Health Information Organization

case study Risk evaluation
Am J Health-Syst Pharm—Vol 69 May 15, 2012 885
case study
Risk evaluation and mitigation strategies:
Assessment of a medical center’s policies
and procedures
Lindsey Childs, Earnest Alexander, and Minh-Tri Duong
Lindsey Childs, Pharm.D., M.P.H., is Postgraduate
Year (PGY) 2 Infectious Diseases Pharmacy Resident,
South Texas Veterans Health Care System, San Antonio, TX; at the time of writing, she was PGY 1 Pharmacy Resident,
Pharmacy Services, Tampa General Hospital, Tampa, FL. Earnest
Alexander, Pharm.D., is Manager, Clinical Pharmacy Services,
and Program Director, PGY 2 Critical Care Residency, Pharmacy
Services; and Minh-Tri Duong, Pharm.D., is Director of Residency
Programs and Education Coordinator, Pharmacy Services, Tampa
General Hospital.
Address correspondence to Dr. Childs at South Texas Veterans
Health Care System, 7400 Merton Minter Street, San Antonio, TX
78229 ([email protected]).
The authors have declared no potential conflicts of interest.
DOI 10.2146/ajhp110356
An audio interview which supplements the
information in this article, is available on
AJHP’s website at www.ajhp.org/site/misc/
podcasts.xhtml.
Medications can cure disease,
increase longevity, and improve quality of life, but all
medications have adverse effects that
can range from a nuisance to potential lethality. For decades, the Food
and Drug Administration (FDA)
has sought to identify and mitigate
the risks associated with medication
use. One of the more recent efforts
by FDA in this area is the required
use of risk evaluation and mitigation
strategies (REMS).
Authorization for the REMS initiative was signed into law as a part
of the Food and Drug Administration Amendments Act (FDAAA) in
September 2007.1
The creation of
the REMS program allows FDA to
require and enforce postmarketing
surveillance after a drug is approved.
During the drug approval process,
FDA identifies drugs that may produce serious adverse effects and requires that the manufacturer create a
Purpose. The results of a hospital’s initiative to evaluate and improve compliance
with federally mandated risk evaluation and
mitigation strategies (REMS) are presented.
Summary. Food and Drug Administration
approved REMS plans are required for more
than 145 drugs, but clear guidance on
strategies for achieving REMS compliance
is lacking. As a first step toward determining the extent of REMS compliance at a
large medical center, a systematic assessment was conducted to ascertain existing
policies and procedures for the use of drugs
subject to REMS requirements applicable in
the inpatient setting. About 123 drugs with
such “inpatient-applicable” REMS requirements were identified; of those, 10 had
been ordered by hospital providers during
a specified 18-month time frame and were
included in the assessment of policies and
procedures. The assessment revealed that
the hospital lacked a formal REMS policy
and had no REMS-compliant procedures in
place for 7 evaluated drugs (ambrisentan,
buprenorphine–naloxone, darbepoetin alfa,
epoetin alfa, oxycodone controlled-release
tablets, prasugrel, and pregabalin). Pursuant
to the compliance assessment, new procedures to help ensure the safe use of those 7
drugs were developed, and REMS-focused
educational programs, order-entry system
enhancements, and drug storage modifications were implemented.
Conclusion. Quality-improvement initiatives including staff education, incorporation of REMS requirements into existing
policy, development of an electronic
resource, and creation of a separate storage section for drugs subject to REMS were
implemented at a large academic medical
center to help ensure compliance with
inpatient-applicable REMS requirements.
Index terms: Administration; Compliance;
Computers; Education; Food and Drug Administration (U.S.); Hospitals; Quality assurance; Risk management; Storage; Toxicity
Am J Health-Syst Pharm. 2012; 69:885-9
REMS plan for those drugs. Notably,
before the passage of the FDAAA,
some drugs already were subject to
FDA risk minimization action plans
or medication guide requirements;
since the law’s enactment, the manufacturers of those drugs have been
permitted to resubmit those plans for
approval as REMS plans. Additionally, manufacturers have the option
of voluntarily creating REMS for any
drug.
