The Opportunities and Challenges of Specialty DistributionThe distribution of infusible specialty medications comes with difficulties that must be addressed by pharmacies and payers.
Berger
NAT IONAL PHARMACEU T ICAL COUNCIL
Value Depends on Real-World EvidenceHealthcare stakeholders must work with regulators and policy makers to reduce barriers that prevent the alignment of a drug’s value and price.
Leonard
Translating Evidence-Based Research into Value-Based Decisions®
®
®The American Journal of
PHARMACY BENEFITS
ORIG INAL RESE ARCH
Establishing Standards of Care for Amiodarone Monitoring in an Outpatient SettingImplementing a quality improvement project that allows for education and interdisciplinary collaboration among pharmacists, cardiologists, and primary care providers can improve rates of amiodarone monitoring.
Cherian and Amarshi
ORIG INAL RESE ARCH
US Primary Care Providers’ Use of Over-the-Counter Medications for Gastroesophageal Reflux Disease and Chronic Constipation The perception and utilization of OTC medications among primary care providers for gastroesophageal reflux disease and chronic constipation shows a need for improved patient education on these medications.
Chey, Chey, Saini, Weissman, Harris and Menees
ORIG INAL RESE ARCH
Cancer Therapeutic Clinical Trials Supporting FDA Approval and Compendia InclusionEvidentiary standards for new or supplementary cancer therapeutic indication approvals by the FDA are consistent with off-label indication inclusions on Medicare-referenced compendia.
Su, Gross, Downing, Adelson, and Ross
102 The American Journal of Pharmacy Benefits® | July/August 2017
The American Journal of
PHARMACYBENEFITS
®
®EDITORIAL BOARDE D I T O R - I N - C H I E F
Jan E. Berger, MD, MJPresident & CEOHealth Intelligence Partners Northbrook, IL
Kimberly A. Bergstrom, PharmDChief Clinical Officer McKesson Corporation San Rafael, CA
J. Lyle Bootman, PhD, ScDDean, College of Pharmacy University of Arizona Tucson, AZ
William B. Bunn, III, MD, JD, MPHVice President of Health, Safety, Security, & ProductivityNavistar International Warrenville, IL
Mitchell P. DeKoven, MHSAPrincipal, Health Economics & Outcomes Research, Real-World Evidence Solutions IMS Health Fairfax, VA
Joseph Doyle, RPh, MBASenior Director, Managed Markets Medical Science DirectorsAlkermes East Hanover, NJ
Steven R. Erickson, MDAssociate Professor, Department of Clinical Pharmacy University of Michigan Ann Arbor, MI
Gail R. Gratz-Levenson, RPhPrincipal, National Clinical PracticeBuck ConsultantsWashington, DC
Laura Long, MD, MPHPrincipalTheLongView, P.C. Columbia, SC
Rose Maljanian, RN, MBAChairman & CEO HealthCAWS, Inc Farmington, CT
Darlene M. Mednick, PhD, RPh, MBAVice President, Pharmacy Services Gorman Health Group New York, NY
Thomas J. Morrow, MDChief Medical OfficerNext ITSpokane, WA
Kavita Nair, PhDDepartment of Clinical Pharmacy University of Colorado Denver, CO
Cyndy Nayer, MACEO Center of Health Value Innovation Naples, FL
Edmund J. Pezalla, MD, MPHConsultantEJ Pezalla Independent ConsultantWethersfield, CT
Richard G. Popiel, MD, MBAExecutive Vice President & Corporate Chief Medical Officer Cambia Health SolutionsPortland, OR
Helen Sherman, PharmDVice PresidentSolid Benefit GuidancePortland, OR
William H. Shrank, MDDivision of Pharmacoepidemiology Harvard Medical School Boston, MA
Yvonne Southwell, RPhVice President, Clinical Affairs CVS/Caremark Northbrook, IL
Dong-Churl Suh, PhD, MBADepartment of Pharmacy Practice and Administration Rutgers University Piscataway, NJ
Michael L. Taylor, MDFormer Chief Medical Officer Truven Health Analytics Ann Arbor, MI
MISSIONTo provide pharmacy and formulary decision makers with the information they need to improve the efficiency and health outcomes in managing pharmaceutical care.
EDITORIAL OVERVIEWThe American Journal of Pharmacy Benefits® publishes peer-reviewed research that examines the impact of formulary management strategies on the utilization, cost, and quality of pharmacy services. The Journal presents case studies, research, and evidence-based tools to help decision makers develop clinical strategies to manage pharmacy benefits for large populations.
Areas of particular interest include utilization management strategies (ie, prior authorization, step therapy, generic substitution, etc), outcomes research on Medicare Part D, formulary development and implementation strategies, research on adherence and compliance, cost-sharing strategies (ie, co-pays, coinsurance, CDHPs, HDHPs, etc), cost utility analyses, economic burden of disease, and comparative effectiveness analysis of drug therapies.
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CHAIRMAN’S LETTER
Opinions expressed by authors, contributors, and advertisers are their own and not necessarily those of Pharmacy & Healthcare Communications, LLC, the editorial staff, or any member of the editorial advisory board. Pharmacy & Healthcare Communications, LLC, is not responsible for accuracy of dosages given in articles printed herein. The appearance of advertisements in this journal is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality, or safety. Pharmacy & Healthcare Communications, LLC, disclaims responsibility for any injury to persons or property resulting from any ideas or products referred to in the articles or advertisements.
I n this issue of The American Journal of Pharmacy Benefits®, the topic of value in healthcare takes center stage. While the industry continues to move towards
a value-based system, there are many factors that create challenges for stakeholders to overcome.
Thus far, first-generation, value-based contracts among manufacturers and payers have yet to achieve the success levels neces-sary to spark systemic change, with many of these agreements covering a single drug and/or with a greater focus on volume. However, contracts that base reimbursement on improved patient outcomes and drug efficacy are beginning to gain prominence.
Dan Leonard, president of the National Pharmaceutical Council, dis-cusses the importance of real-world evidence to drive value in healthcare. Leonard notes that payers and biopharmaceutical companies are increas-ingly tying the cost of a medication to how well the treatment performs or how it affects the total cost of care. He added that a large majority of insurance plans look favorably upon such arrangements.
However, there are still regulatory hurdles that restrict communication between payers and manufacturers that must be addressed to achieve more progress in establishing these innovative contracts.
This issue also features an analysis of the value specialty pharmacies can provide to payers and patients, but also discusses how restrictive plan designs can frequently create an undue burden during the treatment process.
Realizing value in treatment, however, does not exclusively apply to high-cost drugs, as Samuel W. Chey et al discuss the use of OTC drugs to treat gastroesophageal reflux and chronic constipation. They found that while some OTC drugs offer similar efficacy at a reduced cost, many patients remain unaware of these less costly treatment options.
With the massive growth projected for pharmacy spending through the next decade, the studies in this issue make it clear that stakeholders need to explore innovative new contracts and programming to ensure value is realized for the patients they serve.
Comparative Effectiveness and Costs of Insulin Pump Therapy for DiabetesRonald T. Ackermann, MD, MPH; Amisha Wallia, MD, MS; Raymond Kang, MA; Andrew Cooper, MPH; Theodore A. Prospect, FSA, MAAA; Lewis G. Sandy, MD, MBA; and Deneen Vojta, MD
ajmc.com/link/2239
Medication Therapy Management and Health Care ReformCourtney C. Rerecich, PharmD Candidate and Joseph L. Fink III, BSPharm, JD, DSc (Hon), FAPhA
pharmacytimes.com/link/164
Time Is Bone: Unchecked Rheumatoid Arthritis Affects More Than JointsDavy James, Managing Editor
specialtypharmacytimes.com/link/2242
Does the Offer of Free Prescriptions Increase Generic Prescribing?Bruce Stuart, PhD; Franklin Hendrick, PhD; J. Samantha Dougherty, PhD; and Jing Xu, PhD
ajmc.com/link/2240
104 The American Journal of Pharmacy Benefits® | July/August 2017
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®The American Journal of
Translating Evidence-Based Research into Value-Based Decisions®PHARMACY BENEFITS
The Opportunities and Challenges of Specialty DistributionJan Berger, MD, MJ 105The distribution of infusible specialty medications comes with difficulties that must be addressed by pharmacies and payers.
O R I G I N A L R E S E A R C H
Establishing Standards of Care for Amiodarone Monitoring in an Outpatient Setting Sibyl Cherian, PharmD; and Rahemat Amarshi, PharmD, MS 108Implementing a quality-improvement project that allows for education and interdisciplinary collaboration among pharmacists, cardiologists, and primary care providers can improve rates of amiodarone monitoring.
