http://www.center4research.org/nchr-statement-fda-meeting-risk-evaluation-mitigation-strategies-rems/.
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    In response to this feedback, FDA is proposing to post to the 
Approved REMS web page (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm) a summary of FDA's review of the applicant's REMS 
Assessment Report (hereafter referred to as Summary of the REMS 
Assessment) submitted according to the timetable specified in the 
approved REMS. The Summary of the REMS Assessment is intended to 
provide a general understanding of what has been learned from specific 
REMS programs. The Summary of the REMS Assessment will include a high-
level summary of the data included in the applicant's REMS Assessment 
Report and will include a summary of the FDA review of whether the REMS 
is meeting its risk mitigation goals. FDA will notify the applicant 
prior to posting the Summary of the REMS Assessment to the web page. 
Although the Agency acknowledges that information on specific 
stakeholder participation in REMS might be useful, this information 
would not be provided in the summaries of individual REMS \9\ because, 
as mentioned above, it is considered CCI. Information on participation 
in shared system REMS would be provided in aggregate (e.g., number of 
prescribers, pharmacies, and/or patients enrolled in the shared system 
program).
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    \9\ An individual REMS encompasses one or more prescription drug 
products and is developed and implemented by one applicant.
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II. Summary of the REMS Assessment for Web Posting

    This Federal Register notice provides an example of a Summary of 
the REMS Assessment that would be publicly available. The Summary of 
the REMS Assessment would include the following sections: A. 
Introduction; B. Background; C. Key Findings; D. Conclusions; and E. 
Next Steps. Section A. Introduction will include a brief paragraph that 
includes the reporting time point (e.g., 2-Year Drug X REMS Assessment 
Report), the reporting period (e.g., November 28, 2017, through 
November 27, 2018), and the FDA submission date. Section B. Background 
will include a summary of the approved indication, the safety issue 
warranting a REMS, the date the REMS was approved, the goals and 
objectives of the REMS, the REMS requirements, and the timetable for 
submission of assessments. Section C. Key Findings will include the 
brief summary of the results of data used to inform each objective. 
Section D. Conclusions will include both the applicant's and FDA's 
conclusion about whether the REMS is meeting its goals. Section E. Next 
Steps will include whether modifications to the REMS program or to the 
REMS Assessment Plan is warranted.

III. Example of the Summary of the REMS Assessment for Web Posting

    For the purpose of this example, we are using a fictitious product 
referred to as ``Drug X.''

A. Introduction

    This is a summary of the FDA evaluation of the 2-Year REMS 
Assessment Report (Third Assessment Report) of the Drug X REMS from the 
reporting period of November 28, 2017, through November 27, 2018, 
submitted to FDA on January 27, 2019.

B. Background

    Drug X is approved to treat the symptoms of a genetic, progressive, 
neurodegenerative disorder for which there are limited approved 
therapies. Drug X is an injectable medication given at a dose of 500 
milligrams (mg) intravenously over 60 minutes weekly for 4 weeks, and 
monthly thereafter. A REMS was required at initial approval to mitigate 
the risk of anaphylaxis, which occurred in clinical trials in 
approximately 10 percent of patients within 30 minutes of receiving a 
dose of Drug X. The risk of anaphylaxis occurred with any dose and 
patients appeared to be at higher risk if they experienced a prior 
event (e.g., hypersensitivity, allergic events). The Drug X REMS was 
approved on January 28, 2016.
    The goal of the Drug X REMS is to mitigate the risk of negative 
outcomes associated with Drug X-induced-anaphylaxis. Objectives of the 
REMS include:
    (1) Ensuring prescribers are educated on the risk of anaphylaxis 
associated with the use of Drug X, that the risk may occur with any 
dose, and that all