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886 Am J Health-Syst Pharm—Vol 69 May 15, 2012
Background
An FDA-approved REMS plan can
contain any or all of the following
four elements: a medication guide,
a communication plan, elements to
assure safe use (ETASU), and an implementation system. FDA requires
that medication guides be given to
patients to educate them on the risks
associated with the use of REMSrequiring drugs.2
Communication
plans take the form of “Dear Health
Care Provider” or “Dear Pharmacist”
letters sent by drug manufacturers
to inform clinicians of medication
risks and any applicable ETASU and
implementation-system requirements. ETASU are designed to ensure
that drugs are used only in appropriately selected patients and are
prescribed and dispensed by properly trained health care providers.
Some examples of ETASU include
physician and pharmacist training,
pharmacy and hospital certification
programs, and the use of patient
registries. Implementation systems
allow manufacturers to monitor the
application of ETASU; examples include databases of certified providers
and registered patients.
Problem
As of April 2011, there were over
145 drugs subject to REMS requirements, with that number increasing
rapidly.3
FDA allows the manufacturers of those drugs to create a
REMS plan for each drug and individualized processes for the plan’s
fulfillment; this has led to a lack of
standardization of requirements and
processes.
Hospitals, as well as their medical
staffs and pharmacists, are required
to comply with REMS requirements.
However, due to the relatively recent
development of the REMS initiative, an ever-increasing number of
REMS-requiring drugs, and the lack
of REMS standardization, hospitals
and their administrators often do
not have clear guidance on the most
feasible strategies to ensure compliance.4
There is an obvious need for
hospitals and health care systems to
critically evaluate each drug’s REMS
requirements and conduct a systematic analysis for the presence of
policies and procedures that satisfy
those requirements as the first steps
in determining REMS compliance.
The purpose of the qualityimprovement project described below was to determine the extent of
the development and adoption of
policies and procedures for REMS
compliance at a large academic medical center in order to identify opportunities to improve REMS processes. The medical center is a level I
trauma center licensed for 959 acute
care beds and 59 rehabilitation beds.
At the time of the study, medication
orders were written on paper charts,
and pharmacists were responsible
for order entry; the hospital implemented a computerized prescriber
order entry (CPOE) in October 2011.
Analysis and resolution
A retrospective medication-use
evaluation targeting drugs subject
to REMS requirements, as well as
an evaluation of associated hospital
policies and procedures, was conducted. First, a list of all drugs with
FDA-approved REMS plans (as of
October 31, 2010) was obtained
from the FDA website3
; 145 drugs
were identified. Figure 1 illustrates
the process used to evaluate drugs
for potential inclusion in the study.
Each drug’s required REMS components were identified and classified
as being applicable or not applicable
in the inpatient setting. Drugs with
“inpatient-applicable” REMS components were defined as those requiring ETASU or the distribution of a medication guide in the
inpatient setting, as described in
FDA-approved REMS documentation.3
For drugs requiring only a
medication guide, FDA stipulates
that the handouts must be provided
in compliance with Section 21 of
the Code of Federal Regulations (21
CFR 208.24), which states that medication guides are required when a
medication is dispensed to a patient
for outpatient self-administration.2
Since ETASU rules require the
verification of patient and prescriber
enrollment, as well as pharmacy
enrollment in some cases, all drugs
requiring ETASU were deemed to be
subject to inpatient-applicable REMS
requirements.
All final determinations of inpatient applicability were made by the
investigators and supported by the
institution’s pharmacy and therapeutics (P&T) committee. Only drugs
with inpatient-applicable REMS requirements were included in the initial evaluation. Of the 145 drugs evaluated, 123 were excluded from the
project because the associated REMS
were required in the outpatient setting only. The 22 drugs deemed to
have inpatient-applicable REMS
requirements were alglucosidase
alfa, alosetron, alvimopan, ambrisentan, bosentan, buprenorphine–
naloxone, buprenorphine transdermal film, certolizumab, darbepoetin
alfa, eculizumab, eltrombopag, epoetin alfa, lenalidomide, olanzapine
extended-release injection, oxycodone
controlled-release tablets, prasugrel,
pregabalin, romiplostim, sacrosidase, thalidomide, tocilizumab,
and vigabatrin.