O R I G I N A L R E S E A R C H
US Primary Care Providers’ Use of Over-the-Counter Medications for Gastroesophageal Reflux Disease and Chronic ConstipationSamuel W. Chey; William D. Chey, MD; Sameer D. Saini, MD; Arlene Weissman, PhD; Linda Harris; and Stacy B. Menees, MD 116The perception and utilization of OTC medications among primary care providers for gastroesophageal reflux disease and chronic constipation shows a need for improved patient education on these medications.
O R I G I N A L R E S E A R C H
Cancer Therapeutic Clinical Trials Supporting FDA Approval and Compendia InclusionKevin W. Su, MD; Cary P. Gross, MD; Nicholas S. Downing, MD; Kerin B. Adelson, MD; and Joseph S. Ross, MD, MHS 122Evidentiary standards for new or supplementary cancer therapeutic indication approvals by the FDA are consistent with off-label indication inclusions on Medicare-referenced compendia.
N A T I O N A L P H A R M A C E U T I C A L C O U N C I L
Value Depends on Real-World EvidenceDan Leonard, President, National Pharmaceutical Council 131Healthcare stakeholders must work with regulators and policy makers to reduce barriers that prevent the alignment of a drug’s value and price.
Vice President of Editorial Services and ProductionKerrie Keegan
Vice President of Digital MediaJung Kim
Chief Creative OfficerJeff Brown
Director of Human ResourcesShari Lundenberg
Visit the journal archives section of ajpb.com for past issues and web exclusive articles from The American Journal of Pharmacy Benefits®.
Vol. 9, No. 4 | The American Journal of Pharmacy Benefits® 105www.ajpb.com
T he world of specialty medications gets more complicated and more important each day. My column in the May/June 2016 issue discussed
some of the issues associated with specialty medica-tions. In this column, I want to focus specifically on the issues associated with the distribution of infusible specialty medications.
First, let me say that I am a big fan of specialty pharmacies. Many of them bring value to both the patient and the payer. That said, I also believe they often forget how some of their decisions can affect the patient.
This is even more evident when speaking about the specialty medications that are most often covered by the medical benefit. For a long time, specialty pharmacies had little to do with these medications. Over the past year, in working with my clients, I have seen a move-ment in which specialty pharmacies are managing the specialty medications, regardless of whether they are paid for through the pharmacy or the medical benefit. Additionally, I have noticed an increase in specialty pharmacies offering my clients cost savings for limiting where the patient receives their infusible medications.
These plan designs are touted as a method of payers to decrease medication costs. Unfortunately, there is little discussion around the financial impact or care disruption that occurs for the patient. Please don’t get me wrong. I do understand the cost implications of these very expensive medications for a payer. I just don’t believe that many payers understand the overall implications of the decisions being made.
Let’s start this conversation by looking at the potential cost implications for a patient. To best articulate this issue, I will use payer X as the payer, patient Y as the patient, and Remicade as the drug. Payer X was offered a plan design that required their members to receive the infused medication from a specialty pharmacy’s mail-order program, much like they have been doing for self-injectable specialty medications.
At first glance, the program seemed to make a good deal of sense. The member had the convenience of receiving the medication directly at their home, and the payer saved money. Unfortunately, the discussion did not go deeper than that. The contract gave the payer the opportunity to lower the cost of Remicade by receiving a portion of the rebate that the specialty pharmacy was receiving from the manufacturer. This lowered the overall net cost of the medication.
In many cases, this is a good thing. Unfortunately, the net cost implication was not passed on to the member. For members who have a coinsurance plan design model, receiving the medication directly from the specialty pharmacy has the potential to have a significant negative implication, as the coinsurance does not take the rebate into consideration. I have found this to be occurring more often recently.
The Opportunities and Challenges of Specialty DistributionJan Berger, MD, MJ
Over the past year, in working with my clients, I have seen a movement in which specialty pharmacies are managing the specialty medications, regardless of whether they are paid for through the pharmacy or the medical benefit.
LETTER FROM THE EDITOR
106 The American Journal of Pharmacy Benefits® | July/August 2017
The second area where we are increasingly seeing a negative impact on the consumer is in the difficulty they face getting their medication infused once it is sent to their home. It is not unusual for providers to refuse to give medications, such as Remicade, to a patient if the medication was not dispensed from their office.
The reasons that providers give vary, but most often focus on the safety and liability associated with the handling of the medication. If a patient’s physician declines to infuse the medication, it falls on the consumer to find someone who will do the infusion, such as a home health agency or an infusion center. Doing so can be equally as difficult, which leads to a disruption in care that creates the potential for wasted medication.
The message is 2-fold: first, specialty pharmacies that are managing infused medications need to create a system that includes care coordination that integrates medication delivery and infusion. Do not leave this integration to the patient.
Second, it is important that the payer understand the implications that the plan design has on the patient. It is not unreasonable to use a coinsurance model for infused medications, but it is unreasonable to require that a patient go to a more expensive distribution model. Additionally, it is unfair to require a patient to identify providers who will infuse a medication when their physicians refuse to do so. Plan designs need to pass a headline test: Does the design create undue burden on any affected stakeholder?
I look forward to hearing from you.
LETTER FROM THE EDITOR
Advancements in Managing CINV: Opportunities for Pharmacists to Improve Patient CareEXPIRES: MAY 22, 2018
pharmacytimes.org/landing/963This activity is supported by an educational grant from Eisai Inc. and Tesaro, Inc.
Applying Managed Care Strategies to the Advancing Landscape of Multiple Sclerosis EXPIRES: MAY 25, 2018
pharmacytimes.org/landing/966This activity is supported by an educational grant from Sanofi Genzyme.
Heart Failure: Emerging Therapies and the Pharmacist’s Role at Discharge and BeyondEXPIRES: SEPTEMBER 2, 2017
pharmacytimes.org/landing/865This activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.
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108 The American Journal of Pharmacy Benefits® | July/August 2017
ABSTRACT
Objectives: To assess rates of monitoring of liver, thyroid, and pulmonary function in the 6 months before and after initiation of a quality improvement project, and to evaluate the effect of pharmacist-managed dual warfarin and amiodarone monitoring on maintaining target international normalized ratio (INR).
Study Design: Retrospective electronic chart review.
Methods: Rates of monitoring according to current guidelines for amiodarone monitoring were evaluated. Patients who filled prescriptions for a) amiodarone AND b) warfarin OR any of the following direct oral anticoagulants: apixaban, rivaroxaban, or dabigatran between May 1, 2014, and April 30, 2015, were reviewed. Percent time spent in target therapeutic INR range (% TTR) was used as an outcome parameter to evaluate effect on maintaining target INR.
Results: Seventy-three subjects were in the pre-intervention group and 69 patients were in the post intervention group. All rates of 6-month monitoring increased in the post intervention group as compared with the pre-intervention group. Both the rates of monitoring of alanine aminotransferase (P = .03) and free thyroxine (P <.001) were found to be significantly higher in the post intervention group, as compared with the pre-interven-tion group. The % TTR was 64% in the pre-intervention group and 58% in the post intervention group.
Conclusions: Collaboration with pharmacists in an outpatient setting leads to improved rates of recommended laboratory tests for amiodarone monitoring. This study demonstrated the effectiveness of an established anticoagulation clinic in maintaining target INR.
Am J Pharm Benefits. 2017;9(4):108-115
A miodarone is a Vaughan Williams class III anti-arrhythmic agent indicated for the management of ventricular fibrillation or unstable ventricular
tachycardia.1 Although not currently approved by the FDA for the treatment of atrial fibrillation (AF), it has been used in the past for this condition.2,3 Amiodarone is a life-saving and effective medication, particularly in patients in whom other agents, such as calcium channel blockers and beta blockers, are contraindicated. Moreover, epidemiologists predict that there will be a rise in the prevalence of AF in North America by 2050 to more than 12 million, which is nearly a 2-fold increase from present numbers.4 Consequently, we expect to see an increase in the use of amiodarone in the future.