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patients need be observed for 30 minutes following each dose.
    (2) Ensuring that Drug X is dispensed only in certified healthcare 
settings that have immediate access onsite to equipment, emergency 
medication, and personnel trained to manage anaphylaxis.
    (3) Ensuring that healthcare providers observe patients for at 
least 30 minutes after each injection.
    (4) Informing patients about the risk of anaphylaxis associated 
with Drug X and the importance of remaining at the healthcare setting 
for 30 minutes after each injection.
    The Drug X REMS includes the following key requirements: (1) The 
sponsor must implement a communication plan including sending a REMS 
letter to all potential prescribers of Drug X outlining the risks and 
REMS requirements (communication plan completed January 2019); (2) 
healthcare providers that prescribe Drug X must become certified, which 
includes completing REMS training, successfully completing a knowledge 
assessment, and enrolling in the Drug X REMS; (3) certified prescribers 
must counsel patients prior to administration of the first dose; (4) 
healthcare settings that order and dispense Drug X must become 
certified, which includes completing REMS training, successfully 
completing a knowledge assessment, enrolling in the Drug X REMS, and 
attesting to having immediate access onsite to equipment, emergency 
medication, and personnel trained to manage anaphylaxis; and (5) 
certified healthcare setting must observe patients for a minimum of 30 
minutes after each injection and complete and submit a completed post-
injection form to the Drug X REMS.
    The Drug X REMS assessment reporting frequency is 6 months, 12 
months, and annually after initial approval of the REMS.

C. Key Findings Informing REMS Goals and Objectives

    Goal: To mitigate the risk of negative outcomes associated with 
Drug X-induced anaphylaxis.
    Objective 1: Ensuring that prescribers are educated on the risk of 
anaphylaxis associated with the use of Drug X, that the risk may occur 
with any dose, and that all patients need be observed for 30 minutes 
following each dose.
    Data evaluated: Number and recipients of REMS letter; successful 
completion of prescriber knowledge assessment, surveys of prescribers' 
knowledge.
    Key findings:
     REMS letters were distributed to likely prescribers of 
Drug X during the reporting period; about 75 percent of the letters 
were emailed to neurologists with an email open rate of 14 percent, 
which is consistent with the email open rate of other REMS programs.
     All enrolled prescribers completed the knowledge 
assessment with a score of 100 percent; only 15 percent of prescribers 
required two attempts to achieve this score.
     Prescriber survey respondents demonstrated knowledge of 
the risks and safe use conditions with a mean knowledge rate of 88 
percent.\10\
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    \10\ The knowledge rate is the proportion of subjects who know 
the key message out of all subjects; the target knowledge rate for 
this prescriber survey was 80 percent.
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    Conclusion: FDA concluded that this objective is being met because 
the applicant notified the appropriate prescriber population with 
information about the Drug X REMS and certified prescribers 
successfully completed the training program and the knowledge 
assessment prior to enrollment. In addition, prescriber survey 
respondents demonstrated knowledge of the risks and the safe use 
conditions necessary for Drug X.
    Objective 2: Ensuring that Drug X is dispensed only in certified 
healthcare settings that have immediate access onsite to equipment, 
emergency medication, and personnel trained to manage anaphylaxis.
    Data evaluated: Shipment of Drug X only to certified healthcare 
settings; surveys of healthcare settings, audits of healthcare 
settings.
    Key findings: No shipments of Drug X were sent to non-certified 
healthcare settings during the reporting period. Audits of 10 percent 
of certified healthcare settings found that all were in compliance with 
the requirement to have immediate access onsite to equipment, emergency 
medication, and personnel trained to manage anaphylaxis after receiving 
Drug X.
    Conclusion: FDA concluded that this objective is being met because 
Drug X is being dispensed in certified healthcare settings.
    Objective 3: Ensuring that healthcare settings observe patients for 
at least 30 minutes following Drug X dosing.
    Data evaluated: Completed post-injection forms, surveys of 
healthcare settings, and audits of healthcare settings.
    Key Findings:
     Certified healthcare facility personnel survey respondents 
demonstrated knowledge of the risk of anaphylaxis following Drug X 
infusion with a knowledge rate of 87 percent. When asked about their 
facilities' compliance with post-injection observation, 90 percent 
reported that patients are observed for 30 minutes following each 
injection at their facility.
     Audits of 10 percent of healthcare settings found that 75 
percent of healthcare settings had policies and procedures in place to 
ensure that patients were observed for 30 minutes following each 
injection.
     Of the post-injection forms that were received:

--Less than 0.1 percent of the forms noted that the patient did not 
stay for 30 minutes; each facility reporting this was sent a warning 
letter; future non-compliance may result in decertification as outlined 
in the non-compliance action plan.
--Less than 0.1 percent of the forms documented anaphylaxis; no events 
occurred more than once in a given patient.

