ajhp_12152009

7/27/2019 ajhp_12152009

http://slidepdf.com/reader/full/ajhp12152009 1/24

www.ajhp.org

Official journal

of the

American Society

of Health-System

Pharmacists®

Encompassing

the full scope of

pharmacy practice

in hospitals and

health systems

American Journal of Health-System Pharmacy™

VOLUME 66 | NUMBER 24 | SUPPLEMENT 7

DECEMBER 15, 2009

Ensuring drug safety in health systems:

Role of the Food and Drug Administration

Amendments Act of 2007, risk evaluation

and mitigation strategies, and restricted drug

distribution systems

This activity is supported by an educational

donation provided by Amgen

7/27/2019 ajhp_12152009


The American Society of Health-System Pharmacists is accredited by the

Accreditation Council for Pharmacy Education as a provider of continuing

pharmacy education. The supplement as a whole provides 2.0 hours (0.2 CEU)of continuing-education credit (program number 204-000-09-006-H03P,knowledge-

based activity).

Copyright © 2009American Society of Health-System Pharmacists, Inc.

All rights reserved.

AJHP is a federally registered trademark.

Coden: AHSPEK

ISSN: 1079-2082

December 15, 2009

American Journal of Health-System Pharmacy™7PMVNFt/VNCFSt4VQQMFNFOU

www.ashp.org

Official Journal

American Society of Health-System Pharmacists

Henri R. Manasse, Jr.

Executive Vice President

S2 Introduction

Rita Shane

S3 The Food and Drug Administration

"NFOENFOUT"DUPG%SVHTBGFUZBOEIFBMUITZTUFNQIBSNBDZ

JNQMJDBUJPOT

Brian M. Meyer

4 3JTLFWBMVBUJPOBOENJUJHBUJPOTUSBUFHJFT

*NQBDUPOQBUJFOUTIFBMUIDBSF

QSPWJEFSTBOEIFBMUITZTUFNT

Rita Shane

4 4QFDJBMUZQIBSNBDJFTBOEPUIFSSFTUSJDUFE

ESVHEJTUSJCVUJPOTZTUFNT'JOBODJBMBOETBGFUZDPOTJEFSBUJPOTGPSQBUJFOUT

BOEIFBMUITZTUFNQIBSNBDJTUT

Bonnie E. Kirschenbaum

S21 Continuing education

Ensuring drug safety in health systems:Role of the Food and Drug AdministrationAmendments Act of 2007, risk evaluationand mitigation strategies, and restricted

drug distribution systems

Articles based on the proceedings of a symposium held June 15, 2009, during the ASHP

2009 Summer Meeting and Exhibition in Rosemont, IL. The content of this supplement

was written by a professional writer and reviewed and approved by the authors. This

activity was supported by an educational donation provided by Amgen, Inc.

See page S21 or http://ce.ashp.org to locate the continuing-education learning objectives,

self-assessment questions, and instructions covering the articles in this supplement.

S1Am J Health-Syst Pharm—Vol 66 Dec 15, 2009 Suppl 7

7/27/2019 ajhp_12152009


S2 Am J Health-Syst Pharm—Vol 66 Dec 15, 2009 Suppl 7

SYMPOSIUM Introduction

S YM PO S I UM

The Food and Drug AdministrationAmendments Act of 2007: Drug safety

and health-system pharmacy implications

IntroductionR ita Shane

Am J Health-Syst Pharm. 2009; 66(Suppl 7):S2-3

R ita Shane, PhaRm.D., FaShP, FCShP, is Director, Pharmacy Ser-vices, Cedars-Sinai Medical Center, Los Angeles, CA, and AssistantDean, Clinical Pharmacy, University o Caliornia, San Francisco.

Address correspondence to Dr. Shane at Pharmacy Services,Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room A-845,Los Angeles, CA 90048 ([email protected]).

Based on the proceedings o a symposium held June 15, 2009,during the ASHP 2009 Summer Meeting and Exhibition in Rose-

mont, IL, and supported by an educational donation provided by Amgen. The content o this supplement was written by Susan R.

Dombrowski, M.S., rom transcripts o the live educational activity and was reviewed and approved by the authors. Dr. Shane receivedan honorarium or her participation in the symposium and or thepreparation o this article. Dr. Shane reports that she has served asa consultant or Abbott (one-time process) and as a grant revieweror Amgen.

Copyright © 2009, American Society o Health-System Pharma-

cists, Inc. All rights reserved. 1079-2082/09/1202-00S2$06.00.DOI 10.2146/ajhp090459

In the past, the Food and Drug Ad-ministration (FDA) was criticizedor delays in the approval o po-

tentially lie-saving drugs; this criti-cism led to eorts to expedite thedrug-approval process. However,the studies used to obtain product

approval typically involve limitedpatient populations, and seriousadverse events oten do not becomeapparent until ater approval. FDAhas made an eort to develop morerobust postmarketing surveillanceprocesses to ensure drug saety. TheFDA Center or Drug Evaluationand Research recently reorganizedand expanded its Ofce o Surveil-lance and Epidemiology (ormerly the Ofce o Drug Saety). Previ-

ously, this ofce operated separately rom the FDA Ofce o New Drugs,but these two ofces recently es-tablished a memorandum o agree-

ment to collaborate in the manage-ment o signiicant saety issuesinvolving pending and approveddrug products.1

The Food and Drug Administra-tion Amendments Act (FDAAA) o 2007 enhanced the postmarketing

authorities o FDA with respect todrug saety.2 This legislation hasimportant implications or health-system pharmacists. The FDAAAgrants FDA new authorities to re-quire postmarketing studies or clini-cal trials o drugs and to require risk evaluation and mitigation strategies(REMS) or managing known orpotential serious drug risks. Health-system pharmacists may ind therequirements or REMS daunting.

Patients may be deterred rom usingdrug products with REMS require-ments because o the saety inorma-tion provided.

Restricted drug distribution sys-tems established by specialty phar-macies, group purchasing organi-zations, wholesale distributors, orother specialty suppliers may be acomponent o REMS. These systemspresent challenges or health-system

pharmacists, with important logisti-cal, fnancial, and saety implicationsor patients and health systems.3 Thespecialty drug products suppliedthrough specialty pharmacies andother restricted distribution systemsare among the costliest available (e.g.,injectable biotechnology products).

The frst article in this supplementdescribes the drug saety provisionso FDAAA, including REMS, and theimplications or health-system phar-

macists. The second article discussesthe impetus or these REMS andtheir evolution, their components,and their impact on patients, health

7/27/2019 ajhp_12152009



SYMPOSIUM Drug safety and health-system pharmacy implications

care providers, and health systems.Finally, the third article addresseshealth-system pharmacists’ concernsabout the use o specialty pharmacies

and other restricted drug distribu-tion systems and emerging trends inthe management o and reimburse-ment or specialty drugs.

References

1. U.S. Food and Drug Administration.Prescription Drug User Fee Act (PDUFA)IV drug saety ive-year plan 2008–2012. December 2008. http://www.da.

gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM119244.pd (accessed 2009 Jun 18).

2. 110th U.S. Congress. Food and Drug Ad-ministration Amendments Act o 2007.

http://rwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=:publ085.110 (accessed 2009Jun 17).

3. Armitstead J, Loyd L, Pane F et al. Implica-tions o the specialty drug marketplaceor health-system pharmacy: a roundtablediscussion. Am J Health-Syst Pharm. 2007;64:2364-72.

The Food and Drug Administration Amendments

Act of 2007: Drug safety and health-systempharmacy implications

Brian M. Meyer

Purpose. To describe the drug saety pro-

visions o the Food and Drug Administra-

tion Amendments Act (FDAAA) o 2007,

including risk evaluation and mitigation

strategies (REMS), and the implications or

health-system pharmacists.

Summary. The FDAAA grants FDA new

authorities to require postmarketing stud-

ies or clinical trials o human drugs and to

require REMS. The REMS provisions o the

FDAAA represent the evolution o FDA drug

saety requirements. Components o REMS

include medication guides, patient pack-

age inserts, and communication plans or

health care providers. For medications with

known saety risks, the FDAAA requires the

inclusion in the REMS process o elements

to ensure sae use. These elements may

Brian M. Meyer , M.B.a., is Director, Government Aairs Division,American Society o Health-System Pharmacists, Bethesda, MD.

Address correspondence to Mr. Meyer at ASHP, 7272 WisconsinAvenue, Bethesda, MD 20814 ([email protected]).

Based on the proceedings o a symposium held June 15, 2009, dur-ing the ASHP 2009 Summer Meeting and Exhibition in Rosemont,IL, and supported by an educational donation provided by Amgen.The content o this supplement was written by Susan R. Dombrowski,

M.S., rom transcripts o the live educational activity and was re-viewed and approved by the authors. Mr. Meyer made a contribution

to the ASHP Research and Education Foundation in lieu o receivingan honorarium or his participation in the symposium and or thepreparation o this article. Mr. Meyer reports that he has no a-liation with or nancial interest in a commercial organization thatposes a confict o interest with this article.

Copyright © 2009, American Society o Health-System Pharma-cists, Inc. All rights reserved. 1079-2082/09/1202-00S3$06.00.

DOI 10.2146/ajhp090460

include special training or certifcation or

prescribing or dispensing, dispensing only

under certain circumstances, special moni-

toring, and the use o patient registries.

Conclusion. Standardization o elements

to ensure the sae use o drugs with known

serious risks is needed so that REMS are

not unduly burdensome or the health care

delivery system and do not needlessly limit

patient access to the drugs.

Index terms: Food and Drug Administra-

tion (U.S.); Pharmacists, hospital; Pharmacy,

institutional, hospital; Postmarketing sur-

veillance; Regulations; Risk management;

Toxicity

Am J Health-Syst Pharm. 2009; 66(Suppl

7):S3-5

The Food and Drug Administra-tion Amendments Act (FDAAA)o 2007 was signed into law on

September 27 o that year.1 It amendsthe Federal Food, Drug, and Cos-metic Act, which provides the statu-

tory authority or FDA. The need toreauthorize the Prescription DrugUser Fee Act (PDUFA), which has ave-year sunset clause ater which itceases to be eective, served as theprimary impetus or passage o theFDAAA. The FDAAA reauthorizedthe PDUFA, which was set to expireon September 30, 2007. Reauthoriza-tion o the PDUFA is required every ve years; the legislation has beenreauthorized three times since 1992,

and reauthorization will be requiredagain in 2012. The current PDUFA(known as PDUFA IV) authorizesFDA to collect user ees rom manu-

acturers o human drug and bio-logical products, which acilitates the

FDA review process and expeditesapproval o these products.2

7/27/2019 ajhp_12152009




FDAAA

The FDAAA is a lengthy docu-ment with 11 “titles” addressing vari-ous topics, including medical device

user ees, the use o prescriptiondrugs and medical devices in pedi-atric patients, and disclosure o andaccess to clinical trial databases.1 TitleIX o the FDAAA enhances the post-marketing authorities o FDA withrespect to drug saety, and section901 o that title is particularly note-worthy because it grants FDA new authorities to require postmarketingstudies or clinical trials o humandrugs and to require risk evaluation

and mitigation strategies (REMS).These new authorities were the resulto experience with cyclooxygenase-2inhibitors and certain other problem-atic drugs in the marketplace and alack o clear authority or the agency to require that manuacturers conductpostmarketing research to clariy sae-ty concerns surrounding such drugs.Recommendations rom the Instituteo Medicine or an enhanced role andauthority o FDA in postmarketinginormation gathering on drug saety also contributed to the enactment o these provisions in the FDAAA.3

The FDAAA authorizes FDA torequire postapproval studies or clini-cal trials o a drug product to assessa known serious risk related to useo the product, to assess signals o a serious risk related to use o theproduct, or to identiy an unexpectedserious risk when available data indi-cate the potential or a serious risk.1 The FDAAA also allows FDA to re-

quire changes in the approved prod-uct labeling as indicated on the basiso new saety inormation generatedater approval.