Some drugs with inpatientapplicable REMS requirements were
excluded from the analysis because
they were not ordered in the hospital
during the specified study time frame
(January 2009 through June 2010);
of the 22 initially identified drugs, 12
were excluded from the final analysis
on that basis.
Once a list of drugs that had
inpatient-applicable REMS components and were ordered within
the study time frame was finalized,
the existence or lack of associated
pharmacy policies and procedures
was assessed. Of the 10 drugs included in this phase of the project,
3 were subject to an existing policy
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Am J Health-Syst Pharm—Vol 69 May 15, 2012 887
or procedure that satisfied REMS
requirements: alvimopan, bosentan,
and romiplostim. For alvimopan, an
order set stating the maximum number of allowed doses was in use at the
time of the analysis. For bosentan,
an alert flag in the pharmacist orderentry system explained the need for
patient and physician enrollment in
REMS registries before the medication is provided; and romiplostim
was dispensed only if the patient and
prescriber were enrolled in the appropriate registries.
The seven REMS-requiring drugs
for which a formal policy or procedure was found to be lacking
were ambrisentan, buprenorphine–
naloxone, darbepoetin alfa, epoetin
alfa, oxycodone controlled-release
tablets, prasugrel, and pregabalin.
Educational initiatives. Several
quality-improvement initiatives were
undertaken to address the absence
of policies or procedures addressing REMS requirements for some
drugs. Educational initiatives were
developed and undertaken; these
included a presentation to the hospital’s P&T committee about the REMS
initiative and REMS requirements.
Additionally, the hospital staff was
educated through various means. An
article was written for the physician
newsletter to provide an introduction to REMS requirements and
explain which drugs had inpatientapplicable requirements. The pharmacy staff was educated through an
accredited grand rounds continuingeducation presentation focused on
understanding REMS and the role
Figure 1. The process by which medications were evaluated for inclusion in the assessment of the medical center’s policies and
procedures on the use of drugs subject to risk evaluation and mitigation strategies (REMS) applicable to inpatients.
Drugs with
inpatient-applicable
REMS
requirements?
YES
YES
Ordered during
study period?
n = 22
YES
No further action
needed
n = 3
Excluded from
analysis
n = 123
Excluded from
analysis
n = 12
Develop policy or
procedure
n = 7
NO
NO
REMS-requiring drugs
n = 145
NO
Policy or procedure
that satisfies REMS
requirements?
n = 10
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888 Am J Health-Syst Pharm—Vol 69 May 15, 2012
of the pharmacist when REMSrequiring drugs are ordered.
REMS policies and procedures. One of the primary qualityimprovement initiatives undertaken
was the development of an institutional REMS policy. Due to constantly evolving REMS requirements and
the varied procedures required for
each drug, the creation of one broad
policy on REMS-requiring drugs,
as opposed to several drug-specific
policies, was deemed the best course
of action. It was also decided that
instead of a standalone REMS policy,
statements regarding drugs subject to
REMS would be included in the hospital’s existing policy on medication
order processing. The statements
developed for this purpose emphasized the responsibility of prescribers to enroll in REMS programs for
those medications they order and the
responsibility of pharmacists to ensure that all REMS requirements are
met before entering the medication
order. The revised medication orderprocessing policy was approved by
the hospital’s medical executive committee, medication-use improvement
committee, and P&T committee.
The lack of formal procedures discovered in the analysis was addressed
by the P&T committee. The formulary status of most REMS-requiring
drugs had not been evaluated by the
committee at the time of the analysis.
Pursuant to the analysis, the P&T
committee added all such drugs to
the formulary as “restricted” drugs;
their use is now restricted to prescribers and patients who have fulfilled all
REMS requirements. It was also decided that henceforth, if any drug with
inpatient-applicable REMS requirements is presented to the P&T committee for formulary consideration,
those requirements must be detailed
in the drug monograph.
One of the most successful initiatives was the development of a REMS
reference document. Formatted as a
spreadsheet, the REMS reference includes information about why a drug
is subject to REMS requirements, the
specific pharmacist actions required,
and links to websites containing the required registration forms and medication guides. The reference document is
stored on a shared disk drive so that all
health care providers can access it from
any computer in the hospital.