Due to the drug’s lipophilic properties and large volume of distribution, the drug is stored in muscle and tissue as well as in highly perfused organs, including the liver, lungs and skin. Consequently, the drug has a variable half-life, averaging about 58 days.1 It is primarily eliminated through hepatic metabolism and biliary excretion. Due to amiodarone’s complex pharmacokinetic properties and lipophilicity, it has numerous drug interactions and can cause numerous potential adverse events (AEs).1
The AEs of amiodarone range from mild—such as nausea, photosensitivity, or skin discoloration—to more serious, such as liver, thyroid, and lung toxicities.1 Amiodarone is an iodine-containing compound that is structurally similar to thyroxine. Through multiple mechanisms, amiodarone has the capability of causing hypothyroidism or hyperthyroidism. 5
One of the more serious AEs is interstitial lung disease. In a study by Dusman et al, amiodarone pulmonary toxicity was found to be more common with higher doses, advanced age, lower pretreatment diffusion lung capacity for carbon monoxide (DLCO), and high plasma concentration of the active metabolite, desethylamiodarone.6 Patients who receive a total daily dose of 400 mg for 2 months or 200 mg daily for 2 years are considered at greater risk.7 Pulmonary function tests (PFTs), including DLCO, as well as chest x-rays (CXR) can help diagnose amiodarone-induced pulmonary toxicity.8
Establishing Standards of Care for Amiodarone Monitoring in an Outpatient SettingSibyl Cherian, PharmD; and Rahemat Amarshi, PharmD, MSc
ORIGINAL RESEARCH
Vol. 9, No. 4 | The American Journal of Pharmacy Benefits® 109www.ajpb.com
Amiodarone Monitoring in an Outpatient Setting
Another amiodarone-induced toxicity is hepatotoxicity. About 25% of patients will have a transient elevation in alanine aminotransferase (ALT) levels. Symptomatic hepatitis is shown to occur in about 3% of patients on amiodarone. If untreated, more serious complications include cirrhosis, and hepatic failure can occur.9,10 Therefore, monitoring of liver function tests (LFTs) is recommended prior to amiodarone initiation and every 6 months thereafter.11
Numerous drug interactions can occur with amiodarone therapy.12-15 Amiodarone has a significant drug interaction with warfarin. The anticoagulant effect of warfarin is potentiated with the addition of amiodarone. By inhibiting the activity of CYP2C9 and CYP1A2, warfarin cannot be metabolized to inactive metabolites, ultimately leading to an increase in international normalized ratio (INR). Literature suggests a reduction in warfarin dose is recommended with the addition of amiodarone to a regimen.16,17 Within our facility, warfarin weekly dose will be lowered by 30% if amiodarone is added to the patient regimen.
Due to the numerous AEs and toxicities associated with amiodarone, patients being started on this drug must be closely monitored. The North American Society of Pacing and Electrophysiology (NASPE) has specific recommendations regarding baseline and routine monitor-ing of patients being initiated on amiodarone therapy, as outlined in TABLE 1.11
Despite these recommendations, several studies suggest that the rates of laboratory monitoring are lower than recommended.18-20 The use of pharmacists to improve laboratory monitoring of amiodarone has been evaluated in several studies, and the results demonstrate that utilizing pharmacists for amiodarone monitoring improved adherence to appropriate monitoring.2 To date, only one study has evaluated amiodarone monitoring in a collaborative setting with pharmacists in a Veterans Affairs (VA) Healthcare System. Graham et al demonstrated that implementing a pharmacy-managed protocol significantly improved the rates of maintenance amiodarone monitoring. However, the rates of baseline monitoring were low (<50% for all baseline parameters).21 Due to the collaborative efforts of our cardiology team and pharmacists, we hypothesized that our rates for ongoing monitoring would be higher when compared with those of other facilities. We also anticipated that the addition of a quality improvement project with the involvement of pharmacists would greatly improve our rates of 6-month and annual monitoring.
To date, no studies have evaluated concomitant pharmacist-led monitoring of warfarin and amiodarone in a clinic setting. Little literature is available that provides an accurate mean percentage in which the INR was in therapeutic range. In a meta-analysis conducted by Baker et al, AF patients spent a mean of 55% in their therapeutic range. It was also hypothesized that these patients treated in community setting compared with anticoagulation clinic spent 11% less time in therapeutic INR range.22 Landmark studies involving warfarin use in AF have ranged in percentage of time in therapeutic INR range (TTR) from 55% to 64%.23-25 Our study would greatly add to the data that are already available for the management of warfarin outside of a controlled study environment.
METHODSDescription of Amiodarone Monitoring Quality Improvement Project The Amiodarone Monitoring Quality Improvement Project was established as a pilot clinic within the anticoagulation clinic at a VA hospital. The anticoagulation clinic primarily manages warfarin and direct oral anticoagulant (DOAC) monitoring of all veterans within the local VA system. Prior
PRACTICAL IMPLICATIONS■■ Amiodarone is a life-saving medication that is becoming more frequently utilized, but the rates
of recommended monitoring continue to be lacking.
■■ Implementing a quality-improvement project that allows for education and interdisciplinary collaboration among pharmacists, cardiologists, and primary care providers improves rates of amiodarone monitoring.
Table 1. Amiodarone Monitoring Protocol Per North American Society of Pacing and Electrophysiology (NAPSE)
Type of Test Per NASPE guidelines Per local VA protocol
On baseline
ê LFTs (AST/ALT) ê Chest x-ray ê TFTs (T4, TSH) ê PFTs (with DLCO) ê ECG
ê LFTs (AST/ALT, alkaline phosphatase) ê Chest x-ray ê TFTs (T4, TSH) ê PFTs (with DLCO) ê ECG
6 weeks None
ê LFTs (AST/ALT, alkaline phosphatase) ê Chest x-ray ê TFTs (T4, TSH) ê PFTs (with DLCO)
6 months ê LFTs (AST/ALT) ê TFTs (T4/TSH)
ê LFTs (AST/ALT) ê TFTs (T4/TSH)
Annual ê Chest x-ray ê Chest x-ray ê PFTs (with DLCO)
ALT indicates alanine aminotransferase; AST, aspartate transaminase; DLCO, diffusion lung capacity for carbon monoxide; ECG, electrocardiogram; LFT, liver function test; PFT, pulmo-nary function test; T4, thyroxine; TFT, thyroid function test; TSH, thyroid-stimulating hormone.
110 The American Journal of Pharmacy Benefits® | July/August 2017
Cherian | Amarshi
to establishing the pilot clinic, pharmacists met with the hospital cardiologists in order to establish an amiodarone monitoring protocol (Table 1). As identified in Table 1, this protocol is more stringent than current amiodarone monitoring guidelines due to local cardiology preference. In the previous process, amiodarone would be initiated on an appropriate patient within the inpatient setting after obtaining baseline laboratory values and tests. At 6 weeks and at 6 months, the patient would return to the electrophysiology clinic for monitoring. After 6 months, patients would be discharged to primary care to be followed by primary care providers for their continued 6-month and annual monitoring thereafter.
In the VA facility, ongoing education and protocols were implemented over the past several years to ensure that amiodarone monitoring was done appropriately during the transition of care from cardiology to primary care. We have continued to see improvement in the rates of monitoring. In order to further assist in continuity of care, a quality improvement project was established on November 1, 2014. Patients who are on warfarin and DOACs are routinely monitored within the medication management clinic. Patients on warfarin therapy have routine INR follow-up and patients on DOAC therapy are periodically assessed for renal function, drug interactions, and other issues that may preclude them from continuing DOAC therapy. During this routine monitoring, pharmacists identify if these patients are also on amiodarone. If amiodarone was initiated within the past 6 weeks, pharmacists use a computerized template to write a note into the patient’s chart. If there are certain baseline laboratory values or imaging that are incomplete, the pharmacist orders these labs so that
baseline values are available for future comparison. While ideally baseline monitoring is done prior to amiodarone initiation, if baseline monitoring was not completed at that time, it is still important to complete baseline labs or imaging as soon as possible after initiation. For patients already on maintenance amiodarone, the pharmacists assess whether 6-month and annual monitoring were completed. If any monitoring points are missing, pharmacists can place orders for the missing laboratory values. CXRs are not ordered directly by a pharmacist, but if a CXR is not completed, the appropriate provider is alerted about overdue required monitoring. FIGURES 1 and 2 highlight the study intervention on Patient X on warfarin/DOAC with concurrent amiodarone.
This study is a retrospective chart review approved by the Central Arkansas Veterans Healthcare System (CAVHS) Department of Veterans Affairs Institutional Review Board (IRB) and CAVHS Research and Development Committee. The CAVHS Computerized Patient Recording System (CPRS) database was utilized for the study. A patient list was obtained by identifying patients who had filled a prescription for a) amiodarone AND b) warfarin OR any of the following DOACs: apixaban, rivaroxaban, or dabigatran.
This chart review was done in 2 phases: The first phase was six months prior to the pilot clinic and the second phase was six months after the establishment of the pilot clinic for amiodarone monitoring. The following patient information was collected: age; gender; race; amiodarone dose; amiodarone indication, and warfarin or DOAC indication. If amiodarone was newly initiated during the evaluated time period, patient charts were reviewed to see if appropriate laboratory values and imaging were
Usual care: Monitored baseline measurements can be obtained only by inpatient cardi-ologists prior to amiodarone initiation. Baseline monitoring includes LFTs (AST/ALT), TFTs (T4, TSH), CXR, PFT with DLCO.