Risk minimization action plans,which are saety programs designedto minimize risk associated with aproduct, were required by FDA priorto enactment o the FDAAA.4 TheREMS and postmarketing saety activities outlined in the FDAAA rep-resent the evolution o FDA require-

ments or improving drug saety.

REMS

FDA may require a manuacturerto submit proposed REMS prior toapproval and marketing o a drug

product to ensure that the drug’sbenefts outweigh its risks.1 Factorstaken into consideration by FDA indetermining whether REMS are re-quired beore product approval arelisted in Table 1.

FDA may require postapprovalREMS or drug products withoutREMS prior to approval i new saety inormation suggests that such strat-egies are needed to ensure that thedrug’s benefts outweigh its risks.1

Possible sources o this new saety in-ormation include clinical trials (e.g.,the postmarketing clinical trials re-quired by FDA through the FDAAA),adverse event reports, the peer-reviewed biomedical literature, andFDA’s new Sentinel Initiative, whichis a national strategy or monitoringdrug and medical product saety.1,5

The FDAAA requirements orREMS include assessments 18months, three years, and seven yearsater the strategy is initially approved.However, the seven-year assessmentmay be omitted i FDA determinesthat any serious risks associated withthe drug have been adequately iden-tifed and assessed and are adequately managed.6

Components o REMS may includea medication guide and package insertor distribution to patients.6 Pos-sible additional components includea communication plan or healthcare providers (e.g., sending letters to

Estimated size o the population likely to use the drug

Seriousness o the disease or condition or which the drug will be used

Expected beneft rom the drug with respect to the disease or condition

Expected or actual duration o treatment with the drug

Seriousness o any known or potential adverse events related to use o the drug and

background rate o such events in the population likely to use the drug

Whether the drug is a new molecular entity

Table 1.

Considerations in Determining the Need for Risk Evaluation and

Mitigation Strategies before FDA Approval of a Drug Product1

health care providers, correspondingthrough proessional organizations).

The FDAAA also has provisionsto support sae access to drugs that

have known serious risks and thatwould otherwise be unavailable.6 Aspart o REMS FDA may require theuse o one or more o the elementslisted in Table 2 to ensure sae use o such drugs because o their inherenttoxicity or potential harmulness.6 Restricted drug distribution systemsprovide some o these elements.

The FDAAA requires the FDADrug Saety and Risk ManagementAdvisory Committee to seek input

rom patients, physicians, pharma-cists, and other health care provid-ers about how the elements to en-sure sae use may be standardizedso as not to be unduly burdensomeor the health care delivery systemor to needlessly limit patient accessto a drug. The FDAAA calls or amechanism or evaluating at leastannually the elements or one ormore drugs.

FDA held a public meeting in lateMay 2009 to obtain input into thedevelopment o REMS or extended-release opioid analgesics.7 A noticeo the meeting was published in theFederal Register , and testimony wasreceived rom more than 80 individ-uals and representatives o organiza-tions, including the American So-ciety o Health-System Pharmacists(ASHP), other pharmacy organiza-tions, and patient advocacy groups.In its testimony, ASHP emphasizedthe need to standardize REMS and

7/27/2019 ajhp_12152009




conduct research to determine whichelements in Table 2 mitigate the risksassociated with opioid analgesics.ASHP advocated exemption o hos-pital inpatients rom REMS require-ments because o the presence o saety systems in hospitals and healthsystems.

The act that the extended-releaseopioid REMS will apply to a class o drugs rather than a specifc agent hasimportant implications. The FDAAA

allows FDA to deer assessment o approved REMS or a drug class untilone or more public meetings havetaken place to consider possible re-sponses. Public meetings may involveadvisory committees, workshops,or both. Meetings are ollowed by publication o notices in the Federal Register and requests or comments.The process can be time consuming.

Special training, experience, or certifcation o health care providers who prescribe thedrug

Special certifcation o pharmacies, practitioners, or health care settings that dispense

the drug

Dispensing o the drug to patients only in certain health care settings, such as

hospitals

Dispensing o the drug to patients with evidence or other documentation o sae-use

conditions, such as laboratory test results

Use o special monitoring or each patient receiving the drug

Enrollment o each patient receiving the drug in a registry

Table 2.

Elements to Ensure Safe Use of Drugs with Known Serious Risks as

Part of FDA Risk Evaluation and Mitigation Strategies6,a

aFDA may require one or more o these elements as part o risk evaluation and mitigation strategies to ensurethe sae use o a drug because o its inherent toxicity or potential harmulness.

The process or developing REMS orextended-release opioid analgesicshas not yet concluded. The deadlineor written comments was June 30,2009.

Conclusion

The FDAAA arose rom postmar-keting drug saety concerns, andrequirements or REMS representthe evolution o FDA drug saety requirements. The agency recog-

nizes the need to balance the risksand benefts o drugs, the need orpatient access to drugs with knownserious risks, and the need to mini-mize the burden o requirements orREMS on health systems. Standard-ization o the elements to ensurethe sae use o drugs with knownserious risks is needed so that REMSare not unduly burdensome or the

health care delivery system and donot needlessly limit patient access tothe drugs.

References

1. 110th U.S. Congress. Food and Drug Ad-ministration Amendments Act o 2007.http://rwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=:publ085.110 (accessed 2009Jun 11).

2. U.S. Food and Drug Administration.Prescription Drug User Fee Act (PDUFA).http://www.da.gov/ForIndustry/User-Fees/PrescriptionDrugUserFee/deault.htm (accessed 2009 Jun 17).

3. Institute o Medicine. The uture o drugsaety: promoting and protecting the healtho the public. September 22, 2006. http://www.iom.edu/CMS/3793/26341/37329.aspx (accessed 2009 Jun 18).

4. Agency or Healthcare Research andQuality and U.S. Food and Drug Ad-ministration. Implementation o risk minimization action plans (RiskMAPs)to support quality use o pharmaceuti-cals: opportunities and challenges; publicworkshop. http://www.da.gov/OHRMS/DOCKETS/98r/07-2574.pd (accessed2009 Jun 11).

5. U.S. Food and Drug Administration. TheSentinel Initiative: a national strategy or monitoring medical product saety.http://www.da.gov/Saety/FDAsSentinelInitiative/ucm089474.htm (accessed 2009Jun 11).

6. U.S. Food and Drug Administration.

Sec. 505-1. [21 USC §355-1] Risk evalu-ation and mitigation strategies. http://www.da .gov/Regula toryInorma-tion/Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/ucm109090.htm(accessed 2009 Jun 11).

7. U.S. Food and Drug Administration. Risk evaluation and mitigation strategies orcertain opioid drugs; notice o publichearing. April 20, 2009. http://www.da.gov/OHRMS/DOCKETS/98r/E9-8992.pd (accessed 2009 Jun 11).

7/27/2019 ajhp_12152009



SYMPOSIUM Risk evaluation and mitigation strategies

Risk evaluation and mitigation strategies:Impact on patients, health care providers,

and health systemsR ita Shane

Purpose. To describe the impetus or andevolution, components, and potential

impact on patients, health care providers,

and health systems o risk evaluation and

mitigation strategies (REMS) required by

the Food and Drug Administration (FDA)

or managing known or potential serious

drug risks.

Summary. A 2006 report rom the In-

stitute o Medicine criticizing FDA or

drug withdrawals due to saety problems

provided the impetus or FDA to enhance

postmarketing surveillance and to require

REMS or medications with actual or

potential saety concerns. Componentso REMS may include medication guides,

patient package inserts, communica-

tion plans or health care providers, and

elements to ensure sae use (e.g., special

training or certication or prescribing or

dispensing, dispensing only under certain

circumstances, special monitoring, use o

patient registries). Recent increases in the

number o drugs with REMS requirements,

MedWatch alerts, and the development

o the new Sentinel Initiative reect FDA’s

R ita Shane, PhaRm.D., FaShP, FCShP, is Director, Pharmacy Ser-vices, Cedars-Sinai Medical Center, Los Angeles, CA, and AssistantDean, Clinical Pharmacy, University o Caliornia, San Francisco.

Address correspondence to Dr. Shane at Pharmacy Services,Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room A-845,Los Angeles, CA 90048 ([email protected]).

Based on the proceedings o a symposium held June 15, 2009,during the ASHP 2009 Summer Meeting and Exhibition in Rose-mont, IL, and supported by an educational donation provided by Amgen. The content o this supplement was written by Susan R.

Dombrowski, M.S., rom transcripts o the live educational activity and was reviewed and approved by the authors. Dr. Shane receivedan honorarium or her participation in the symposium and or thepreparation o this article. Dr. Shane reports that she has served asa consultant or Abbott (one-time process) and as a grant revieweror Amgen.


DOI 10.2146/ajhp090461

commitment to drug saety. Patients maybe overwhelmed by inormation about

drugs with REMS requirements, which

could deter the use o potentially benecial

therapies. Pharmacists can help patients

weigh the risks and beneits o drug

therapy. Pharmacists, other health care pro-

viders, and health systems may nd REMS

requirements challenging, but FDA is cog-

nizant o the need to balance the goals o

ensuring drug saety and providing patient

access to drugs without placing an undue

burden on the health system.

Conclusion. The goal o improving drug

saety is sought by the FDA, patients, healthcare providers, and health systems alike.

Collaboration among health care providers

may provide efciencies in meeting FDA

REMS requirements.

Index terms: Food and Drug Administra-

tion (U.S.); Patient inormation; Pharma-

cists; Postmarketing surveillance; Regula-

tions; Risk management; Toxicity


7):S6-12

A2006 Institute o Medicine

(IOM) report to the U.S. Con-gress on drug saety criticized

the Food and Drug Administration(FDA) because o drug withdrawalsrom the marketplace due to saety concerns.1 In that report, the IOMrecommended several actions toaddress the problem, most notably clarifcation o the agency’s regulato-ry authority with a ocus on require-ments or postmarketing risk man-agement programs. These programs

may include restricted distributiono a drug to certain acilities, phar-macists, or physicians with specialtraining or experience; perormanceo specifed additional clinical trialsor other studies; and maintenance o an active adverse drug event surveil-lance system. The IOM report alsorecommended evaluation o all new data on new molecular entities nolater than fve years ater approval.

In response to that 2006 report,

FDA and the Agency or HealthcareResearch and Quality held a two-day joint public workshop in lateJune 2007 on the implementation

o risk minimization action plans(RiskMAPs) to support quality use

o pharmaceuticals.2 The goal o the workshop was to obtain input

7/27/2019 ajhp_12152009




rom stakeholders, including phar-macists, about mechanisms orminimizing the risks o medicationswith unusual saety and patient

monitoring concerns. These mecha-nisms evolved into the current risk evaluation and mitigation strategies(REMS) required as part o the Foodand Drug Administration Amend-ments Act (FDAAA) o 2007, whichwas signed into law in September o that year.3

Eorts to minimize the risks asso-ciated with certain medications withknown saety concerns began beorethe 2006 IOM report was released.

For example, dispensing o the atypi-cal antipsychotic agent clozapine hasbeen contingent upon the resultso baseline and periodic blood testssince the introduction o the drug in1990, because o the risk o potential-ly lie-threatening agranulocytosis.4

Many RiskMAPs date back toOctober 2002, when the PrescriptionDrug User Fee Act III was enacted.5 By February 2007, a RiskMAP insome ormat (Table 1) had been es-tablished or 30 drugs. The simplestRiskMAPs involve education andoutreach. Patient education with ac-knowledgment or use o an inormedconsent orm was used in RiskMAPs

Education and outreach: medication guides or patients, continuing-education

programs or health care providers

Reminder systems: prompts, reminders, double checks, or guides or health careproviders, patients, or both

Patient education with acknowledgment or use o inormed consent orms

Health care provider attestation or acknowledgment

Dispensing o a limited supply

Perormance-linked access systems

Prescribing and dispensing only by specially trained and certifed health care

practitioners

Dispensing only under conditions that meet evidence-o-sae-use

requirements

Mandatory enrollment or registration o patients, prescribers, or pharmacists

in restricted drug distribution programs or registries

Drug administration in special settings

Table 1.