Additionally, alert flags for REMSrequiring drugs have been built into
the order-entry pathway to inform
or remind pharmacists of REMS
requirements and direct them to the
REMS reference. The REMS resource
and all order-entry alerts were approved by the P&T committee and
added to the appropriate computer
systems by an informatics pharmacist, a clinical pharmacy manager,
or a member of the medical center’s
information technology staff.
Since the development of the
REMS reference and the implementation of the order-entry alerts,
pharmacists have reported feeling
much more secure in their REMS
knowledge and ability to ensure that
all REMS requirements are fulfilled
before order entry.
Drug storage modifications. An
extra alert for pharmacists and pharmacy technicians was added by creating a separate section in the pharmacy for the storage of drugs subject
to REMS. All REMS-requiring drugs
are now stored in the passwordprotected narcotics vault in the main
pharmacy; this step has created a
physical reminder about which drugs
carry REMS requirements. Since the
creation of the dedicated storage
section, pharmacists and pharmacy
technicians have stated that their recognition of REMS-requiring drugs
has increased.
Example of improved REMS
compliance. One example of the
institution’s enhanced REMS compliance is the adoption of a recently created protocol that complies with REMS requirements for
erythropoiesis-stimulating agents
(ESAs): the ESA APPRISE (Erythropoiesis Stimulating Agents Assisting Providers and Cancer Patients
with Risk Information for Safe Use
of ESAs) oncology program.5
The
protocol includes ensuring that the
hospital’s oncology providers are
registered with ESA APPRISE by requiring the pharmacist to verify that
the provider and patient have completed the patient acknowledgment
form (PAF) before entering an ESA
order. A hospital-specific version of
the PAF, which includes the hospital’s
program enrollment identification
number, is available on a shared
drive accessible for provider use
from all hospital computers. The PAF
requires providers to include their
enrollment identification number,
allowing pharmacists to verify that
they are enrolled in ESA APPRISE.
The PAF and the patient’s chart are
retained in the system even after discharge so that information is readily
available in case of an audit by the
APPRISE program.
REMS requirements for ESAs also
stipulate that patients receiving the
agents for chemotherapy-induced
anemia must be provided with a
medication guide every 30 days. To
help ensure this is done, pharmacists
who process ESA orders create a
“pending-work” item in the pharmacist workload system and include a
note listing the next 30-day deadline;
the pending-work item is seen by all
pharmacists responsible for the patient’s care until its status is changed
to “complete.”
Discussion
Through the analysis described
here, we found that our institution had no policies in place for
REMS drugs and had procedures
for only 3 of the 10 drugs with
inpatient-applicable REMS requirements that were ordered over
the 18-month study time frame.
Quality-improvement initiatives
implemented in response to those
findings included the incorporation of REMS requirements into the
medication order-processing policy,
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Am J Health-Syst Pharm—Vol 69 May 15, 2012 889
the designation of REMS-requiring
drugs as restricted-use drugs within
the formulary, the development of an
electronic REMS resource, and the
creation of a separate storage section
for drugs subject to REMS.
Future directions for our institution in this area include REMSrelated quality-improvement measures within the new CPOE system
and ongoing assessment of institutional compliance with REMS
requirements. Current plans include
alerts in the order-entry pathway in
the new CPOE system, with links
to relevant documents such as the
REMS reference document, medication guides, and patient and prescriber enrollment forms. With these
modifications, the new CPOE system
will allow for easier analysis of compliance with REMS requirements.
A few limitations of the REMS
compliance assessment and subsequent quality-improvement measures
bear special mention. First, drugs subject to REMS approved by FDA after
June 2010 were not included in the
analysis. Additionally, drugs that were
ordered after the study time frame
at our institution (e.g., olanzapine
extended-release injection) were not
captured in the analysis; however, to
be as current as possible with REMS
requirements, post hoc evaluations
of those drugs were performed, and
the results were included in the REMS
reference. Thus, some drugs not
included in the analysis of policies
and procedures were included in the
quality-improvement initiatives. Ongoing analysis and maintenance will
be required to maintain a current
list of drugs subject to REMS and
to monitor changes to inpatientapplicable requirements.