Usual care: Amiodarone 6-month and annual monitoring can be obtained only by primary care provider. Six-month monitoring includes LFTs (AST/ALT), TFTs (T4, TSH). Annual monitoring includes CXR.
Figure 1. New Amiodarone Start Figure 2. Amiodarone Started Prior to Study Period
Patient X
DOAC/warfarinAmiodarone*
STUDY INTERVENTION
Anticoagulation pharmacists evaluate if 6-month and annual labs completed;
obtain laboratory and imaging as necessary
Warfarin INR/DOAC follow-up completed in anticoagulation clinic
Warfarin INR/DOAC follow-up completed in anticoagulation clinic
Vol. 9, No. 4 | The American Journal of Pharmacy Benefits® 111www.ajpb.com
Amiodarone Monitoring in an Outpatient Setting
or were not obtained upon amiodarone initiation. These baseline monitoring parameters include ECG, ALT, aspartate transaminase (AST), thyroid-stimulating hormone (TSH), free thyroxine (free T4), PFTs with DLCO, and CXR. If amiodarone was already initiated prior to the evaluated time period, TSH, free T4, AST, and ALT should be done every 6 months, and data were evaluated for completion of these monitoring parameters. CXR should be done annually, and the data were analyzed to see if CXR was obtained in past year. Since all patients were started on amiodarone inpatient by cardiologists and ECG is routinely completed, assessment of completion of baseline ECG was not included. INR values for all patients on concomitant warfarin, who met exclusion and inclusion criteria, were also reviewed.
All eligible veterans being monitored by the VA anti-coagulant clinic who initiated on amiodarone therapy or were currently receiving amiodarone therapy between May 1, 2014, and April 30, 2015, were included. Subjects in whom amiodarone was started by an outside provider, had received less than 6 weeks of amiodarone therapy, were pregnant, were under hospice care, or were in home-based primary care (HBPC) were excluded. For the secondary outcome, excluded INR readings were those collected at first initiation of warfarin as well as subtherapeutic INRs at times when warfarin therapy was temporarily halted before or after certain procedures.
The primary outcome was to assess the rates of 6-month monitoring (LFTs, thyroid function tests [TFTs]) and annual monitoring (CXR) in the pre- and post intervention groups. The secondary outcome was to assess the rates of baseline monitoring of liver (AST, ALT), thyroid (TSH, free T4), and pulmonary function (PFTs with DLCO, CXR) in the pre- and
postintervention group. Another secondary outcome was to evaluate the effect of pharmacist-managed dual warfarin and amiodarone monitoring on maintaining target INR. This will be measured using the fraction of INRs method of % TTR (number of INRs in target range, divided by total number of INR in selected time interval, multiplied by 100).
Baseline characteristics of race and gender were compared between the pre- and post intervention groups using the Pearson’s c2 test, except for Student’s t test for age and Mann Whitney U test for dosing. Primary outcome assessing rates of monitoring was compared using Pearson’s c2 test. P values <.05 were considered statistically significant.
RESULTSA total of 202 patients were identified as having concomitant amiodarone and warfarin or DOAC prescriptions filled between the time period of May 1, 2014, and April 30, 2015 (FIGURE 3): 108 were stratified into the pre-intervention group and 90 were stratified into the post intervention group. After evaluating exclusion criteria, 73 and 69 patients remained in the pre-and postintervention groups, respectively.
The baseline characteristics of the pre- and post interven-tion group were similar, as shown in TABLE 2. Overall, the mean ages were 69.8 and 70 years for the pre- and post intervention groups, respectively. The majority of subjects were male and nonblack. Most subjects were receiving vitamin K antagonists for anticoagulation (79.5% in pre-intervention group vs 71% in post intervention group) and most subjects were receiving anticoagulation for the indication of AF. Most subjects were taking a maintenance amiodarone dose of 200 mg/day (83.6% and 76.8% in the pre- and post intervention groups, respectively).
Our primary outcome was to assess the rates of 6-month monitoring of liver (AST, ALT), thyroid (TSH, free T4), and pulmonary function (PFTs with DLCO, CXR) in the pre- and post intervention groups. All rates of 6-month monitoring increased in the postintervention group (TABLE 3, FIGURE 4) compared with the pre-intervention group. Differences between the rates of monitoring of ALT (P = .03) and free T4 (P <.001) were found to be statistically significant between the pre- and postintervention groups. No significant differences in the rate of annual CXR monitoring were discovered (TABLE 4).
To keep the pre- and post intervention groups indepen-dent, if subjects were initiated on amiodarone during the post intervention time period, the baseline monitoring would only be counted towards the post intervention group if completed on initiation or within 6 weeks of amiodarone intervention during the study period. During the study period, there were only 15 patients newly initiated on
DOAC indicates direct oral anticoagulant
Figure 3. Study Enrollment
Patients receiving concomitant amiodarone and warfarin or DOAC between May 1, 2014, and April 30, 2015
N = 202
Pre-interventionMay 1, 2014 -
October 31, 2014N = 108
Post interventionNovember 1, 2014 -
April 30, 2015N = 90
EXCLUSION CRITERIA
ê Subjects in whom amiodarone was started by outside provider
ê Received less than 6 weeks of amiodarone therapy
ê Pregnant ê Hospice care ê Patients in HBPC
Post interventionN = 69
Pre-interventionN = 73
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amiodarone (TABLE 5). In the pre-intervention group, all 73 patients were assessed if baseline monitoring was completed on initiation or within 6 weeks of initiation, even if it was done before the study period. This is because prior to the establishment of pilot clinic, there was no change in usual care of amiodarone monitoring. Patients were initiated on amiodarone and monitoring was completed by cardiologists. Although we did note improvements and maintenance in the rates of monitoring, there were
no statistical differences between baseline monitoring in the pre- and post intervention groups.
Our secondary outcome was to evaluate the effect of a pharmacist-managed dual warfarin and amiodarone monitoring protocol to maintain target INR as measured by % TTR. After exclusion of INRs taken while warfarin was being held for a procedure or upon warfarin initiation, % TTR was 64% in the pre-intervention group and 58% in the post intervention group (TABLE 6).
DISCUSSIONIn this study, rates of amiodarone monitoring before and
after establishing a quality improvement project within an outpatient clinic setting were compared. In terms of baseline monitoring, there was not a significant change between the pre- and post intervention group, likely because baseline monitoring was completed before amiodarone initiation in the inpatient setting. Current rates of baseline amiodarone monitoring were sustained within the inpatient setting, possibly due to the extensive education done by our inpatient pharmacists and cardiologists during the establishment of the amiodarone monitoring protocol.
For the 6-month monitoring, the impact of collaborating with pharmacists could clearly be noted. All rates of monitoring were improved in the post intervention group compared with the pre-intervention group. For annual monitoring, annual monitoring of CXR did not improve, likely because the post intervention time period was six months and CXR are annual monitoring tests. In the pre-intervention group, a year had already lapsed, and as long as CXR had been done within the prior year, it would count towards the rate of monitoring. We anticipate that if the post intervention period was extended to a year, we would see a statistically significant difference. Statistically significant differences were noted in both the rates of ALT and free T4 monitoring. There was no significant difference between the treatment groups for AST monitoring; this may be because clinic pharmacists only order 6-month labs if they are not already done, and AST labs may have been previously ordered, while ALT may have been missing.
Current literature about appropriate amiodarone monitor-ing is sparse. The rates of monitoring seen in several studies leave much room for improvement. In a cross-sectional retrospective chart review, Stelfox et al noted that PFTs were completed at baseline for 52% of patients, which is much higher than our rate of baseline PFT monitoring. A potential reason for this difference in rates of monitoring is that the study by Stelfox et al did not specify if PFTs with DLCO were completed. 23 In our study, if DLCO was not obtained as recommended by NASPE guidelines, then PFTs would
Table 3. Primary Outcome: 6-Month Monitoring of the Study Participants, by Treatment Group
Characteristics Pre-Intervention Post Intervention P
Table 2. Baseline Characteristics of the Study Participants, by Treatment Group
Characteristics Pre-Intervention Post Intervention P
Age: years ± SDa 69.8 ± 8.8 70 ± 9.7 .45
Gender: n (%)b
.59 Male 71 (97.3%) 68 (98.6%)
Female 2 (2.7%) 1 (1.4%)
Race: n (%)b
.19 Black 13 (17.8%) 7 (10.1%)
Nonblack 60 (82.2%) 62 (89.9%)
Anticoagulant: n (%)b
.24 Warfarin 58 (79.5%) 49 (71%)
DOAC 15 (20.5%) 20 (29%)
Indication: n (%)b
.26 AF/flutter 70 (95.9%) 63 (91.3%)
Other 3 (4.1%) 6 (8.7%)
Amiodarone dose: n (%)b
.61 200 mg 61 (83.6%) 53 (76.8%)
100 mg 5 (6.8%) 6 (8.7%)
Other 7 (9.6%) 10 (14.5%)
AF indicates atrial fibrillation; DOAC, direct oral anticoagulant.aStatistical test: Independent Student’s t test.bStatistical test: Pearson’s χ2 test.