Possible Formats for Risk Minimization Action Plansa

a The strength o the saeguard increases rom the top to the bottom o this list.

or drugs such as thalidomide. Dis-pensing o a limited supply was usedor drugs such as isotretinoin (30days) and thalidomide (28 days).

Perormance-linked access sys-tems provide the greatest saeguardsamong the various ormats orRiskMAPs. These systems limit ac-cess o target populations to drugproducts that have unique beneftsbut a high risk o irreversible mor-bidity or death. Such systems may require prescribing and dispensingonly by specially trained and certifedhealth care practitioners; dispens-ing only under conditions that meet

evidence-o-sae-use requirements(e.g., negative pregnancy test resultsor thalidomide and isotretinoin);mandatory enrollment or registra-tion o patients, prescribers, orpharmacists in restricted drug dis-tribution programs or registries;and drug administration in specialsettings (e.g., inpatient hospitaliza-tion or at least three days during ini-tiation o the antiarrhythmic agentdoetilide).6-8

The biologic response modifernatalizumab, which is used or mul-tiple sclerosis and Crohn’s disease,was temporarily withdrawn romthe market in 2005 because o the

risk o progressive multiocal leu-koencephalopathy, an opportunisticinection o the brain that usually leads to death or severe disability.9 A

restricted drug distribution programthat requires drug administrationby authorized inusion centers andregistration o patients, prescribers,pharmacies, and inusion centerswas implemented when the drug wasreintroduced to the market in 2006.10 Prescribers and patients participat-ing in this program are required tounderstand the risks associated withnatalizumab treatment.

Current FDA focus on safety

Evidence o a recent increase inemphasis on drug saety by FDAincludes the addition o new REMSrequirements or drugs, increasedactivity o the MedWatch program,an increase in the number o medica-tions with black box warnings, andthe Sentinel Initiative, a new nationalstrategy or monitoring drug andmedical product saety.11 MedWatch,FDA’s saety inormation and ad-verse event reporting program,provides inormation about saety alerts, recalls, market withdrawals,and key labeling changes. Currently,430 drugs (including salt orms) arelabeled with black box warnings.12 The goal o the Sentinel Initiative isactive surveillance or saety prob-lems instead o passive surveillance.Government and commercial da-tabases (e.g., databases o managedcare organizations and prescriptionbeneit management companies)

will be used in the Sentinel Initiativeto conduct population surveillanceand identiy saety issues in groupso patients rather than relying onisolated case reports. A systematicapproach using data rom disparatedata sources (Figure 1) will be usedto monitor the eects o drugs inpopulations, identiy saety problemsand the need or drug-use modifca-tions or restrictions, and acilitate anevidence-based approach to adverse

drug event monitoring.

7/27/2019 ajhp_12152009




Drugs that are the subject o activesaety alerts or recalls have increasedmarkedly in recent months. In thecourse o only one week in early May

2009, our saety alerts were postedthrough the MedWatch program.These alerts involved (1) REMS un-der review or mycophenolate moetiland mycophenolic acid to address therisk o pregnancy loss and congenitalmalormations, (2) the need or med-ication guides addressing the risk o suicide rom antiepileptic drugs, (3)a new boxed warning on the labelingo testosterone gel cautioning againstinadvertent secondary exposure o

children to the gel, and (4) new saety inormation added to the la-beling or erlotinib about gastroin-testinal peroration; potentially atalbullous, blistering, and exoliativeskin conditions; and corneal pero-ration and ulceration.13-16 Manag-ing the alerts can be a challenge orpharmacists and other health carepractitioners, who may be over-whelmed by the volume o alerts andmay disregard important notices. AtCedars-Sinai Medical Center, inor-mation received through MedWatchabout drug products known to be

Figure 1. A potential organizational structure for the Sentinel Initiative system.

ResearchComponent

Sentinel SystemStructure

Query DataSources

Subject to consentof data owners andconsistent withestablished privacy

and securitysafeguards

DatabaseDatabase

DatabaseDatabase

Database

• FDA• Partners (Data Owners)• Subject-Matter Experts• Other Government Agencies

Sentinel InitiativePrivate–Public Partnership

Data(Remains with Data Owners)

extensively used in the institutionis communicated promptly to themedical sta through a newsletterand brought to the attention o the

pharmacy and therapeutics commit-tee and other medical sta commit-tees as appropriate.

Increased postmarketing surveil-lance and requent saety alerts alsohave the potential to aect patientsby causing conusion and deterringthe use o potentially benefcial drugtherapies. Pharmacists can provide avaluable service to patients by help-ing them sort through the saety datato weigh the benefts and risks o

drug therapy.Risk evaluation and mitigation

strategies

REMS are designed to manage aknown or potential serious risk as-sociated with a drug or biologicalproduct. The goal o REMS is simi-lar to that o RiskMAPs, but REMSrepresent an increased ocus on drugsaety and postmarketing surveillancein response to criticism o FDA orailure to conduct such surveillance inthe past. Drugs that were the ocus o RiskMAPs were “grandathered.” The

initial list o drugs “deemed to have ineect an approved REMS” in March2008 (e.g., isotretinoin and clozapine,which were approved or marketing

by FDA in 1982 and 1989, respec-tively) is shown in Table 2.17 As o July 2009, 52 drugs had approved REMSlisted on the FDA website. O these,ambrisentan is the only one that wason the initial list in March 2008.18

Components o REMS may in-clude medication guides, patientpackage inserts, or communicationplans or health care providers (e.g.,web-based educational materials,presentations to health care proes-

sionals by medical science liaisons)or elements to ensure sae use.19 Medication guides are handoutsrequired by FDA or certain drugproducts that pose a serious and sig-nifcant public health concern.20 Theguides usually pertain to productsused on an outpatient basis and aregiven to patients unless the physiciandetermines that it is not in a particu-lar patient’s best interest because o signifcant concerns about the eecto the medication guide on the pa-tient. Medication guides are intendedto provide inormation needed or

Abarelix

Alosetron

Ambrisentan

Bosentan

Clozapine

Dofetilide

Eculizumab

Fentanyl PCAa

Isotretinoin

Lenalidomide

Mifepristone

Natalizumab

Smallpox (vaccinia) vaccine, live

Sodium oxybate

Thalidomide

Table 2.

Initial List of Drugs with

Approved Risk Evaluation and

Mitigation Strategies17

aPCA = patient-controlled analgesia.

7/27/2019 ajhp_12152009




the sae and eective use o drugproducts. They tend to be lengthy,which can contribute to inorma-tion overload or patients. Patients

with literacy limitations or or whomEnglish is not their primary languagemay have diiculty understand-ing medication guides. FDA has norequirements or creating medica-tion guides in languages other thanEnglish, although translations aremade by some institutions to accom-modate their non-English-speakingpatient populations.

The products chosen by FDA ormedication guide development are

those or which patient labeling couldhelp prevent serious adverse eects,products with serious risks (relativeto benefts) that patients should bemade aware o because inormationabout the risks could aect the deci-sion to start or continue to use theproduct, or products that are impor-tant to health and or which patientadherence is crucial to eectiveness.20 Medication guides contain inorma-tion approved by FDA and are parto the FDA-approved drug label-ing. Currently, 240 drug productshave medication guides. Medicationguides may be required or drugswith or without REMS.

The need or REMS is determinedby FDA at the time o drug approval,and REMS must be assessed at speci-fed intervals. FDA also is requiredto conduct regular, biweekly screen-ing o its Adverse Event ReportingSystem (AERS) database and post aquarterly report on the AERS web-

site o any new saety inormationor potential signal o a serious risk identifed by the AERS within thepast quarter.21

The FDAAA outlines elements toensure sae use o drugs with knownserious risks as part o REMS (e.g.,special training or certifcation orprescribing or dispensing, dispensingonly under certain circumstances,special monitoring, use o patientregistries). 19 The documentation

required by FDA or meeting these

requirements can be challenging orpharmacists and other health carepractitioners. Elements to ensure saeuse are currently required or only

our drugs (alvimopan, romiplostim,eltrombopag, and sacrosidase).18

Drugs with new REMS require-ments anticipated in 2009 includebotulinum toxin, because o prob-lems related to spread o the drugrom the area o injection to otherareas o the body, and metoclopr-amide, because o tardive dyskinesiaassociated with chronic use.22,23 REMS or erythropoiesis-stimulatingagents are also under consideration.24

Ealizumab, a psoriasis drug withREMS requirements, was voluntarily withdrawn rom the market in 2009because o progressive multiocalleukoencephalopathy.25

The penalties that FDA may im-pose on manuacturers or violationo REMS requirements can be sub-stantial, costing up to $250,000 perviolation and $1 million or all viola-tions adjudicated in a single proceed-ing.26 I a violation continues aterthe manuacturer receives writtennotice, a penalty o up to $10 millionmay be imposed or all violations ina single proceeding. In determiningthe amount o the penalty, FDA takesinto consideration whether the com-pany is making eorts to correct theviolation.

Organizational approach to REMS

requirements

At Cedars-Sinai Medical Center,the approach used to address the

REMS requirements and elements toensure sae use o new drugs is simi-lar to what was previously establishedor natalizumab when the drug wasreintroduced to the market, and ordoetilide. Initially, the pharmacy andtherapeutics committee and medica-tion saety committee were educatedabout the FDA requirements and ele-ments to ensure sae use, but the needto extend these eorts to includethe health-system administration,

risk management nursing leader-

ship, and medical sta was quickly recognized. The REMS requirementsand elements to ensure sae use wereintegrated into the ormulary evalua-

tion process.A task orce was established at

Cedars-Sinai Medical Center to de-velop an overall approach to evaluat-ing new drugs with saety concerns.Roles and responsibilities o variousmembers o the health care team oreducating patients and other healthcare providers about saety concernsand collecting saety data about thenew drug to meet REMS require-ments were identiied. Resources,

including medication inormation,procedures to ollow when a new order is received, and record-keepingrequirements or each medication,are provided on the hospital’s intra-net. For some medications, order setsare also created to ensure that REMSrequirements or elements to ensuresae use are ulflled. This approachwas used initially or natalizumab.

In order to comply with the REMSrequirements or romiplostim,27,28 which include elements to ensuresae use, the pharmacy and nurs-ing management are responsible orensuring the training o their respec-tive stas in sae use o the drug,orders or the drug are approved by the pharmacy director or a drug-usepolicy pharmacist, orders are flledater verifcation o patient and phy-sician enrollment in the manuac-turer’s REMS program, and patientsreceive the medication guide beorestarting treatment and again with

each dose. The prescriber responsibleor enrollment o inpatients mustensure that the drug will be avail-able as needed rom an outpatientprovider who is also enrolled in themanuacturer’s REMS program. Thisresponsibility is oten shared withthe pharmacy department to ensurecontinuity o drug therapy providedin the inpatient and outpatient set-tings. Other requirements o the pro-gram include maintenance o records

by the pharmacy, perormance o

7/27/2019 ajhp_12152009




complete blood counts and plateletcounts weekly until values are stableand monthly thereater, prompt re-porting o adverse drug events, and

completion o a saety survey every six months. There are a number o pharmacy record-keeping require-ments as well.29

Opioid analgesics

Concerns about misuse, abuse,and accidental overdosage o extended-release opioid analgesicshave led FDA to consider requir-ing REMS or this class o drugs.30 A public meeting was held in late

May 2009, and written commentswere solicited rom stakeholderswith a deadline or submission o June 30, 2009. A nal rule is yet to bepublished. The REMS will apply to24 products containing entanyl, hy-dromorphone, oxycodone, oxymor-phone, methadone, or morphine.Elements to ensure sae use are likely to be included. The large number o drug products and patients aected,need or extensive record keepingacross the continuum o care, andpotential or delays in providingpatient care are concerns associatedwith REMS or these products. In anotice published by FDA in the Fed-eral Register in April 2009 announc-ing the public meeting and solicitingwritten comments, the agency raisedquestions and sought input aboutthe type o education and meansor certiying prescribers to ensurethat they understand the risks o extended-release opioid products,

the proper selection o patients, andthe importance o patient counsel-ing about sae and proper use o theproducts.30 Education and certica-tion o pharmacists and other healthcare providers who dispense or ad-minister these products is another is-sue under evaluation by FDA. Theseproviders may be asked to veriy thatthe prescriber is properly certied.The type o education or patientsand the need or a signed prescriber–

patient agreement acknowledging

the patient’s receipt o inormationabout the risks and proper use o themedication are other actors underconsideration by FDA in making its

inal rule. The prescriber–patientagreement could be required at thetime o initiation o drug therapy and periodically thereater.