Second, the lack of a uniform definition of inpatient-applicable REMS
requirements posed a challenge. For
the study described here, all drugs
requiring ETASU, as well as drugs
for which the REMS documentation
implied that medication guides are
to be provided in the inpatient setting, were deemed to be subject to
inpatient-applicable requirements.
For example, the REMS documentation for prasugrel states that “hospital
blister packs, which are intended to
support initial dosing and use during
the patient’s stay in the hospital, will
contain sufficient copies of the medication guide in the carton so that one
can be given to each patient.”6
However, during the quality-improvement
phase of the project, FDA released a
draft guidance document stating that
a medication guide must be provided
in the inpatient setting only if the patient or a caregiver requests one.7
Our
institution chose to follow that guidance and not distribute medication
guides to inpatients unless requested.
Consequently, two drugs included in
the analysis and quality-improvement
initiatives (prasugrel and pregabalin) are no longer deemed to carry
inpatient-applicable REMS requirements. In a related development, the
REMS requirement for sacrosidase
was rescinded in December 20108
;
this did not affect the analysis, but the
drug was removed from the REMS
resource. Evolving REMS and the lack
of standardized REMS processes will
continue to present a challenge for any
institution wanting to institute procedures satisfying REMS requirements.
Third, the study described here
focused on inpatient-applicable
REMS requirements and therefore
did not assess the presence of policies or procedures for those drugs
with only outpatient-applicable
requirements—a category that includes the majority of REMS drugs.
However, the general assessment
process outlined in this study could
serve as a guide to developing policies and procedures suitable for use
in outpatient settings, including clinics and community pharmacies.
With the lack of standardization
of approved REMS and the evergrowing number of drugs requiring
REMS, the burden on health care
systems to understand the expectations and achieve compliance will
continue to grow. With this expanding compliance burden, the overall
effectiveness of REMS in ensuring
the appropriate use of certain drugs
and decreasing the associated adverse
effects should be evaluated. This
study did not assess the impact of
REMS compliance on clinical outcomes; future studies addressing this
issue should be undertaken.
Conclusion
Quality-improvement initiatives
including staff education, incorporation of REMS requirements into
existing policy, development of an
electronic resource, and creation of a
separate storage section for drugs subject to REMS were implemented at a
large academic medical center to help
ensure compliance with inpatientapplicable REMS requirements.
References
1. Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, 121
Stat. 823.
2. Medication guides for prescription drug
products (codified at 21 CFR §208; 2009).
3. Food and Drug Administration. Approved
risk evaluation and mitigation strategies
(REMS). www.fda.gov/Drugs/DrugSafety/
PostmarketDrugSafetyInformationfor
PatientsandProviders/ucm111350.htm
(accessed 2011 May 10).
4. Crespi Lofton J, ed. White paper on designing a risk evaluation and mitigation
strategies (REMS) system to optimize the
balance of patient access, medication safety, and impact on the health care system.
J Am Pharm Assoc. 2009; 49:729-43.
5. Amgen and Centocor Ortho Biotech
Products, L.P. ESA APPRISE oncology
program. https//www.esa-apprise.com/
ESAAppriseUI/ESAAppriseUI/default.jsp
(accessed 2011 May 10).
6. Food and Drug Administration. Effient (prasugrel) risk evaluation and
mitigation strategy. www.fda.gov/down
loads/Drugs/DrugSafety/PostmarketDrug
SafetyInformationforPatientsandProviders/
UCM187493.pdf (accessed 2011 May 10).
7. Food and Drug Administration. Guidance for industry: medication guides—
distribution requirements and inclusion
in risk evaluation and mitigation strategies (REMS). www.fda.gov/downloads/
Drugs/GuidanceComplianceRegulatory
Information/Guidances/UCM244570.pdf
(accessed 2011 May 10).
8. Food and Drug Administration.
REMS assessment acknowledgment.
www.accessdata.fda.gov/drugsatfda_
docs/appletter/2010/020772s011ltr.pdf
(accessed 2011 May 10).
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