Health Information Organization

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885Am J Health-Syst Pharm—Vol 69 May 15, 2012

c a s e s t u d y

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 Anto-

nio, 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.

M edications can cure disease, increase longevity, and im- prove quality of life, but all

medications have adverse effects that can range from a nuisance to poten- tial 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 ini- tiative was signed into law as a part of the Food and Drug Administra- tion 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 pro- duce serious adverse effects and re- quires that the manufacturer create a

Purpose. The results of a hospital’s initia- tive 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 determin- ing the extent of REMS compliance at a large medical center, a systematic assess- ment 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 require- ments 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 proce- dures to help ensure the safe use of those 7 drugs were developed, and REMS-focused educational programs, order-entry system enhancements, and drug storage modifica- tions were implemented. Conclusion. Quality-improvement initia- tives including staff education, incorpora- tion of REMS requirements into existing polic y, development of an elec tronic resource, and creation of a separate stor- age 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 Ad- ministration (U.S.); Hospitals; Quality assur- ance; 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 manu-

facturers of those drugs have been permitted to resubmit those plans for approval as REMS plans. Addition- ally, manufacturers have the option of voluntarily creating REMS for any drug.

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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 im- plementation system. FDA requires that medication guides be given to patients to educate them on the risks associated with the use of REMS- requiring 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 require- ments. ETASU are designed to ensure that drugs are used only in appro- priately selected patients and are prescribed and dispensed by prop- erly 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 in- clude databases of certified providers and registered patients.

Problem As of April 2011, there were over

145 drugs subject to REMS require- ments, with that number increasing rapidly.3 FDA allows the manufac- turers of those drugs to create a REMS plan for each drug and indi- vidualized 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 initia- tive, 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 compli-

ance.4 There is an obvious need for hospitals and health care systems to critically evaluate each drug’s REMS requirements and conduct a sys- tematic analysis for the presence of policies and procedures that satisfy those requirements as the first steps in determining REMS compliance.

The pur pose of the qualit y- improvement project described be- low was to determine the extent of the development and adoption of policies and procedures for REMS compliance at a large academic med- ical center in order to identify op- portunities to improve REMS proc- esses. 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 imple- mented 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 con- ducted. 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 compo- nents were identified and classified as being applicable or not applicable in the inpatient setting. Drugs with “inpatient-applicable” REMS com- ponents were defined as those re- quiring ETASU or the distribu- tion of a medication guide in the inpatient setting, as described in FDA-approved REMS documenta- tion.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 medi- cation guides are required when a medication is dispensed to a patient for outpatient self-administration.2 Since ETASU r ules 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 inpa- tient applicability were made by the investigators and supported by the institution’s pharmacy and therapeu- tics (P&T) committee. Only drugs with inpatient-applicable REMS re- quirements were included in the ini- tial evaluation. Of the 145 drugs eval- uated, 123 were excluded from the project because the associated REMS were required in the outpatient set- ting only. The 22 drugs deemed to have inpatient-applicable REMS requirements were alglucosidase alfa, alosetron, alvimopan, ambris- entan, bosentan, buprenorphine– naloxone, buprenorphine transder- mal film, certolizumab, darbepoetin alfa, eculizumab, eltrombopag, epo- etin alfa, lenalidomide, olanzapine extended-release injection, oxycodone controlled-release tablets, prasugrel, pregabalin, romiplostim, sacro- sidase, thalidomide, tocilizumab, and vigabatrin.

S om e d r u g s w i t h i n p a t i en t - applicable 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 com- ponents 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 in- cluded in this phase of the project, 3 were subject to an existing policy

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or procedure that satisfied REMS requirements: alvimopan, bosentan, and romiplostim. For alvimopan, an order set stating the maximum num- ber of allowed doses was in use at the time of the analysis. For bosentan, an alert flag in the pharmacist order- entry system explained the need for patient and physician enrollment in REMS registries before the medica- tion is provided; and romiplostim was dispensed only if the patient and prescriber were enrolled in the ap- propriate registries.

The seven REMS-requiring drugs for which a formal policy or pro- cedure 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 address- ing REMS requirements for some drugs. Educational initiatives were developed and undertaken; these

included a presentation to the hospi- tal’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 introduc- tion to REMS requirements and explain which drugs had inpatient- applicable requirements. The phar- macy staff was educated through an accredited grand rounds continuing- education 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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of the pharmacist when REMS- requiring drugs are ordered.

R E M S p o l i c i e s a n d p r o c e - dures. One of the primary quality- improvement initiatives undertaken was the development of an institu- tional REMS policy. Due to constant- ly 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 hos- pital’s existing policy on medication order processing. The statements developed for this purpose empha- sized the responsibility of prescrib- ers to enroll in REMS programs for those medications they order and the responsibility of pharmacists to en- sure that all REMS requirements are met before entering the medication order. The revised medication order- processing policy was approved by the hospital’s medical executive com- mittee, medication-use improvement committee, and P&T committee.