FDA also sought input aboutwhether and how controls might beestablished or distributors that pro-vide extended-release opioid analge-sics to pharmacies and other healthcare providers.30 The need to main-tain an ecient drug distributionprocess without placing an undue

burden on the health care system wasacknowledged by FDA in its notice.

Nonprescription analgesics

In late April 2009, FDA issueda inal rule requiring new organ-specic warnings and related labelingor nonprescription analgesic, anti-pyretic, and antirheumatic drugs.31 The warnings relate to severe livertoxicity rom acetaminophen andstomach bleeding rom nonsteroidalanti-infammatory drugs (NSAIDs).The nal rule takes eect on April29, 2010, and applies to combinationproducts containing acetaminophenor NSAIDs, as well as products con-taining these drugs as a single ingre-dient. Although aspirin has been theocus o much FDA concern, the new labeling requirements apply to allNSAIDs (e.g., ibuproen, ketoproen,naproxen).

Warnings will be required onthe labels o products containing

acetaminophen or NSAIDs advisingpatients who consume three or morealcoholic drinks a day to consulta doctor beore taking the drug orother pain relievers/ever reducers.31 These warnings must appear in con-

junction with warnings about liverdamage rom acetaminophen andstomach bleeding rom NSAIDs.

A new warning will be requiredadvising patients receiving wararinto ask their doctor beore taking

acetaminophen, because acetamino-

phen can increase the anticoagulanteect o wararin.31 Warnings will bestrengthened in the acetaminophenlabeling cautioning patients to avoid

exceeding the maximum recom-mended dose and to avoid concomi-tant use with other products con-taining acetaminophen. The labelingo some manuacturers’ productsalready complies with the new FDAlabeling requirements.

FDA was required to estimate thepotential benets o the nonprescrip-tion analgesic labeling changes.31 Anannual cost savings o $5.6 to $16.8million (in 2001 dollars) was project-

ed; this was based on an estimated1% to 3% annual reduction in ad-verse health events (e.g., poisoning,acute kidney ailure). The savingsprojection is derived rom reduc-tions in hospitalizations, emergency department visits, use o dialysis, anddeaths due to unintentional over-doses, using a value o $5 million orpremature loss o a statistical lie.

Some patient advocates concernedabout the saety o nonprescriptionanalgesics have speculated about thepotential beneits o reclassiyingthese drugs to “behind-the-counter”status, similar to the approach cur-rently used or pseudoephedrine,although the burden on pharmacistswould be a consideration. ASHPsupports the establishment o an in-termediate category o drug productsthat would not require a prescrip-tion but would be available rom apharmacist ater appropriate patientassessment and proessional consul-

tation.32 This intermediate class hasbeen contemplated or certain drugscurrently available only by prescrip-tion that could be used saely withappropriate pharmacist oversight.This oversight might improve the saeuse o acetaminophen and NSAIDswithout compromising patient accessto or benet rom the drugs.

Patient perspective

Patients receive inormation about

medications rom a wide variety o

7/27/2019 ajhp_12152009




sources, including health care proes-sionals, direct-to-consumer adver-tisements, medication guides, patientpackage inserts, product websites,

and other sources o drug-relatedinormation on the Internet.33 Themessages rom these sources may becomplex and inconsistent, causingconusion. Thus, saety inormationcould needlessly deter the use o po-tentially benecial drug therapies.

Drugs or which REMS are es-tablished may present unique chal-lenges or patients because o thepotentially overwhelming inorma-tion they are required to receive. A

coordinated eort by pharmacistsand other health care proessionalsis needed to communicate eec-tively with patients about drugs withREMS requirements.

Health-system perspective

The potential burden on pharma-cists and health systems o FDA drugsaety requirements is considerable,especially i, or example, REMS re-quirements were imposed or eacho the 430 drugs and drug salts withblack box requirements. FDA is cog-nizant o the need to balance the o-ten competing goals o ensuring drugsaety and providing patient access topotentially harmul drugs withoutimposing an undue burden on thehealth system. Restricted drug distri-bution programs oten increase thecomplexity o the drug procurementprocess, cause delays in treatment,and create paperwork and logisticalburdens or health care providers.

To minimize this burden, ASHPadvocates a standardized approachto REMS as part o established drugprocurement systems.34

Pharmacists and other health careproviders have an opportunity to de-vise a one-stop-shopping approachor drugs with REMS requirementsby creating a standard ramework and sharing it with their colleagues.This approach could address patientselection based on established saety

criteria, patient education, and re-

quired record keeping. Although thesaety criteria might vary dependingon the drug, a standard ramework would be helpul. A database might

be created and posted on the Internetto acilitate sharing o REMS inor-mation among institutions. Collab-orative eorts could help reduce theworkload involved in meeting REMSrequirements both or health systemsand or the pharmaceutical industry.Collaboration also could enable thecompilation o saety data or popu-lation analyses in order to determinethe presence and prevalence o ad-verse events associated with specic

medications.The role o group purchasingorganizations, wholesalers, andspecialty pharmacies in REMS stan-dardization remains to be claried.Currently, specialty pharmaciesmanage many drugs with REMSrequirements.

Pharmacists have a responsibility to educate members o the phar-macy and therapeutics, medicationsaety, and other medication-relatedcommittees and the pharmacy,medical, and nursing stas aboutFDA REMS requirements. A cen-tralized pharmacy resource (i.e.,sta and inrastructure) should beestablished to coordinate REMS.This resource might be modeled a-ter the investigational drug servicesprovided by pharmacy departments,since many o the requirements aresimilar. Risk management person-nel should be involved in evaluationo REMS as part o the ormulary

evaluation process.The optimal approach to meeting

FDA requirements or REMS re-mains to be determined. Establish-ing a dialogue among stakeholdersthroughout the supply chain (rommanuacturer to provider) is therst step in creating partnershipsto minimize the burden o theserequirements. Patients should alsobe included in these partnershipsto ensure that their perspectives are

taken into consideration.

Conclusion

Recent increases in FDA drugsaety activities refect a greater com-mitment o the agency to postmar-

keting surveillance o drug saety than in the past. Eorts have beenmade by FDA to balance the need orimproved drug saety with the needto provide patient access to drugproducts and avoid placing an undueburden on the health system. Col-laboration among pharmacists andother health care providers is neededto minimize the burden o FDA drugsaety requirements while improvingpatient saety.

References

1. Institute o Medicine. The uture o drug saety: promoting and protect-ing the health o the public. Septem-ber 22, 2006. http://www.iom.edu/CMS/3793/26341/37329.aspx (accessed2009 Jun 18).

2. Agency or Healthcare Research andQuality and U.S. Food and Drug Ad-ministration. Implementation o risk minimization action plans (RiskMAPs)to support quality use o pharmaceuti-cals: opportunities and challenges; publicworkshop. http://www.da.gov/OHRMS/DOCKETS/98r/07-2574.pd (accessed2009 Jun 11).

3. 110th U.S. Congress. Food and DrugAdministration Amendments Act o 2007. http://rwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=:publ085.110(accessed 2009 Jun 11).

4. McEvoy GK, ed. Clozapine. In: AHFSDrug Information 2009. Bethesda, MD:American Society o Health-SystemPharmacists; 2009:2464-77.

5. U.S. Food and Drug Administration.Guidance or industry: development anduse o risk minimization action plans.March 2005. http://www.da.gov/ohrms/dockets/ac/05/brieng/2005-4136b1_03_Risk%20Minimization%20Action%20

Plans.pd (accessed 2009 Jun 11).6. Thalidomid package insert. Summit, NJ:

Celgene Corporation; 2007 Feb.7. Accutane package insert. Nutley, NJ:

Roche Laboratories Inc; 2008 Nov.8. Tikosyn package insert. New York, NY:

Pzer Labs; 2004 Mar.9. McEvoy GK, ed. Natalizumab. In: AHFS

Drug Information 2009. Bethesda, MD:American Society o Health-SystemPharmacists; 2009:3704-9.

10. Tysabri package insert. South San Fran-cisco, CA: Elan Pharmaceuticals Inc; 2008Oct.

11. U.S. Food and Drug Administration.The Sentinel Initiative: a national strat-

egy or monitoring medical product

7/27/2019 ajhp_12152009




saety. http://www.da.gov/Saety/FDAsSentinelInitiative/ucm089474.htm(accessed 2009 Jun 11).

12. Formulary Productions. Drugs withblack box warnings—comprehensivelist. http://www.ormularyproductions.c o m / m a s te r / sh o w p a g e . p h p ? d i r =blackbox&whichpage=9 (accessed 2009Jun 11).

13. U.S. Food and Drug Administration.Risk evaluation and mitigation strategy (REMS) under review or CellCept andMyortic. http://www.da.gov/Drugs/DrugSaety/PostmarketDrugSaety InormationorPatientsandProviders/ucm148735.htm (accessed 2009 Jun 11).

14. U.S. Food and Drug Administration.Antiepileptic drugs. http://www.da.gov/Saety/MedWatch/SaetyInormation/SaetyAlertsorHumanMedicalProducts/ucm074939.htm (accessed 2009 Jun 11).


Testosterone gel products (AndroGel 1%and Testim 1%). http://www.da.gov/Saety/MedWatch/SaetyInormation/SaetyAlertsorHumanMedicalProducts/ucm149346.htm (accessed 2009 Jun 11).

16. U.S. Food and Drug Administration.Tarceva (erlotinib) May 2009. http://www.da.gov/Saety/MedWatch/Saety Inormation/SaetyAlertsorHumanMedicalProducts/ucm150596.htm(accessed 2009 Jun 11).

17. U.S. Food and Drug Administration.Identiication o drug and biologicalproducts deemed to have risk evalua-tion and mitigation strategies or pur-poses o the Food and Drug Administra-

tion Amendments Act o 2007. http://www.da.gov/OHRMS/DOCKETS/98r/E8-6201.pd (accessed 2009 Jun 11).

18. U.S. Food and Drug Administration. Ap-proved risk evaluation and mitigation strat-egies (REMS). http://www.da.gov/Drugs/DrugSaety/PostmarketDrugSaety InormationorPatientsandProviders/ucm111350.htm (accessed 2009 July 5).

19. U.S. Food and Drug Administration.Sec. 505-1. [21 USC §355-1] Risk evalu-ation and mitigation strategies. http://

www.da.gov/RegulatoryInormation/Legi s la t ion/Federa lFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/ucm109090.htm(accessed 2009 Jun 11).

20. U.S. Food and Drug Administration.Medication guides or prescription drugproducts. http://www.accessdata.da.gov/scripts/cdrh/cdocs/cCFR/CFRSearch.cm?CFRPart=208&showFR=1 (accessed2009 Jun 18).