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not be marked as complete. Another potential reason is that the patient may not be stable enough to complete PFTs prior to amiodarone initiation and the PFTs may have been obtained soon after. Stelfox et al also demonstrated that ongoing monitoring after baseline monitoring occurs in 22% of patients.23 Compared with Stelfox’s results and those of other published studies, our rates of 6-month monitoring appear to be consistently better. Our study had higher rates of 6-month monitoring of ALT (84% vs 88%), free T4 (41% vs 65%), and annual monitoring of CXR (57% vs 70%) and PFTs (52% vs 68%) compared with the pharmacist-managed group in Spence et al.3 Our rates of monitoring is also better compared with those studied by Tjia et al, in which 6-month monitoring of LFTs and TFTs were completed in 35% and 20% of patients, respectively. In addition, only half of the patients had annual CXRs completed.20 Our improved monitoring-completion numbers are likely a result of the education process that was implemented within our facility among pharmacists and primary care providers and the use of a more collaborative approach. Another reason for our improved rates of monitoring could be that our study was conducted in a VA facility, which is generally a closed medical care system. Pharmacists are able to review monitoring parameters conducted in different
settings of any VA facility. Nonetheless, compared with the study conducted by Graham et al in a VA facility, our rates of baseline monitoring were still improved.21
This study demonstrated the effectiveness of an anti-coagulation clinic in maintaining target INR. We were able to demonstrate % TTR similar to those obtained in randomized control trials.24-26 The % TTR was similar in both the pre- and post intervention groups. This is likely because the pharmacists in the anticoagulation clinic have always been vigilant in monitoring for drug interactions with warfarin and preemptively adjusting warfarin doses. Percent TTR may have been lower in the post intervention group as compared with the pre-intervention group due to various reasons. The postintervention time period was from November to April, and patients may have been less likely to routinely maintain compliance and attend clinic appointments in the wintertime. In addition, the winter months tend to see higher antibiotic use, which can lead to INR variations.27
LimitationsThere were a few limitations to this study, one of which was the time limitation of 6 months in the pre- and postintervention group. We were not able to identity within
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the electronic system if monitoring was done at another facility. Furthermore, we excluded patients if amiodarone was started by a non-VA provider. However, since the pilot clinic was monitoring patients regardless of whether or not amiodarone was initiated by a non-VA provider, excluding these patients may have decreased the rates of monitoring. Additionally, subjects being followed in the community-based outpatient clinic (CBOC) facilities were included but were not being monitored by the pilot clinic, since CBOCs have their own clinic that routinely monitored warfarin and DOAC patients. Another potential limitation of our study is that laboratory testing, CXR, and PFTs may have been obtained for a reason other than amiodarone monitoring. This may overestimate our identified rates of amiodarone monitoring. Because the IRB approval process for research took an extended time, it was not possible to extensively re-educate those involved in the quality improvement project. However, this will be continued on an annual basis in our facility. Finally, major trials involving warfarin have used the Rosendaal method of % TTR,24-26 which incorporates the frequency of INR measurements and the INR values, and assumes that changes between consecutive INR measures are linear. Our calculation of % TTR using fraction of INRs does not take this into account. One disadvantage of using fraction of INRs is that more frequent testing in patients with labile INRs would result in underestimation of TTR.28 Therefore, it is possible that our % TTR may be even higher than depicted.
It is important to bear in mind that this study was conducted in a VA facility, which is largely a closed medical care system. The pilot clinic was able to be sustainable because outpatient pharmacists are able to review if labora-tory values and imaging were done at any point and in any setting within a VA facility. It would be difficult to expect similar results in open care systems in which patients may see varying providers for follow-up care and monitoring. A clinic within a hospital system may not be easily privy to patient data from other facilities. Finally, our results may not be generalizable to female patients since our study sample involved 97% to 98% male patients. Nevertheless, while amiodarone use may sometimes present differences in AEs between males and females, no differences exist between recommended amiodarone monitoring parameters.
CONCLUSIONSThis study demonstrates that incorporating pharmacists into a collaborative management of patients on amiodarone leads to sustained and improved rates of monitoring on recommended laboratory tests. The interdisciplinary involvement of our electrophysiology team, cardiology
team, pharmacists, and primary care providers has been pivotal to the improved monitoring for amiodarone seen in our facility. Further research can delve into the impact of improved monitoring on outcome measurements, such as discontinuation of amiodarone due to toxicities or prevention of emergency department visits.
Author Affiliations: Fairleigh Dickinson University (SC), Florham Park, NJ; Central Arkansas Veterans Healthcare System (RA), Little Rock, AR.
Source of Funding: None.
Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information: Concept and design (SC, RA); acquisition of data (SC, RA); analysis and interpretation of data (SC, RA); drafting of the manuscript (SC, RA); critical revision of the manuscript for important intellectual content (SC, RA); statistical analysis (SC, RA); administrative, technical, or logistic support (SC, RA).
Address correspondence to: Sibyl Marie Cherian, PharmD, BCPS, BCGP, Fairleigh Dickinson University, 230 Park Ave, Florham Park, NJ 07932. E-mail: [email protected].
REFERENCES 1. Cordarone [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals, Inc; 2004. 2. Zimetbaum P, Ho KK, Olshansky B, et al; FRACTAL Investigators. Variation in the utilization of antiarrhythmic drugs in patients with new-onset atrial fibrilla-tion. Am J Cardiol. 2003;91(1):81-83.3. Spence MM, Polzin JK, Weisberger CL, Martin JP, Rho JP, Willick GH. Evalua-tion of a pharmacist-managed amiodarone monitoring program. J Manag Care Pharm. 2011;17(7):513-522. 4. Ehrlich JR, Nattel S. Novel approaches for pharmacological management of atrial fibrillation. Drugs. 2009;69(7):758-774. doi: 10.2165/00003495-200969070-00001. Review.5. Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med. 2005;118(7):706-714. Review.6. Dusman RE, Stanton SS, Miles WM, et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation 1990;82(1):51-9.7. Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J. 2009;16(2):43-48. 8. Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA. 2007;298(11):1312-1322. Review.9. Lewis JH, Ranard RC, Caruso A, et al. Amiodarone hepatotoxicity: preva-lence and clinicopathologic correlations among 104 patients. Hepatology. 1989;9(5):679-685.10. Richer M, Robert S. Fatal hepatotoxicity following oral administration of amiodarone. Ann Pharmacother. 1995;29(6):582-586.11. Goldschlager N, Epstein AE, Naccarelli GV, et al; Practice Guidelines Sub-committee, North America Society of Pacing and Electrophysiology (HRS). A practical guide for clinicians who treat with amiodarone: 2007 [published correction appears in Heart Rhythm. 2007;4(12):1590]. Heart Rhythm. 2007;4(9):1250-1259.12. US Food and Drug Administration. Information for healthcare professionals: simvastatin (marketed as Zocor and generics), ezetimibe/simvastatin (mar-keted as Vytorin), niacin extended-release/Simvastatin (marketed as Simcor), used with amiodarone (Cordarone, Pacerone). FDA website. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124362.htm. Updated August 15, 2013. Accessed September 30, 2014.13. US Food and Drug Administration. Altoprev (Lovastatin extended-release) tablets detailed view: safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER). FDA website. www.fda.gov/Safety/Med-Watch/SafetyInformation/ucm303638.htm. Accessed September 30, 2014. 14. US Food and Drug Administration. Cordarone (amiodarone HCl) tablets detailed view: safety labeling changes approved by FDA Center for Drug Evalu-ation and Research (CDER). FDA website. www.fda.gov/Safety/MedWatch/SafetyInformation/ucm239971.htm. Accessed September 30, 2014.