The lack of formal procedures dis- covered in the analysis was addressed by the P&T committee. The formu- lary 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 prescrib- ers and patients who have fulfilled all REMS requirements. It was also de- cided that henceforth, if any drug with inpatient-applicable REMS require- ments is presented to the P&T com- mittee for formulary consideration, those requirements must be detailed in the drug monograph.

One of the most successful initia- tives was the development of a REMS reference document. Formatted as a spreadsheet, the REMS reference in- cludes information about why a drug

is subject to REMS requirements, the specific pharmacist actions required, and links to websites containing the re- quired registration forms and medica- tion 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 REMS- requiring 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 ap- proved by the P&T committee and added to the appropriate computer systems by an informatics pharma- cist, a clinical pharmacy manager, or a member of the medical center’s information technology staff.

Since the development of the REMS reference and the imple- mentation 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 phar- macy technicians was added by cre- ating a separate section in the phar- macy for the storage of drugs subject to REMS. All REMS-requiring drugs are now stored in the password- protected 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 rec- ognition of REMS-requiring drugs has increased.

Example of improved REMS compliance. One example of the institution’s enhanced REMS com- pliance is the adoption of a re- cently created protocol that com- plies with REMS requirements for erythropoiesis-stimulating agents (ESAs): the ESA APPRISE (Eryth- ropoiesis Stimulating Agents Assist-

ing 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 re- quiring the pharmacist to verify that the provider and patient have com- pleted 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 dis- charge 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 pharma- cist workload system and include a note listing the next 30-day deadline; the pending-work item is seen by all pharmacists responsible for the pa- tient’s care until its status is changed to “complete.”

Discussion Through the analysis described

here, we found that our institu- tion had no policies in place for REMS drugs and had procedures for only 3 of the 10 drugs with i n p a t i en t - a pp l i c a b l e R E M S re - quirements that were ordered over the 18-month study time frame. Quality-improvement initiatives implemented in response to those findings included the incorpora- tion of REMS requirements into the medication order-processing policy,

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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 insti- tution in this area include REMS- related quality-improvement mea- sures within the new CPOE system and ongoing assessment of insti- tutional 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, medica- tion guides, and patient and pre- scriber enrollment forms. With these modifications, the new CPOE system will allow for easier analysis of com- pliance with REMS requirements.

A few limitations of the REMS compliance assessment and subse- quent quality-improvement measures bear special mention. First, drugs sub- ject 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. On- going analysis and maintenance will be required to maintain a current list of drugs subject to REMS and to monitor changes to inpatient- applicable requirements.

Second, the lack of a uniform defi- nition 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 set-

ting, were deemed to be subject to inpatient-applicable requirements. For example, the REMS documenta- tion 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 medi- cation guide in the carton so that one can be given to each patient.”6 How- ever, 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 pa- tient or a caregiver requests one.7 Our institution chose to follow that guid- ance and not distribute medication guides to inpatients unless requested. Consequently, two drugs included in the analysis and quality-improvement initiatives (prasugrel and prega- balin) are no longer deemed to carry inpatient-applicable REMS require- ments. 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 proce- dures satisfying REMS requirements.

Third, the study described here focused on inpatient-applicable REMS requirements and therefore did not assess the presence of poli- cies or procedures for those drugs w ith only outpatient-applicable requirements—a category that in- cludes the majority of REMS drugs. However, the general assessment process outlined in this study could serve as a guide to developing poli- cies and procedures suitable for use in outpatient settings, including clin- ics and community pharmacies.

With the lack of standardization of approved REMS and the ever- growing number of drugs requiring REMS, the burden on health care systems to understand the expecta- tions and achieve compliance will

continue to grow. With this expand- ing 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 out- comes; future studies addressing this issue should be undertaken.

Conclusion Quality-improvement initiatives

including staff education, incorpo- ration of REMS requirements into existing policy, development of an electronic resource, and creation of a separate storage section for drugs sub- ject to REMS were implemented at a large academic medical center to help ensure compliance with inpatient- applicable REMS requirements.

References 1. Food and Drug Administration Amend-

ments 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 de- signing a risk evaluation and mitigation strategies (REMS) system to optimize the balance of patient access, medication safe- ty, 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. Ef- fient (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. Guid- ance for industry: medication guides— distribution requirements and inclusion in risk evaluation and mitigation strate- gies (REMS). www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM244570.pdf (accessed 2011 May 10).

8. F o o d a n d D r u g A d m i n i s t r a t i o n . REMS assessment acknowledg ment. www.a cces s da t a .fda .gov /dr u g sat fd a_ docs/appletter/2010/020772s011ltr.pdf (accessed 2011 May 10).

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