21. U.S. Food and Drug Administration.Potential signals o serious risks/new saety inormation identifed rom theAdverse Event Reporting System (AERS).http://www.da.gov/Drugs/GuidanceComplianceRegulatoryInormation/Survei l lance/AdverseDrugEects/UCM082196 (accessed 2009 Jun 11).

22. U.S. Food and Drug Administration. FDArequires boxed warning or all botulinumtoxin products. April 30, 2009. http://

www.da.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149574.htm(accessed 2009 Jun 11).

23. U.S. Food and Drug Administration.FDA requires boxed warning and risk mitigation strategy or metoclopramide-containing drugs: agency warns againstchronic use o these products to treatgastrointestinal disorders. February 26,2009. http://www.da.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149533.htm (accessed 2009 Jun 11).

24. U.S. Food and Drug Administration.Questions and answers on medicationguides or erythropoiesis-stimulatingagents (ESAs). http://www.da.gov/

Drugs/DrugSaety/PostmarketDrugSae ty InormationorPat i entsandProviders/ucm109380.htm (accessed2009 Jun 19).

25. U.S. Food and Drug Administration.FDA statement on the voluntary with-drawal o Raptiva rom the U.S. mar-ket. April 8, 2009. http://www.da.gov/N e w s E v e n t s / N e w s r o o m / P r e s sAnnouncements/ucm149561 .htm(accessed 2009 Jun 11).


Questions and answers on the FederalRegister notice on drugs and biologicalproducts deemed to have risk evalua-tion and mitigation strategies. http://www.da.gov/RegulatoryInormation/Legi s la t ion/Federa lFoodDrugandC o sm e t i c A c tF D C A c t / S i g n i i c a n tAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActo2007/ucm095439.htm (accessed2009 Jun 11).

27. Nplate package insert. Thousand Oaks,CA: Amgen Inc; 2008 Aug.

28. Perreault S, Burzynski J. Romiplostim: anovel thrombopoiesis-stimulating agent. Am J Health-Syst Pharm. 2009; 66:817-24.

29. Ordering Nplate. Answering your ques-tions about the Nplate (romiplostim)NEXUS program. http://www.nplatenexus.com/ordering.html (accessed 2009Jun 18).

30. U.S. Food and Drug Administration. Risk

evaluation and mitigation strategies orcertain opioid drugs; notice o publichearing. April 20, 2009. http://www.da.gov/OHRMS/DOCKETS/98r/E9-8992.pd (accessed 2009 Jun 11).

31. U.S. Food and Drug Administration.Organ-specifc warnings; internal analge-sic, antipyretic, and antirheumatic drugproducts or over-the-counter humanuse; fnal monograph. April 29, 2009.http://edocket.access.gpo.gov/2009/pd/E9-9684.pd (accessed 2009 Jun 11).

32. American Society o Health-SystemPharmacists. ASHP statement on criteriaor an intermediate category o drugproducts. Am J Health-Syst Pharm. 2009;

66:502-5.33. Aker JL. Consumer comprehension &outcomes research: risk communicationadvisory committee. May 1, 2009. http://www.da.gov/ohrms/dockets/ac/09/slides/2009-4421s2-02.pd (accessed 2009Jun 11).

34. Anon. House passes user ee and drugsaety legislation. July 12, 2007. http://www.ashp.org/import/news/NewsCapsules/article.aspx?id=86 (accessed2009 Jun 11).

7/27/2019 ajhp_12152009



SYMPOSIUM Financial and safety considerations

Specialty pharmacies and other restricted drugdistribution systems: Financial

and safety considerations for patientsand health-system pharmacists

Bonnie e. KirschenBaum

Purpose. To discuss the role o restricted

drug distribution systems in the imple-

mentation o risk evaluation and mitigation

strategies (REMS), health-system pharma-

cists’ concerns associated with the use o

specialty pharmacies and other restricted

drug distribution systems, reimbursement

policies or high-cost specialty drugs,

supply chain models or traditional and

specialty drugs, and emerging trends in the

management o and reimbursement or

specialty pharmaceuticals.

Summary. Restricted drug distribution sys-

tems established by pharmaceutical manu-acturers, specialty pharmacies, or other

specialty suppliers may be a component o

REMS, which are required by the Food and

Drug Administration or the management

o known or potential serious risks rom

certain drugs. Concerns o health-system

pharmacists using specialty suppliers

include access to pharmaceuticals, opera-

tional challenges, product integrity, nan-

cial implications, continuity o care, and

patient saety. An ambulatory care patient

Bonnie e. KirschenBaum, m.s., FashP, FcshP, is Healthcare Con-sultant and Columnist, Breckenridge, CO.

Address correspondence to Ms. Kirschenbaum at P.O. Box 8322,Breckenridge, CO 80424 ([email protected]).

Based on the proceedings o a symposium held June 15, 2009, dur-ing the ASHP 2009 Summer Meeting and Exhibition in Rosemont,IL, and supported by an educational donation provided by Amgen.The content o this supplement was written by Susan R. Dombrowski,M.S., rom transcripts o the live educational activity and was re-

viewed and approved by the authors. Ms. Kirschenbaum receivedan honorarium or her participation in the symposium and or thepreparation o this article. Ms. Kirschenbaum reports that she has noaliation with or nancial interest in a commercial organization thatposes a confict o interest with this article.


DOI 10.2146/ajhp090462

taking a specialty drug product rom home

to a hospital outpatient clinic or inpatient

setting or administration, a practice

known as “brown bagging,” raises concerns

about product integrity and institutional

liability. An institution’s nances, tolerance

or liability, and ability to skillully manage

the processes involved oten determine its

choice between an approach that prohibits

brown bagging but is costly and one that

permits the practice under certain condi-

tions and is less costly. The recent shit

rom a traditional supply chain model to

a specialty pharmacy supply chain modelor high-cost pharmaceuticals has the

potential to increase pharmaceutical costs

or health systems. A dialogue is needed

between health-system pharmacists and

group purchasing organizations to address

the latter’s role in mitigating the nancial

implications o this change and to help

clariy the saety issues. Some health plans

have shited part o the cost o expensive

drugs to patients by establishing a ourth

tier o drugs with a large copayment based

on a substantial percentage o the cost o

the drug. The number and cost o specialty

drugs are expected to increase in the u-

ture. New approaches and reimbursement

models are emerging to manage the high

cost o new pharmaceuticals.

Conclusion. Health-system pharmacists

can improve drug saety and manage costs

by collaborating with group purchasing or-

ganizations, establishing policies or brown

bagging, and making eforts to reconcile

drug therapy provided in diferent settings

through traditional drug channels and spe-

cialty pharmacies or other restricted drugdistribution systems.

Index terms: Costs; Drug distribution

systems; Economics; Food and Drug

Administration (U.S.); Health-benet pro-

grams; Pharmacists, hospital; Pharmacy;

Pharmacy, institutional, hospital; Regula-

tions; Reimbursement; Risk management;

Specialties; Toxicity


7):S13-20

The Food and Drug Administra-tion (FDA) requires risk evalu-ation and mitigation strategies

(REMS) or managing known or

potential serious risks rom certaindrugs.1,2 These REMS are approachesestablished by FDA or working withpharmaceutical manuacturers to re-

duce risk rom the use o a particularproduct. Although REMS vary basedon the drug product, they have a com-mon ramework and components.

7/27/2019 ajhp_12152009




The number o drugs with REMSrequirements is increasing, reect-ing an increasing commitment o FDA to postmarketing surveillance.

Restricted drug distribution systemsmay be a component o REMS, al-though REMS requirements do notnecessarily include restricted drugdistribution systems. The scope o restricted drug distribution systemsextends beyond ulfllment o REMSrequirements. Restricted drug distri-bution systems are entrepreneurialor business approaches to workingwith manuacturers, third-party payers, or pharmaceutical distribu-

tors. Restricted drug distributionsystems may be established by themanuacturer, specialty pharmacies,wholesale distributors, or other spe-cialty suppliers, including businessesseeking to provide services related tothe distribution and administrationo drugs with known serious risksthat would otherwise be unavailableor those that are not commercially available and require sterile com-pounding. Restricted drug distribu-tion systems provide an avenue ormanuacturers to implement REMSor medications that require ele-ments to ensure sae use.

Issues and concerns

In 2008, a task orce was con-vened by the American Society o Health-System Pharmacists (ASHP)to identiy key issues associated with

Evaluate health care market trends and evolving business models or managing

chronic diseases

Consider size and complexity o hospitals and health systems and identiy how patient

medication needs are addressed in various settings (e.g., inpatient, outpatient,

community, home care, long-term care)

Identiy evolving issues regarding continuity o care that result rom increased use o

these models and the devices used to administer many o these medications

Identiy challenges with policies and procedures, education, and communication and

their impact on patient care and saety

Table 1.

Considerations for Pharmacists Arranging Specialty Drug Deliveryto Patients through Restricted Drug Distribution Systemsa

aAs identifed by the ASHP Task Force on Caring or Patients Served by Specialty Suppliers.

Access considerations

Time management

Education

Rules and regulations relating to

product integrity

Continuity o care

Financial impact

Patient saety

Health care provider relationships

and evidence-based practice

Table 2.

Concerns of Patients, HealthCare Providers, and HealthFacilities Interacting with

Specialty Pharmacies or Other

Restricted Drug DistributionSystemsa

aAs identifed by the ASHP Task Force on Caring orPatients Served by Specialty Suppliers.

specialty drug delivery to patientsthrough restricted drug distributionsystems (Table 1). The task orcealso identifed “domains o concern”

reecting problems aced by patients,health care providers, and healthacilities interacting with specialty pharmacies or other restricted drugdistribution systems (Table 2). Con-cerns about access to the drug prod-uct arise or both the patient and thepharmacy that needs to supply thedrug to the patient. A major consid-eration or members o the task orceis the labor involved in understand-ing and implementing the individual

requirements o each specialty phar-macy and the investment o time by purchasing, pharmacy, and nursingsta. Educating nurses and otherhealth care providers about require-ments or obtaining and handlingthe drug also is a concern. Productsthat are administered by portable orimplantable inusion devices poseurther concerns and educationalneeds. Many problems related to pa-tient access can be traced to a lack o sufcient education and knowledgeabout the operations o specialty pharmacies or other restricted drugdistribution systems and about theuse o portable or implantable inu-sion devices.

Most products supplied throughspecialty pharmacies and other re-stricted drug distribution systemsinitially are used in ambulatory

care. Rules and regulations relat-ing to product integrity come intoplay when a patient initiates drugtherapy on an outpatient or ambu-

latory care basis and then requireshospitalization and continuation o drug therapy either in the inpatientsetting or in an outpatient clinic us-ing a drug product obtained outsidethe institution (a practice knownas “brown bagging”). Table 3 sum-marizes problems that may arise.Continuity o care is a considerationin providing drug therapy when pa-tients make the transition rom onesetting to another. Fragmentation o

care provided in multiple settingscan lead to errors and compromisepatient outcomes.

Drug products supplied throughspecialty pharmacies and otherrestricted distribution systems areamong the costliest available, with alarge impact on the pharmacy bud-get. The task orce considered thefnancial impact o specialty pharma-cies and the need to ensure patientsaety to be vital issues. Relationshipsamong health care providers in di-erent practice settings and the useo evidence-based practice also wereconcerns or members o the task orce. A report rom the task orce,

7/27/2019 ajhp_12152009




with recommended approaches oraddressing these concerns and solv-ing problems, will be published in the

American Journal of Health-SystemPharmacy .

Organizational issues

A culture o saety is essential orsupporting the smooth integrationo REMS into a health system. Fulfll-ing REMS requirements will presenta challenge i administrators merely pay lip service to the need to ensuresaety.

The ASHP Section o Pharmacy Inormatics and Technology recently conducted a survey o the use o in-ormatics and technology or variouspurposes in health systems, including

ulfllment o REMS requirements.The survey was designed to ascertainthe extent to which the pharmacy orhospital inormation system is be-ing used to simpliy the handling o products with REMS requirements.Ideally, the inormation system al-lows the tracking o patients receiv-ing drugs with REMS requirementsand suppliers o these drugs and pro-vides inormation about REMS re-quirements and policies or ulflling

them by including these data in the

Table 3.