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15. Siddoway LA. Amiodarone: guidelines for use and monitoring. Am Fam Physician. 2003;68(11):2189-2196.16. Almog S, Shafran N, Halkin H, et al. Mechanism of warfarin potentiation by amiodarone: dose- and concentration-dependent inhibition of warfarin elimination. Eur J Clin Pharmacol. 1985;28(3):257-261.17. Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationship with long-term therapy. CHEST. 2002;121(1):19-23. 18. Raebel MA, Carroll NM, Simon SR, et al. Liver and thyroid monitoring in ambulatory care patients prescribed amiodarone in 10 HMOs. J Manag Care Pharm. 2006;12(8):656-664. 19. Bickford CL, Spencer AP. Adherence to the NASPE guideline for amiodarone monitoring at a medical university. J Manag Care Pharm. 2006;12(3):254-259. 20. Tjia J, Field TS, Garber LD, et al. Development and pilot testing of guidelines to monitor high-risk medications in the ambulatory setting. Am J Manag Care. 2010;17(7):489-496. 21. Graham MR, Wright MA, Manley HJ. Effectiveness of an amiodarone proto-col and management clinic in improving adherence to amiodarone monitoring guidelines. J Pharm Technol. 2004;20(1):5-10.
22. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm. 2009;15(3):244-252. 23. Stelfox HT, Ahmed SB, Fiskio J, Bates DW. Monitoring amiodarone’s toxici-ties: recommendations, evidence, and clinical practice. Clin Pharmacol Ther. 2004;75(1):110-122.24. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. doi: 10.1056/NEJMoa0905561.25. Granger CB, Alexander JH, McMurray J, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365 (11):981-992. doi: 10.1056/NEJMoa110703926. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonval-vular atrial fibrillation. N Engl J Med. 2011;365:883-891.27. Suda KJ, Hicks LA, Roberts RM. Trends and seasonal variations in outpa-tient antibiotic prescription rates in the United States, 2006-2010. Antimicrob Agents Chemother. 2014;58(5):2763-2766. 28. Schmitt L, Speckman J. Quality assessment of anticoagulation dose management: comparative evaluation of time-in-therapeutic range. J Thromb Thrombolysis. 2003;15(3):213-216.
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ABSTRACT
Objectives: Primary care providers (PCPs) treat the vast major-ity of gastroesophageal reflux (GERD) and chronic constipation (CC) patients in the United States. The aim of this study was to evaluate how PCPs perceive and utilize store brand and brand name OTC products for GERD and CC.
Methods: A 33-question survey was electronically sent to 622 eligible PCPs from the Internal Medicine Insider Research panel. The survey asked respondents about their usage of store brand and brand name OTCs for patients with GERD and CC, and requested their opinions about the quality, efficacy, safety, and price of these medications. Chi-square and students' t tests were utilized for bivariate analysis.
Results: A total of 337 PCPs (54% response rate) completed the survey. For the typical GERD and CC patient, 64% and 98% of PCPs utilized OTC medications for first-line treatment, respectively. Proton pump inhibitors (PPIs) were the most common OTC utilized for GERD (59%), while OTC fiber supple-ments (45%) were utilized most commonly for CC. The vast majority of PCPs felt that OTC store brand and brand name PPIs (79%) and polyethylene glycol (PEG) 3350 (87%) were equally effective. Despite this, only 24.7% of physicians have “some or extensive” discussion with patients about the use of store brand products in the treatment of their gastrointestinal disease. PCPs believed that store brand products were less expensive than brand name products, but more than 60% un-derestimated the cost savings (>20%) for both PPIs and PEG 3350. Few physicians had knowledge regarding the regulation of store brands.
Conclusions: For PCPs, OTC drugs are the cornerstone of treating GERD and CC patients. Though the majority of PCPs feel that store brand and brand name treatments offer similar effectiveness and reduced cost for GERD and CC patients, few discuss these points with their patients. Systematic efforts are needed to ensure that patients are better educated about low-cost treatment options for GERD and CC.
Am J Pharm Benefits. 2017;9(4):116-121
G astroesophageal reflux (GERD) and chronic constipation (CC) are common gastrointestinal complaints seen by primary care providers (PCPs). GERD affects at least
20% of the US population and is the fourth most common chronic condition seen in primary care.1,2 Constipation affects 16% of all adults and 33% of adults 60 years or later.3 Both disorders have high direct medical costs, with GERD being the leader of all digestive diseases at $12.1 billion yearly.4 For both disorders, medications contribute significantly to these costs.4
For both GERD and CC, the medication landscape has changed significantly in the last 10 years. This is primarily due to the availability of OTC formulations— either generic or store brand (ie, Target-brand omeprazole or Walmart-brand PEG 3350) or brand name (ie, Prilosec or Miralax)—of drugs previously available only by prescription. Brand name and store brand OTC drugs each contain the same active ingredient, but differ in price. Third-party payers are increasingly refusing to initially cover the cost of high-tier prescription medications for “lifestyle conditions.” This forces patients with conditions like GERD and CC to purchase OTC options out of pocket, placing a premium on economic value in addition to efficacy.
As PCPs see the most patients with GERD5,6 and CC,7 it is critical to understand their prescribing practices regarding prescription and OTC products in this era of cost consciousness. Therefore, the aim of this study was to assess how US PCPs perceive and utilize prescription as well as brand name and store brand OTC medications for GERD and CC, and to assess PCPs’ knowledge of the federal regulation of OTC medications. We hypothesized that US PCPs would be very familiar with and commonly recommend OTC medications for GERD and CC, but that they would have little knowledge of manufacturing, efficacy, and price differences between store brand OTC gastrointestinal medications and brand name alternatives.
MATERIALS AND METHODSSample PopulationAfter attaining exemption through the University of Michigan Medical School institutional review board, a nationally
US Primary Care Providers’ Use of Over-the-Counter Medications for Gastroesophageal Reflux Disease and Chronic ConstipationSamuel W. Chey; William D. Chey, MD; Sameer D. Saini, MD; Arlene Weissman, PhD; Linda Harris; and Stacy B. Menees, MD
ORIGINAL RESEARCH
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representative sample of US internists was surveyed in 2015. For our sampling frame, we utilized the American Col-lege of Physicians (ACP) Research Center’s Internal Medicine Insider Research panel, which is a represen-tative group of ACP members who have voluntarily agreed to participate in periodic physician surveys.8 The eligible population consisted of 622 internists of the 1286 ACP members who are representative of the United States ACP membership across multiple demographic characteristics. Panelists who completed surveys were awarded $10 electronic gift cards. Information was not collected on nonresponders. To attain a 95% confidence level with a 5% margin of error for our results, we required a response from at least 244 of the 662 members.
Survey MethodsThe survey was developed by the authors after careful literature review and consulting with physicians regarding their prescribing practices for GERD and CC. All of the authors reviewed, tested, and edited the questions for readability. This survey was formulated without any influence from our pharmaceutical sponsor. Participants answered 33 questions assessing sociodemographics, including age, race/ethnicity, practice type, years of practice, and weekly patient volume; their usage of store brand and brand name OTCs for GERD and CC; and their knowledge about these products’ source, quality, efficacy, safety, and price, especially in comparison to one another (EAPPENDIX, available at ajpb.com). Respondents were also assessed on their knowledge of the OTC regulatory process.
Statistical AnalysisSurvey data were analyzed using descriptive statistics. Ques-tions were examined to assess differences in respondent’s gender, practice type, practice region, years in practice, and patient volume. Practice years were categorized into 3 categories: 10 years or less, 11 to 20 years, and greater than 20 years. Primary outcome measures were the reported first-line medications used for routine patients with GERD or CC. We then performed bivariate analysis for demographic predictors including age, race/ethnicity, practice type, years in practice, and weekly patient volume for each of the survey’s questions using c2 and students' t tests. Two-sided P values >.05 were considered to be statistically significant. Statistical analyses were performed using SPSS version 23 (IBM Corp; Armonk, New York).
RESULTSOf the 662 potential respondents, 337 internists (54% response rate) completed and returned the survey. Charac-teristics of the study population are described in TABLES 1 and 2. Our study population was comparable with the current composition of US ACP members. The majority of participants were male (58.5%) and Caucasian (63%) with 47% in practice for more than 20 years. Respondents represented all 4 US geographic regions, with the largest response coming from the Western region (31%).
GERDFor the typical acid reflux patient, 64.5% of participants recommended an OTC medication as a first-line treatment
PRACTICAL IMPLICATIONS■■ The majority of internists utilize OTC products as the cornerstone of treatment for both gastro-
esophageal reflux disease and chronic constipation.
■■ Though the majority of primary care providers feel that store brand and brand name treat-ments offer similar effectiveness for both complaints, few directly discussed this opinion with their patients.
■■ More than half of respondents recognized the cost savings associated with store brand versus brand name treatments.