    [ssquf] The majority of patients who experienced anaphylaxis, were 
treated and observed at the healthcare facility and discharged once 
stable.
    [ssquf] A small number were transported to a hospital for 
additional monitoring; outcome for these three patients is outstanding 
and will be reported in the next assessment report.
    Conclusion: FDA concluded that this objective is being partially 
met. While survey findings were acceptable (exceeding the prespecified 
acceptable knowledge rate of >80 percent) and healthcare setting 
personnel indicated by survey that patients were being observed for 30 
minutes, 25 percent of healthcare settings audited did not have 
policies and procedures to ensure patient observation.
    Objective 4: Informing patients about the risk of anaphylaxis 
associated with Drug X and the importance of remaining at the 
healthcare setting for 30 minutes after each injection.
    Data evaluated: Surveys of patients.
    Key Findings: Patient survey respondents showed high knowledge of 
the risk of anaphylaxis (92 percent) and the need to remain at the 
facility for 30 minutes after each injection of Drug X (95 percent).
    Conclusion: FDA determined that this objective is being met because 
the patient knowledge rate exceeded the prespecified acceptable 
knowledge rate of >80 percent.

D. Conclusions About Whether the REMS Goals and Objectives Are Being 
Met

    Sponsor conclusion: The Drug X sponsor concluded that the goal and

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objectives of the Drug X REMS were being met and did not propose any 
changes to the REMS as a result of the REMS assessment findings.
    FDA conclusion: FDA concluded that while not all objectives are 
fully met, the overall goals of the program are being met. Appropriate 
outreach to likely prescribers was completed via REMS letters and the 
open rate for email letters is consistent with communications for other 
REMS. Surveys of a sample of enrolled prescribers showed that they 
understood the risks of Drug X, the need to monitor following dosing, 
and how to treat anaphylaxis. Patients surveyed were also aware of the 
risk and the need to be observed for 30 minutes following each dose. No 
Drug X was shipped to facilities that were not enrolled. Audits of 
facilities were in compliance with the need to have access onsite to 
equipment, emergency medication, and personnel trained to manage 
anaphylaxis; however, findings did reveal that 25 percent did not have 
specific policies and procedures in place to ensure that patients are 
observed 30 minutes following each injection of Drug X. Certified 
healthcare facility personnel surveyed were also aware of the risk and 
stated that they ensure all patients are observed for 30 minutes 
following each injection. Facilities reporting patient non-compliance 
with the 30-minute observation period were warned and will be followed 
in subsequent assessment reports. Although patients experiencing 
anaphylaxis were treated appropriately, three did require transport to 
a hospital and their outcome was not provided in this report.

E. Next Steps

    Based on our review of the findings in the third REMS Assessment 
Report, modifications to the Drug X REMS are not warranted.
    On May 1, 2019, FDA sent a letter to the applicant to acknowledge 
our completion of the third REMS assessment report review. In the 
letter the applicant was instructed to ensure that the audited 
healthcare settings that were out of compliance are fully compliant 
within 3 months of the date of issuance of the letter and that the 
outcome for the three patients that were transferred to a hospital must 
be provided to FDA as soon as possible. The applicant was also 
encouraged to use probability random sampling and recruit a larger 
sample of prescribers in subsequent prescriber surveys.

IV. Additional Issues for Consideration

    FDA is soliciting comment from stakeholders regarding the 
information that would be posted in the Summary of the REMS Assessment. 
In addition to any other aspects of or issues concerning FDA's proposal 
to publicly post a Summary of the REMS Assessment, FDA is interested in 
comments on the following topics:

(1) Whether the information contained in the Summary of the REMS 
Assessment example would be beneficial to the public, and if so, why it 
would be beneficial
(2) whether the Summary of the REMS Assessment would be useful to a 
wide range of stakeholders, including healthcare providers, patients, 
the pharmaceutical industry, and academics, and if so, why it would be 
beneficial
(3) whether any additional information should be included in the 
Summary of the REMS Assessment
(4) possible negative impacts of posting the Summary of the REMS 
Assessment

    Dated: October 30, 2020.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2020-24540 Filed 11-4-20; 8:45 am]
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