When Specialty Products and Oferings Become an Issue

Patient Situation Potential Problems

Lives at home, usesmedications at home

Seen at outpatient clinic, uses

medications at home

Seen at outpatient clinic,

medications administered

in clinic

Admitted as inpatient,

medications needed during

stay

No issues

No issues

Hospital policy; may or may not need additional

contracts or registration to obtain drug;

product integrity concern i medication

is sent to patient; waste management or

unused patient-specifc medications; ability

to charge or services provided

Hospital policy; may or may not need additional

contracts or registration to obtain drug;

product integrity concern i medication

is sent to patient; waste management orunused patient-specifc medications; ability

to charge or services provided

drug master profle or each productwith REMS requirements. The survey results suggest that more widespreaduse o inormatics and technology to ulfll REMS requirements couldhelp simpliy the complex processinvolved. For example, incorporationo REMS requirements into the drugdatabases commonly used in phar-macy inormation systems (e.g., FirstDataBank, Medi-Span), with linksto pharmaceutical manuacturerwebsites or reporting drug saety inormation, would acilitate greateruse o inormatics and technology inulflling REMS requirements.

Specialty pharmacies and

suppliers

Health-system pharmacists otenneed to establish a working relation-ship with a specialty pharmacy orspecialty distributor (e.g., whole-saler) to gain access to certain drugproducts with unique acquisitionrequirements and purchasing ar-rangements. These drug productsare distributed through special-ized channels outside traditionaldrug distribution mechanisms andinclude drugs with REMS require-

ments, drug products carved out

rom traditional distribution chan-nels by manuacturers or wholesalersor various reasons, and ourth-tierdrugs carved out by an insurer or

payer with specifc acquisition re-quirements or the patient to obtaincoverage. The use o drug productsprovided by specialty pharmaciesaects many aspects o patient careand presents logistical and fnancialchallenges to the health care acil-ity. Specialty pharmacies are usually under contract with third-party pay-ers to provide a limited number o high-cost pharmaceutical products(e.g., injectable biological therapies,

oral chemotherapy agents).

3

Health-system pharmacists oten strugglewith issues related to patient saety, in-stitutional liability, and reimbursementor these products. Specialty pharmacy has been characterized in a variety o ways. According to one descrip-tion, specialty pharmacy involves thehandling o biotechnology- or gene-based drug therapies that have oneor more o the characteristics listedin Table 4.4 Several drug productssupplied by specialty pharmaciesare sel-administered at home by inusion using implantable or ex-ternal pumps ater extensive patienteducation about the proper use o both the medication and the inu-sion device.

Specialty pharmacies are highly eective in marketing their servicesto payers. They claim to have greaterknowledge o new clinical develop-ments involving biotechnology andinjectable products that aect payers’

approaches to coverage and reim-bursement than do health-systempractitioners or ambulatory carepharmacies that oversee traditionaldrug distribution systems. Spe-cialty pharmacies also claim to havegreater expertise in managing certainproducts, disease states, and patientpopulations through utilizationmanagement protocols or inject-able products than do practitionersin traditional drug distribution sys-

tems. These utilization management

7/27/2019 ajhp_12152009




protocols ensure patients’ adherenceto therapy in the home care setting.

The protocols could be expandedto address REMS requirements orcollection o saety data. Specialty pharmacies typically handle drugproducts with short shel lives andspecial storage requirements (usually rerigeration). Specialty pharmaciesalso claim to have a better under-standing o Centers or Medicare &Medicaid Services (CMS) reimburse-ment policies and rates and how thepolicies and rates inuence commer-cial payers than do pharmacists whomanage traditional drug distributionsystems. Simplifed and standardizedbilling, coordinated networks orhome drug delivery and inusion ser-vices, and complete data capture ca-pabilities that acilitate comprehen-sive outcomes reporting and analysis(an attractive eature that helps ulfllREMS requirements) are among thepossible services oered by specialty pharmacies.5

As the number o drug prod-

ucts with REMS requirements hasincreased, wholesale distributorsworking with pharmaceutical man-uacturers have reorganized andpositioned themselves to unctionas specialty suppliers or these prod-ucts outside traditional distributionchannels.6 Multiple new creativedistribution channels or costly drugproducts have been established, andhealth-system pharmacists need tocareully consider and integrate these

channels and carved-out products

into their overall purchasing prac-tices and strategies.

Group purchasing organizationscan play a major role in coordinatingspecialty pharmacy and traditionaldrug purchasing contracts and dis-tribution channels. Purchasing abiotechnology product through aspecialty pharmacy on a cost-plus-markup basis is substantially moreexpensive than purchasing the prod-uct rom a traditional wholesalerat a discounted contract price (i.e.,cost-minus basis), and this dierencehas important fnancial implicationsor health systems that should notbe ignored. Carving out the priciestdrug products rom the drug spend-ing pool at the wholesaler level has anegative impact on the contract ratesoered and prepayment status orhealth systems.

Access to specialty pharmaceu-ticals and specialty distributors canbe complex and time consuming orpatients, health-system pharmacists,and other proessionals in health sys-

tems. Patient saety, drug cost, drugproduct integrity, and continuity o care must be taken into considerationin a challenging environment charac-terized by conict related to regula-tory requirements, the high cost o pharmaceuticals, and the fnancialinterests o third-party payers.

Not all drugs with REMS require-ments need to be obtained throughspecialty pharmacies or restricteddrug distribution systems, and not

all drugs handled by these enti-

ties have REMS requirements. Forexample, natalizumab is availablethrough a restricted drug distribu-tion program that requires drug

administration by authorized inu-sion centers, but it does not haveREMS requirements. Clozapine hasREMS requirements, but it is notsupplied by specialty pharmacies.Inliximab, a drug administeredby intravenous (i.v.) inusion andassociated with serious inectiouscomplications (including atalities),is available through specialty phar-macies, but it has neither a restricteddrug distribution system nor REMS

requirements. Epoprostenol, a drugwithout REMS requirements, ishandled only by certain distributorsand administered i.v. or the treat-ment o pulmonary hypertension.3 FDA required drug saety labelingchanges or epoprostenol in 2008because o an increased risk orhemorrhagic complications due tothe drug’s potent inhibition o plate-let aggregation.7 Understandably,the average health-system practi-tioner can be conused when itcomes to knowing which rules andsystems apply to which products.

Pharmaceutical reimbursement

The Medicare program as admin-istered by CMS has three parts (A,B, and D).8 Part A includes hospitalinpatient and outpatient services,nursing home care, home health care,and hospice care. Reimbursement orcovered medications, including someoral cancer chemotherapies, admin-

istered pursuant to a physician’s carealls into Part B, as do physician ser-vices, medical supplies (e.g., durablemedical equipment), and end-stagerenal disease services (Table 5).9 Hos-pital outpatient services are admin-istered through Part A and the Out-patient Prospective Payment System(OPPS). The Medicare prescriptiondrug program alls into Part D andcovers outpatient prescription drugs.

Reimbursable specialty drugs and

biological products alling under Part

Use or treatment o chronic or rare diseases

Annual cost exceeding $5000Administration by a route other than oral

Product delivery to patients via mail or at home, possibly requiring special handling

(e.g., rerigeration)

Administration outside a hospital setting (e.g., physician’s oce, specialty clinic, or

patient’s home)

Management outside the traditional outpatient prescription drug beneft

Requirement or complex care, patient education, and continuous monitoring

Table 4.

Characteristics of Therapies Handled by Specialty Pharmacy4

7/27/2019 ajhp_12152009




B are reimbursed by CMS throughOPPS in one o our ways. In 2009,the basis or reimbursement or new drugs or which a Healthcare Com-mon Procedure Coding System codehas not yet been assigned is 95% o the average wholesale price.10 Pass-through payments may be availableor new drugs and biologicals, andthe basis or these payments is the av-erage sales price (ASP) plus 6% (i.e.,106% o the ASP) or the wholesaleacquisition cost (WAC) plus 6% (i.e.,106% o the WAC) until enough ASPdata are available.

In 2009, when the daily costs o specied covered outpatient drugsexceed the threshold o $60, ASPplus 4% (i.e., 104% o the ASP) isthe basis or reimbursement whenthe products are administered in thehospital outpatient setting.10 I daily drug costs all below $60, the costsusually are packaged (i.e., bundled)

into the payment or an ambulatory payment classication (a diagnosticclassication analogous to an out-patient diagnosis-related group).The costs or “packaged products”are not reimbursed separately withthe exception o antiemetic agents,which are reimbursed separately regardless o daily cost.

The Medicare Part D benet cov-ers only drugs that are classied asD drugs. Generally, Part D drugs in-

clude outpatient prescription drugs

(i.e., drugs prescribed and dispensedor sel-administration by the pa-tient). They also include biologicalproducts, insulin, medical suppliesassociated with the injection o in-sulin (e.g., syringes, needles, alcoholswabs, sterile gauze), and certainvaccines not covered under Part A orB. Pneumococcal and infuenza vac-cines are covered by Part B. HepatitisB vaccine is covered under Part B orindividuals at high or intermediaterisk; or all other individuals, it couldbe covered under Part D. All othercurrently available vaccines and u-ture vaccines would be covered underPart D, but coverage could be subjectto plan prior-authorization require-ments or demonstrating medicalnecessity.

A new ourth tier o drugs hasbeen added to prescription drugplans by some third-party payers andinsurers in response to pressure rom

employers to reduce health care costs.Patients participating in these plansare required to pay 20–30% o thecost o certain high-cost drug thera-pies used to treat certain illnesses(e.g., cancer, rheumatoid arthritis,multiple sclerosis) instead o thefat copayments required or mostdrugs.11 This approach shits someo the cost o the most expensivedrugs to patients. Some o these drugtherapies cost as much as $15,000 per

month, and the out-o-pocket cost o

copayments or patients is substan-tial, although many plans have a cap(i.e., maximum).

Supply chain modelsIn recent years, the approach

used or supply o certain high-costpharmaceutical products has shitedrom a traditional model to a spe-cialty pharmacy model. The patient’ssource o prescription drug prod-ucts and the roles o the hospital orhealth-system pharmacy and grouppurchasing organizations dier be-tween a traditional and a specialty pharmacy supply chain model (Table

6). In a traditional model, patientsobtain prescription drugs rom anoutpatient, retail, or mail order phar-macy. Hospital and other health-system pharmacies purchase drugproducts usually at a contract pricerom a traditional wholesaler on avolume, cost-minus basis. The grouppurchasing organization negotiatescontract pricing or products andwholesaler agreements, and rebatesusually apply.

By contrast, in the specialty pharmacy model, patients obtainprescription drugs rom mail orderor specialty pharmacies, with thepayer oten dictating a single sourceor each product. Drugs with REMSrequirements are supplied by spe-cialty pharmacies. Compoundeddrugs may be obtained rom spe-cialty pharmacies or a physician(e.g., an anesthesiologist who sup-plies opioid analgesics or epiduraladministration using an implant-

able pump). I a hospital or health-system pharmacy is involved in pro-viding drug therapy to the patient,drug products usually are purchasedrom specialty suppliers on a cost-plus-markup basis without thebenet o contract prices, volumediscounts, or rebates.

The shit rom a traditional toa specialty pharmacy supply chainmodel has the potential to increasecosts or health systems. Health-

system pharmacists should establish

Injectables urnished incidental to a physician’s service and usually not sel-

administeredDrugs administered via nebulizer or pump urnished by Medicare

Immunosuppressive drugs or organ transplantation

Hemophilia blood-clotting actors

Certain oral anticancer treatments

Oral antiemetics

Pneumococcal, infuenza, and hepatitis B vaccines

Erythropoietin-like drugs or trained home dialysis patients

Iron dextran, vitamin D injections, and erythropoietin-like drugs administered by

acilities specializing in the care o patients with end-stage renal disease

Osteoporosis drugs

Table 5.