Table 1. Study Participant Characteristics (N = 337)
Variable Categories N %
Physician Practice Residency/fellowship program 95 28
Office-based practice 162 48
Hospital-based practice 6 1.8
Academic 32 9.4
US government 20 5.9
HMO 5 1.5
Other 17 5
Age (years) ≤45 159 47
46-60 128 38
>60 49 15
Gender Male 197 59
Female 140 42
Hispanic, Latin, or Spanish origin
Yes 18 5
Racial group(s) White 212 63
Black/African American 9 3
Asian 92 27
Native Hawaiian/other Pacific Islander 1 <1
American Indian/Alaska Native 4 1
Other 29 9
HMO indicates health maintenance organization.
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(TABLE 3). Proton pump inhibitors (PPIs), both OTC and prescription, were the most commonly prescribed (59.4%) in the typical reflux patient. Almost two-thirds (63.5%) of the respondents who recommended a PPI suggested an OTC product. Thirty-one percent of practitioners started treatment for GERD with either an OTC (17.3%) or prescription (13.7%) H2 receptor antagonist (H2RA). Providers in the Midwest were least likely to utilize H2RAs (7%) for first-line treatment compared with other parts of the country (28.1% Northeast, 20.3% South, 29.7% West [P = .01]). The remaining practitioners (9.3%) recommended OTC antacids. There were no other predictors for the physicians who practiced “step-up” therapy, ie, used an antacid or H2RA as first-line medication.
More than three-fourths of respondents (76%) felt that store brand PPIs had an equal bioequivalence to brand name PPIs, and 82% of respondents felt that store brand PPIs were equally or more clinically effective than brand name PPIs. However, despite this belief, only 25.1% of respondents specifically recommended a store brand PPI “always” or “most of the time.” There were no defining provider or practice characteristics with this recommendation. Conversely, 19.1% of respondents specifically directed
their patients to purchase a brand name PPI “always” or “most of the time.”
Respondents underestimated the cost savings of store brand products compared with brand name products for GERD. Overall, 61% of respondents did not realize that cost savings could exceed 20% by purchasing a store brand OTC instead of a brand name OTC for GERD treatment. However, 46.6% of respondents understood that store brand products offered some cost savings (1%-20%) in comparison with brand name products.
Chronic Constipation For typical patients with CC, more than 98% of respondents utilized an OTC for first-line therapy, including fiber supplements, stimulants, osmotics, and stool softeners (FIGURE). Fiber supplements were the primary first-line therapy utilized for CC, with 45.7% of respondents recommending this therapy. Less than 2% of respondents recommended a prescription medication such as linaclotide as a first-line therapy. No respondents recommended the prescription medication lubiprostone as a first-line therapy. For patients who failed to improve after first-line therapy, nearly 88% of respondents continued to recommend OTCs as a second-line therapy, with osmotics as the first choice (29.8%) and OTC stimulants a close second (27%) (Figure). Only 12.5% of respondents recommended prescription medications for second-line therapies. For those who prescribed OTC fiber as first-line treatment, osmotics (OTC 44.2% and Rx 5.4%) were the most commonly prescribed second-line treatment. OTC stool softeners and stimulants were second-line choices of 32% and 16.3% of providers who initially prescribed fiber, respectively. Stool softeners were utilized by 23.3% and 19.3% of providers for first-line and second-line treatment, respectively. Providers aged 45 years or less were the most likely to use stool softeners (31%) for first-line treatment, compared with physicians aged 46-60 years (18.1%) and older than 60 years (14.3%) (P = .01). No other predictors for CC prescribing practices were seen.
Respondents were asked to assess the effectiveness of store brand polyethylene glycol (PEG) 3350 to its brand name counterpart PEG 3350 (Miralax). Eighty-seven percent of respondents believed that store brand PEG 3350 and Miralax were equally effective, and 2% believed that the store brand was slightly or significantly more effective than the brand name product. Similar to GERD drugs, respondents underestimated the cost savings associated with store brand PEG 3350 versus Miralax. About 30% answered that they thought the store brand product was more than 20% less expensive than the brand name product. A total of 53.4%
Table 3. First-Line Treatment Recommended by Internists (N = 335) for Typical Acid Reflux Patients
Medicine % (n)
OTC antacids 9.3% (31)
OTC H2 receptor antagonists 17.3% (58)
OTC PPIs 37.9% (127)
Rx H2 receptor antagonists 13.7% (46)
Rx PPIs 21.8% (73)
PPI indicates proton pump inhibitor.
Table 2. Study Participant Practice Characteristics (not including physicians in training) (N = 242)
Variable Categories N %
Practice specialty Single specialty 122 50
Multispecialty 120 50
Practice years 1-10 53 22
11-20 75 31
>20 113 47
Employment/professional status Full time 208 86
Part time 34 14
Geographic location Northeast 57 24
Midwest 43 18
West 74 31
South 64 27
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of participants thought the store brand was a little less expensive (1%-20%) than the brand name.
OTC Regulatory ProcessInternists were asked to evaluate their knowledge of the drug approval process for store brand OTC products. More than 70% of respondents reported they had “little” or “no” knowledge of the approval process for store brand products. Furthermore, more than 75% of respondents had “little” or “no” discussion regarding store brand OTC medications as a treatment option for GERD or CC with their patients. We then assessed the internists’ sense of bioequivalence of store brand medica-tions from different retailers. Only 25.5% of internists “strongly” agreed that store brand medications from dif-ferent retailers (Walgreens, Target, CVS, etc) were bioequivalent. Additionally, only 22.6% of respondents “strongly” agreed that production standards and FDA inspections were similar for facilities producing store brand OTCs and brand name products. Forty-three percent of participants correctly indicated that 1 to 2 manufacturers produce the majority of store brand OTC GI medications.
DISCUSSIONOur survey of US PCPs demonstrated some fascinating results on the reported medical treatment of GERD and CC. The majority of PCPs utilize OTC medications as the cornerstone of treatment for both GERD and CC. Although the majority of PCPs feel that store brand and brand name treatments offer similar effectiveness for both complaints, few directly discussed this opinion with their patients. Additionally, more than half the respondents recognized some cost savings associated with store brand versus brand name treatments. However, providers did not know the full extent of the savings.
For treatment of GERD, the most recent guidelines recommend empiric medical therapy with a PPI.9 Six of 10 internists chose a PPI, whether prescription or OTC, for initial use. Still, a significant portion of practitioners (40%) would utilize step-up therapy by starting with either an antacid or H2RA. This practice was common in the early 2000s with close to two-thirds of practitioners utilizing this strategy.10 Shortly thereafter, however, Howden and
colleagues performed a clinical trial within a primary care setting, demonstrating that step-up therapy was inferior for control of GERD symptoms compared with initial PPI and continued dosing.11 A national survey of PCPs published in 2005 seemed to indicate this practice was largely abandoned, with only a minority of providers using this method at that time. However, our survey results suggest that a significant minority of PCPs still utilizes a “step-up” strategy for the treatment of GERD. This may be secondary to the emerging reports suggesting adverse effects associated with PPIs, such as the potential risk of fractures, clostridium difficile infections, hypomagnesemia, and pneumonia.12-19 Because this survey was performed in August 2015, and the associations of PPIs with chronic kidney disease and dementia were published and publicized nationally in 2016,20,21 we may continue to see increased use of step-up therapy in 2017 and beyond.
Internists utilized a variety of OTCs as their first- and second-line treatments for constipation. Even though OTC fiber supplements were the most commonly recommended first-line treatment, they seem to be underutilized by participating providers. National guidelines support the use of fiber supplements as first-line therapy for constipation.3 The use of OTC osmotics, specifically PEG 3350, is also a reasonable first-line choice for CC.3,22 Interestingly, OTC
OTCOsmotics44.2%
Rx Amitiza.7%
Rx Linzess1.4%
Rx Osmotics5.4%
OTCStimulants
16.3%
OTC StoolSofteners
32%OTC Fiber
Supplements17.5%
Rx Amitiza2.5%
Rx Linzess5%
RxOsmotics13.8%
OTCStimulants
46.3%OTC StoolSofteners
15%OTC
Osmotics30.7%
Rx Amitiza2.7%
Rx Osmotics6.7%
OTCStimulants
30.7%OTC FiberSupplements
29.3%
OTCOsmotics24.8%
Rx Linzess.9%
OTCStimulants
4.7%
Rx Osmotics.6%
OTC StoolSofteners23.3%
OTC FiberSupplements
45.7%
Figure. First- and Second-Line Treatment for Chronic Constipation
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stool softeners were almost as commonly utilized for first-line treatment as OTC osmotics; these were used more than twice as commonly by physicians younger than 45 years compared with older physicians. This is troubling, as there is a lack of clinical evidence to support the efficacy of docusate for the management of constipation. The available data demonstrate that docusate is no more effective than placebo.23-25 For second-line treatment for constipation, OTC osmotics were the most popular choice, although only 30% of practitioners chose them. Additionally, there was a marked increase in the use of OTC stimulants from first- to second-line therapy (4.7%-27%), and the persistent use of OTC stool softeners for 1 in 5 providers continued in the second line. OTC stimulants work by propagating colonic contractions with effects on the balance between secretive and absorption.26,27 There were early concerns about the use of stimulants and potential damage to the enteric nerve system; however, this has not been seen in real-world practice.28,29 Stimulants are typically recommended as a third-line medication, as either a rescue therapy or as an adjunct to an osmotic regimen.