Drug Products Covered under Medicare Part B9

7/27/2019 ajhp_12152009




a dialogue with group purchasingorganizations about the fnancial im-plications o the changes associatedwith this paradigm shit.

Challenges

Specialty drug products usu-ally are not an issue or health-systempharmacists when the patient re-ceives the drug at home, even i thepatient visits a physician at a hospitaloutpatient clinic. However, a hospitalpolicy or managing specialty drugproducts is needed or patients whohope to bring products obtainedrom specialty pharmacies or ad-ministration during visits to thehospital outpatient clinic or duringan inpatient stay (Table 3).

Health-system pharmacists may use one o two approaches to brownbagging o drugs with REMS re-

quirements and other specialty drugproducts when the drug has beendispensed to an outpatient who seeksto have the product administered ata hospital outpatient clinic or as aninpatient. In a “pharmacy-centric”approach, policies and proceduresprohibit brown bagging becauseo concerns about product integ-rity and institutional liability. Thehospital dispenses the drug, even i it has already been dispensed by a

specialty pharmacy on an outpatient

basis and paid or by the insurancecarrier. The hospital bears the costo the drug, because reimbursementrom third-party payers is not avail-able or the same product a secondtime. To recoup this cost, patients arecharged by the hospital or acquiring,dispensing, and administering theproduct. Providing these drug thera-pies without capturing these chargesis not an option or the hospital usingthis approach.

In the past, when the number o specialty drug products and the vol-ume o patients receiving these drugswere small and the cost o drugs wasnot as high, this pharmacy-centricapproach had minimal fnancial im-pact on hospitals and health systems.However, because most specialty drug products now are very costly and larger numbers o patients are

receiving them, this approach placesa large burden on the hospital and inturn on the patient.

A “patient-centric” approach may be used to reduce the impact o specialty drug products on patientsand hospitals. In such an approach,brown bagging is permitted in certaincircumstances under strict protocol.In one approach, specialty drugs arebrought to the hospital by the patient(i.e., they are not dispensed by the

hospital), and the cost o the drug is

Table 6.

Comparison of Traditional and Specialty Pharmacy Supply Chain Models

Variable Traditional Model

aREMS = risk evaluation and mitigation strategies.

Specialty Pharmacy Model

Patient source of prescriptiondrug products

Role of hospital or health-system

pharmacy

Role of group purchasing

organization

Outpatient, retail, or mail order pharmacy

Purchases drug products (many at

a contract price) from traditional

wholesalers on volume, cost-minus

basis

Negotiates contract pricing for products

and wholesaler agreements, and

rebates usually apply

Mail order or specialty pharmacy as dictatedby payer (specialty pharmacy for drugs

with REMSa requirements, and specialty

pharmacy or physician for compounded

products)

Purchases drug products (few to none at a

contract price) from specialty suppliers on

cost-plus-markup basis

Few or no contract relationships, rebates

unlikely

borne by the specialty pharmacy. Inanother, the arrangements are madeor delivery o the specialty productdirectly to the hospital pharmacy,bypassing concerns about productintegrity and storage conditions. Ineither case, the only hospital chargeis or administration o the drug(i.e., there is no hospital charge oracquiring or dispensing the drug).The choice between a pharmacy-centric and patient-centric approachto brown bagging oten hinges on theinstitution’s fnances, tolerance orliability, and creativity in managingthis new paradigm.

Hospitals and health systems(e.g., medical centers with multipleseparate acilities) may contemplateestablishing their own specialty pharmacy because o the high costo using outside specialty pharma-

cies. Key considerations in makingthis decision include whether theinstitution is eligible to participate inederal 340B drug discount plans andwhether it has an outpatient depart-ment eligible to participate as a Medi-care Part D sponsor and provider o medication therapy managementservices. A sufciently large patientpopulation is required or the busi-ness venture to be proftable. Servicesmight be marketed to health systems

in the local geographic area to ensure

7/27/2019 ajhp_12152009




the fscal viability o the venture. I the decision is made not to establishan in-house specialty pharmacy, thehealth system will need to determine

whether to use a pharmacy-centric orpatient-centric approach and makeprovisions or some degree o brownbagging.

Recent innovations in technol-ogy and therapeutics have increasedthe numbers o patients who sel-administer sterile compoundedsolutions by i.v. inusion usingimplantable or external pumps orthe treatment o cancer, intractablepain, or chronic illnesses (e.g., pul-

monary hypertension) in the homecare setting. These patients and theircaregivers have learned to use sophis-ticated drug administration devicesand to assume considerable sel-careresponsibility, similar to the increasein patient responsibility or the man-agement o diabetes mellitus that hastaken place over the years. This sel-care capability helps patients remainat home, where their quality o lie isbetter than it would be in a hospital.A wide variety o administration de-vices are available; in some cases, thelanguage in the FDA-approved pack-age insert speciies which speciicinusion device must be used. Thisposes a potential challenge to nursingand pharmacy sta who may be lessamiliar with a particular adminis-tration device than are the patientand the patient’s caregivers.

Some sterile products are com-mercially available, but others mustbe supplied by a compounding phar-

macy (i.e., specialty pharmacy). Theexpiration dates established or ster-ile solutions compounded at someo these pharmacies extend beyondthose that are customary and accept-ed in hospital-based compoundingpractices based on published stability data and USP Chapter 797. In somecases, the evidence supporting the ex-piration dates, credentials and accred-itation status o the compoundingpharmacy, saety o compounding

practices, and integrity and labeling

o compounded products may bequestionable.

Hospitalization o a patient whohas been sel-administering sterile

compounded solutions at home canbe a challenge or health care provid-ers, especially when the patient orcaregivers do not understand why the patient’s own solutions cannotbe used. Hospital policies and proce-dures oten prevent the patient rombringing such solutions rom home,although provisions have not beenmade or therapies that are availableonly rom compounding pharma-cies. Delays in providing therapy

and rustration among hospital sta may result rom a lack o relevantinstitutional policies and procedures,uncertainty about the legitimacy o the compounding pharmacy supply-ing the sterile product, lack o educa-tion and amiliarity with the eaturesand operation o administrationdevices, and concerns about the needto provide care consistent with JointCommission accreditation standardsand CMS regulations pertaining tomedication integrity and saety. Theneed to reconcile drug therapies pro-vided in the outpatient and inpatientsettings to meet Joint Commissionnational patient saety goals and theneed to take a broad view in evaluat-ing all o a patient’s drug therapiesinstead o ocusing on only one pro-vide a strong argument or hospitalpolicies and procedures precludingbrown bagging.

Future of specialty pharmacy

Spending on specialty drugsamounted to approximately $54billion in 2008 and is expected tonearly double to more than $99 bil-lion by the end o 2010.12 Specialty drugs account or 25–30% o theoverall medical costs o a healthplan.13 Shiting costs to patients by classiying specialty drugs in a ourthtier represents an initial strategy orhealth plans coping with the highcost o new therapies. Patient co-

payments or ourth-tier specialty

drugs can add up to nearly $60,000a year or an individual receivingmultiple products.11 As additionalhigh-cost therapies are introduced,

health plans might consider the useo pay-or-perormance and innova-tive manuacturer contract arrange-ments or managing the cost o thesetherapies.14

An integrated approach is neededor managing the costs and ensuringthe saety o specialty drug products.Components o such an approachmight include pharmacy partner-ships with specialty pharmaciesand home inusion networks or

timely product delivery, utilizationmanagement to ensure appropriatetreatment initiation and adherence,coordination and standardization o electronic billing, and comprehensivedata capture and outcomes analysiswith online reporting capabilities.5

The comparative eectivenessand overall value o specialty drugproducts are increasingly under scru-tiny as health plans and other payersseeking to contain costs make theirdecisions about coverage.15 Pharma-ceutical manuacturers are devisinginnovative strategies to ensure thatpatients have access to their productsand that reimbursement is available.Emerging reimbursement models orhigh-cost pharmaceuticals includerisk-sharing agreements betweenmanuacturers and payers, with one-time prepayments or drug therapiesbased on the overall value o therapy instead o payments or each doseadministered.

In the past, many specialty drugproducts were administered atphysician-operated inusion centers.However, rising costs and reductionsin reimbursement have caused many o these centers to discontinue ser-vices, prompting hospitals and healthsystems to step in to fll the need orservices.16 Pharmacists in these set-tings view this as an opportunity toresolve problems with ragmentedcare by improving communication

among physicians and pharmacists.

7/27/2019 ajhp_12152009




The survival o hospital-based inu-sion centers may depend on eectivemanagement o the reimbursementprocess by sta with expertise in re-

imbursement policies.

Conclusion

The changing paradigm in thesupply chain or high-cost pharma-ceuticals to permit brown baggingo drug products obtained throughspecialty pharmacies or other re-stricted drug distribution systemshas important fnancial and saety implications or patients and healthsystems. Health-system pharmacists

can improve drug saety and managecosts by collaborating with grouppurchasing organizations, establish-ing policies or brown bagging, andmaking eorts to reconcile drugtherapy provided in dierent settingsthrough traditional drug channelsand specialty pharmacies or otherrestricted drug distribution systems.

References

1. 110th U.S. Congress. Food and DrugAdministration Amendments Act o

2007. http://rwebgate.access.gpo.gov/

cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=:publ085.110(accessed 2009 Jun 11).

2. U.S. Food and Drug Administration. Sec.505-1. [21 USC §355-1] Risk evaluationand mitigation strategies. http://www. d a . g o v / R e g u l a to r y I n o r m a t i o n /Legi s la t ion/Federa lFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/ucm109090.htm(accessed 2009 Jun 11).

3. Armitstead J, Loyd L, Pane F et al. Impli-cations o the specialty drug marketplaceor health-system pharmacy: a round-table discussion. Am J Health-Syst Pharm. 2007; 64:2364-72.

4. Specialty Pharmacy Network. What isspecialty pharmacy. http://www.specialty pharmacy.com/ (accessed 2009 Jun 11).

5. Prescription Solutions. Specialty phar-macy. https://www.prescriptionsolutions.com/RxsolHcpWeb/specialty_pharma/

index.html (accessed 2009 Jun 11).6. U.S. Food and Drug Administration.

Approved risk evaluation and mitiga-tion strategies (REMS). http://www.da.gov/Drugs/DrugSaety/PostmarketDrugSae ty InormationorPat i entsandProviders/ucm111350.htm (accessed2009 Jun 11).

7. Flolan package insert. Research TrianglePark, NC: GlaxoSmithKline; 2008 Jan.

8. Johnson PE. Pharmaceutical reimburse-ment: an overview. Am J Health-Syst Pharm. 2008; 65(2 Suppl 1):S4-10.

9. Centers or Medicare & Medicaid Ser-vices. Inormation partners can use on:Medicare drug coverage under Medi-

care Part A, Part B, and Part D. Revised

May 2009. http://www.cms.hhs.gov/partnerships/downloads/11315-P.pd (accessed 2009 Jun 23).

10. Centers or Medicare & Medicaid Ser-vices. Hospital outpatient prospec-tive payment system. http://www.cms.hhs.gov/MLNProducts/downloads/HospitalOutpaysysctsht.pd (accessed2009 Jun 20).

11. Rogers C. New Rx co-pay tier hurts ill:some plans push costs o pricey drugs onpatients. Detroit News. 2008; Jul 14.

12. Sullivan SD. The promise o specialty pharmaceuticals: are they worth theprice? J Manag Care Pharm. 2008; 14(4Suppl):S3-6.

13. CuraScript Pharmacy Inc. 2004 spe-cialty pharmacy management guide &trend report. June 2005. http://www.express-scripts.com/industryresearch/industryreports/specialtytrendreport/2004/strFinal.pd (accessed 2009 Jun 23).

14. Next-generation specialty pharmacy management strategies or health plans.July 9, 2008. http://www.aishealth.com/Products/C8P16_070908.html (accessed2009 Jun 22).

15. Learner N. Biotech, pharma frms eyenew payment models based on value.July 24, 2008. http://www.aishealth.com/DrugCosts/DBN_Biotech_Pharma_Payment.html (accessed 2009 Jun 11).

16. Brower A. Inusion centers or specialty drugs: hospitals step up. http://drugt o p i c s . m o d e r n m e d i c i n e . c o m /drugtopicsModern+Medicine+Now/Inusion-centers-or-specialty-drugs-Hospitals-ste/ArticleStandard/Article/

detail/596064 (accessed 2009 Jun 11).

7/27/2019 ajhp_12152009


Continuing EduCation


Continuing Education

Ensuring drug safety in health systems:Role of the Food and Drug

Administration Amendments Actof 2007, risk evaluation and mitigation

strategies, and restricted drugdistribution systemsArticle 204-000-09-006-H03P

Knowledge-based activity Qualifes or 2.0 hours (0.2 CEU) o continuing-education credit

Learning objectives

Ater studying these articles, the reader

should be able to

1. Discuss the impetus or and drug

saety provisions o the Food and

Drug Administration Amendments

Act (FDAAA) o 2007.

2. Describe the evolution, components,

and impact on health-system phar-

macists o risk evaluation and mitiga-

tion strategies (REMS).

3. Explain the impact o restricted drug

distribution systems on patients and

health systems, and identiy a con-

cern o health-system pharmacists

associated with the use o specialty

pharmacies and other restricted drug

distribution systems.4. Describe recent trends in the number

o drugs with REMS requirements.

5. Describe reimbursement consider-

ations or specialty drugs obtained

through restricted drug distribution

systems.

Self-assessment questions

For each question there is only onebest answer.

1. The FDAAA o 2007 granted the

Food and Drug Administration

(FDA) authority toa. Collect user ees rom pharma-

ceutical manuacturers to pay

or postmarketing REMS.

b. Conduct more robust preclinical

drug testing in patient popula-

tions likely to use the product.

c. Regulate specialty pharmacies

and other restricted drug distri-

bution systems.

d. Require postmarketing studies

or clinical trials o human drugs

and require REMS.2. Which o the ollowing provided

the primary impetus or passage o

the FDAAA o 2007?

a. The need to reauthorize the

Federal Food, Drug, & Cosmetic

Act.

b. The need to reauthorize the Pre-

scription Drug and User Fee Act.

c. An investigation by the Cen-

ters or Medicare & Medicaid

Services (CMS) into the fscal

impact o drug saety problems.

d. Testimony beore the U.S.

Congress by pharmaceutical

manuacturers about difculty

anticipating postmarketing drug

saety problems.

3. Which o the ollowing actors is

taken into consideration by FDA

in determining whether REMS are

required prior to drug product

approval?

a. The age o the patient popula-

tion likely to use the drug.

b. The size o the patient popula-

tion studied in preclinical drug

trials.

c. The seriousness o known or

potential adverse events related

to the drug.

d. The cost o treating adverse

events rom the drug.

4. REMS assessments may be required

a. 18 days, 3 months, and 7 months

ater initial approval.

b. 3 months, 7 months, and 18

months ater initial approval.

c. 18 months, 3 years, and 7 years


d. 3 years, 7 years, and 18 years


5. Which o the ollowing provided

the impetus or FDA to develop

REMS?

a. 2006 criticisms by the Institute o Medicine o FDA or drug with-

drawals due to saety problems.

b. 2006 changes in Joint Commis-

sion accreditation standards,

with new requirements to ensure

product integrity.

c. 2009 changes in CMS reim-

bursement regulations or

specialty drug products.

d. 2009 testimony to the U.S. Con-

gress by selected pharmaceutical

manuacturers about the limita-tions o preclinical drug testing.

7/27/2019 ajhp_12152009




6. The new systematic approach by

FDA using data rom disparate data

sources to monitor the eects o

drugs in populations, identiy saety

problems and the need or drug-use modications or restrictions,

and acilitate an evidence-based

approach to adverse drug event

monitoring is known as

a. REMS.

b. The Adverse Event Reporting

System.

c. The MedWatch program.

d. The Sentinel Initiative.

7. Which o the ollowing ormats

or risk minimization action plans

(RiskMAPs) provides the greatestsaeguards?

a. Continuing-education programs

or health care providers.

b. Inormed consent orms or

patients.

c. Perormance-linked access

systems.

d. Reminder systems.

8. Which o the ollowing statements

about the elements to ensure sae

use o drugs with known serious

risks as part o REMS is correct?

a The elements are required

or all drugs with REMS and

may include special training

or certication or prescribing

or dispensing, dispensing only

under certain circumstances,

special monitoring, or use o

patient registries.

b. The elements are required or

some (but not all) drugs with

REMS and may include special

training or certication or pre-

scribing or dispensing, dispens-

ing only under certain circum-

stances, special monitoring, or

use o patient registries.

c. The elements are required or

all drugs with REMS and may

include medication guides,

patient package inserts, or com-

munication plans or health care

providers.

d. The elements are required or

some (but not all) drugs with

REMS and may include medica-

tion guides, patient package

inserts, or communication plansor health care providers.

9. Which o the ollowing is the most

serious concern associated with the

development o REMS or

extended-release opioid analgesics?

a. Confict with medical board

pain management continuing-

education requirements.

b. Potential or delays in providing

patient care.

c. Increased cost o drug therapy.

d. Misuse, abuse, or accidentaloverdose o the drugs.

10. Which o the ollowing was ad-

dressed in the FDA nal rule issued

in 2009 requiring new warnings and

related labeling or over-the counter

analgesic, antipyretic, and antirheu-

matic drugs?

a. Warnings about stomach bleed-

ing rom aspirin and other

nonsteroidal anti-infammatory

drugs (NSAIDs) and severe liver

toxicity rom acetaminophen.

b. Warnings about stomach

bleeding rom aspirin but not

NSAIDs and severe liver toxicity

rom acetaminophen.

c. Warnings against the use o

aspirin during pregnancy and

breasteeding.

d. Warnings against the use o aspi-

rin, wararin, and alcohol in any

combination during pregnancy

and breasteeding.

11. Which o the ollowing approaches

is advocated by the American Soci-

ety o Health-Systems Pharmacists

to minimize the burden o FDA

REMS requirements on health-

system pharmacists?

a. Integrating REMS into the Med-

Watch program.

b. Educating members o

medication-related committees

and pharmacy, medical, and

nursing stas about FDA REMS

requirements.

c. Reclassiying over-the-counter

drugs with REMS to “behind-

the-counter” status.

d. Standardizing REMS as part o

established drug procurementsystems.

12. Which o the ollowing most di-

rectly refects current FDA require-

ments o pharmaceutical manuac-

turers or drug saety?

a. REMS.

b. Restricted drug distribution

systems.

c. RiskMAPs.

d. Specialty pharmacies.

13. Which o the ollowing statements

about REMS and restricted drug

distribution systems is correct?

a. REMS may involve restricted

drug distribution systems, but

restricted drug distribution sys-

tems are not necessarily used or

drugs with REMS requirements.

b. REMS and restricted drug distri-

bution systems are used only or

drugs covered under Medicare

Part B or D.

c. All drugs with REMS require-

ments are handled through

restricted drug distribution

systems.

d. Drugs are handled through

restricted drug distribution

systems only i they are subject

to REMS requirements.

14. Which o the ollowing drugs

is among the earliest supplied

through a restricted drug distribu-

tion system?

a. Clozapine.b. Infiximab.

c. Natalizumab.

d. Romiplostim.

15. The recent shit rom a traditional

supply chain model to a specialty

pharmacy supply chain model or

high-cost pharmaceuticals has the

potential to

a. Increase costs or health systems

because o the negotiation o

contract prices and rebates.

7/27/2019 ajhp_12152009



b. Increase costs or health systems

because o purchasing on a cost-

plus-markup basis.

c. Decrease costs or health systems

because o the negotiation o contract prices and rebates.

d. Decrease costs or health systems

because o purchasing on a

volume, cost-minus basis.

16. Which o the ollowing can play the

largest role in coordinating tradi-

tional and specialty pharmacy drug

purchasing contracts and distribu-

tion channels?

a. CMS.

b. FDA.

c. Group purchasing organizations.d. Pharmaceutical manuacturers.

17. Which o the ollowing is a poten-

tial advantage or health systems

o a patient-centric approach to

brown bagging drug products

obtained rom specialty pharmacies

compared with a pharmacy-centric

approach?

a. Greater patient saety.

b. Less uncertainty about product

integrity.

c. Lower cost.

d. Lower institutional liability.

18. Potential problems or health

systems associated with permitting

brown bagging o compounded

sterile products used with implant-

able or external inusion pumps

include a lack o nurse and pharma-

cist amiliarity with the proper

operation o inusion devices.

a. True.

b. False.19. In recent years, the number o

drugs with REMS requirements has

a. Increased because o a greater

concern among pharmaceutical

manuacturers about product

liability.

b. Increased because o a greater

commitment o the FDA to

postmarketing surveillance and

drug saety.

c. Decreased because o more

extensive preapproval clinicali d

d. Decreased because o greater use

o restricted drug distribution

systems.

20. A ourth tier or specialty drug

products has been created by somehealth plans to:

a. Ensure the capture o charges

or high-cost drugs.

b. Improve drug saety.

c. Reduce the cost o drugs

through volume discounts.

d. Shit a larger portion o the cost

o some drugs to the patient by increasing the copay signifcantly.

AJHP Continuing EducationSupplement: Ensuring drug safety inhealth systems: Role of the Food and

Drug Administration Amendments Act

of 2007, risk evaluation and mitigation

strategies, and restricted drug distribu-

tion systems

ACPE #: 204-000-09-006-H03P

CE Credit: 2.0 hours (0.2 CEU)

Expiration Date: December 15, 2012

The CE Process

The continuing-education (CE) test or

this supplement can be taken online at

the ASHP Learning Center. All tests are

ree to both members and nonmembers.

As you take the test, you may stop and

return to it at any time beore submitting

your fnal answers. I you score 70% or

better on the test, you may immediately

print your CE Statement of Credit or

your records. I you do not score at least

70%, you are permitted to retake the

test. ASHP keeps a record o the credits

you have earned rom this and other CE

activities.

Instructions

• Access this test by going to http://

ce.ashp.org.

• Loginusingyouremailaddressand

password. I you need help logging in,

send an email to [email protected].

I you have orgotten your password,

click on the Forgot Your Password

link to receive an email with your

password or a link to create a new

one.

• When you log in, theMyAccountpage will appear. Click on Take CE

Test or available tests, listed by topic

or by your proession.

• Youcanlterbytopicorpressctrl+F

to search or a specifc test.

• Click the checkbox for the test you

want to take, and then scroll down

and click on Register at the end o the

list.

• Thetestyouhaveselectedwillappear

along with instructions or complet-

ing it.

• Followthepromptattheendofthe

test to complete the evaluation and

print your CE Statement of Credit .

• Note:Youwillnotbeabletoprint

yourCEstatementunlessyoucom-

pletethetestevaluation.

• ToprintyourCEstatement,clickon

the “Print CE Statement” button.

• Note: youmust select the activity

fromthedropdownboxthatreads

“noactivity”(default)beforeyour

CE statement will appear on the

screen.

Questions?

Call the ASHP Processing Center:

866-279-0681 (toll ree)

+1-301-664-8700(internationalcalls)

TheAmericanSocietyofHealth-

SystemPharmacistsis accredited

bytheAccreditationCouncilforPharmacy

Education as a provider of continuing

pharmacyeducation.

ajhp_12152009

Documents