This survey provided evidence of some other interesting thought trends. A majority of the participating internists agreed that store brand and brand name PPIs and PEG 3350 were both bioequivalent and clinically effective. Additionally, the majority underestimated the extent of cost savings associated with store brand OTC PPIs and PEG 3350 compared with brand name medications. Importantly, only a minority had conversations with patients about the clinical effectiveness and cost savings associated with store brand products. Thus, significant cost savings continue to go unrealized by patients. These findings were similar to those that emerged from our survey of practicing gastroenterologists.30 It is worth noting that the cost savings for a particular store brand PPI is directly correlated to the length of time that PPI has been OTC. In addition to practitioners having knowledge deficits about this topic, it is also possible that conversations don’t happen because practitioners are under time constraints during patient visits, with too many other things to discuss. Lastly, most participants admitted to minimal knowledge about the OTC regulatory process, and just about half of internists understood the bioequivalence among store brands of different retailers and that the production standards and FDA inspections are the same for both store brand and brand name products.
This presents an opportunity for further education. In order for an OTC to be approved, the brand name pharmaceutical company has to demonstrate the following: 1) the drug is safe and effective, 2) label comprehension
studies have been performed to ensure the product label is understandable, and 3) actual use studies have been performed to ensure that the general population can use the product correctly according to the label, without a prescriber. If the brand name drug is FDA-approved for OTC use, the brand name pharmaceutical company has 3 years of additional exclusivity after coming off patent. The approval process for the generic market takes approximately 5 to 8 years. Generic pharmaceutical companies must apply for an amended new drug application (ANDA), despite patents on brand name drugs. Fundamentally, brand name and store brand medications contain the same active ingredient. Although phase 3 efficacy trials are not required, bioequivalence studies are needed for FDA approval of store brand products.18 Those companies that file an ANDA may be sued by the brand name pharmaceutical company for patent infringement. If there is litigation and the generic company wins, they can then launch their market formulation. These OTC generic medicines are then sold to retailers and are labeled with a store name, ie, Walmart-brand omeprazole.
LimitationsOur study has some potential limitations. Our survey sampled physicians from the ACP’s membership list. It is possible that the responders may not represent the larger group of practicing PCPs, ie, an internist’s practice may not reflect a family-medicine physician’s practice. The generalizability of these findings to other PCPs is unknown. Additionally, our survey results relied on self-reported data, and so our findings may be subject to a number of unforeseen biases.
CONCLUSIONSFor internists, OTC drugs are the cornerstone of treating GERD and CC patients. Even though the majority of PCPs feel that store brand and brand name treatments offer similar effectiveness and reduced cost for GERD and CC patients, few discuss these points with their patients. Systematic efforts are needed to ensure that patients are better educated about cost-effective treatment options for GERD and CC. .
Author Affiliations: Division of Gastroenterology, University of Michigan Health System (SWC, WDC, SDS, SBM), Ann Arbor, MI; Division of Gastroenterology, Ann Arbor Veterans’ Administration Hospital (SDS, SBM), Ann Arbor, MI; American College of Physicians (AW, LH), Philadelphia, PA; VA Center for Clinical Management Research (SDS), Ann Arbor, MI.
Source of Funding: This study was supported by an unrestricted grant from Perrigo. The sponsor played no role in design of the survey or analysis of the results.
Author Disclosures: Dr W.D. Chey has worked as a consultant for or received grants from Astra-Zeneca, Actavis, Ardelyx, IM Health, Ironwood,
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Nestle, Prometheus, OOL Medical, Salix, SK, Sucampo, Takeda, and Vibrant. Dr Saini was a paid consultant for FMS, Inc, on a modeling study examining the effects of PPI in aspirin users. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information: Concept and design (WDC, SDS, SBM); acquisition of data (SDS, AW, LH); analysis and interpretation of data (SWC, WDC, SDS, AW, LH, SBM); drafting of the manuscript (SWC, SDS, SBM); critical revision of the manuscript for important intellectual content (SWC, WDC, SDS, SBM); statistical analysis (AW, LH);; obtaining funding (WDC); administrative, technical, or logistic support (SWC, WDC, SDS, LH); and supervision (SDS, SBM).
Address correspondence to: Stacy B. Menees, MD, 3912 Taubman Center, SPC 5362, Ann Arbor, MI 48109-5362. E-mail: [email protected].
REFERENCES1. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014;63(6):871-880. doi: 10.1136/gutjnl-2012-304269.2. Ornstein SM, Nietert PJ, Jenkins RG, Litvin CB. The prevalence of chronic dis-eases and multimorbidity in primary care practice: a PPRNet report. J Am Board Fam Med. 2013;26(5):518-524. doi: 10.3122/jabfm.2013.05.130012.3. Bharucha AE, Pemberton JH, Locke GR 3rd. American Gastroen-terological Association technical review on constipation. Gastroenterology. 2013;144(1):218-238. doi: 10.1053/j.gastro.2012.10.028. Review.4. Everhart JE, e., The Burden of Digestive Diseases in the United States, U.S.D.o.H.a.H.S. National Institute of Diabetes and Digestive and Kidney Diseases, Editor. 2008, NIH Publication: Bethesda, MD.5. Friedenberg FK, Hanlon A, Vanar V, et al. Trends in gastroesophageal reflux disease as measured by the National Ambulatory Medical Care Survey. Dig Dis Sci. 2010;55(7):1911-1917. doi: 10.1007/s10620-009-1004-0.6. Halpern R, Kothari S, Fuldeore M, et al. GERD-related health care utilization, therapy, and reasons for transfer of GERD patients between primary care providers and gastroenterologists in a US managed care setting. Dig Dis Sci. 2010;55(2):328-337. doi: 10.1007/s10620-009-0927-9.7. Shah ND, Chitkara DK, Locke GR, Meek PD, Talley NJ. Ambulatory care for constipation in the United States, 1993-2004. Am J Gastroenterol. 2008;103(7):1746-1753. doi: 10.1111/j.1572-0241.2008.01910.x.8. Butkus R, Weissman A. Internists’ attitudes toward prevention of firearm injury. Ann Intern Med. 2014;160(12):821-827. doi: 10.7326/M13-1960.9. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease [published correction appears in Am J Gastroenterol. 2013;108(10)1672]. Am J Gastroenterol. 2013;108(3):308-328; quiz 329. doi: 10.1038/ajg.2012.444.10. Wilcox CM, Heudebert G, Klapow J, Shewchuk R, Casebeer L. Survey of pri-mary care physicians’ approach to gastroesophageal reflux disease in elderly patients. J Gerontol A Biol Sci Med Sci. 2001;56(8):M514-M517.11. Howden CW, Henning JM, Huang B, Lukasik N, Freston JW. Management of heartburn in a large, randomized, community-based study: comparison of four therapeutic strategies. Am J Gastroenterol. 2001;96(6):1704-1710.12. Khalili H, Huang ES, Jacobson BC, Camargo CA Jr, Feskanich D, Chan AT. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ. 2012;344:e372. doi: 10.1136/bmj.e372.13. Targownik LE, Leslie WD, Davison KS, et al; CaMos Research Group. The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based study [corrected] from the Canadian
Multicentre Osteoporosis Study (CaMos) [published correction appears in Am J Gastroenterol. 2013;108(1):157]. Am J Gastroenterol. 2012;107(9):1361-1369. doi: 10.1038/ajg.2012.200.14. Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA. 2005;294(23):2989-2995.15. Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton pump inhibi-tors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010;170(9):772-778. doi: 10.1001/archinternmed.2010.73.16. Hess MW, Hoenderop JG, Bindels RJ, Drenth JP. Systematic review: hypo-magnesaemia induced by proton pump inhibition [published correction ap-pears in Aliment Pharmacol Ther. 2012;36(11-12):1109]. Aliment Pharmacol Ther. 2012;36(5):405-413. doi: 10.1111/j.1365-2036.2012.05201.x.17. Luk CP, et al. Proton pump inhibitor-associated hypomagnesemia: what do FDA data tell us? Ann Pharmacother. 2013;47(6):773-780. doi: 10.1345/aph.1R556.18. Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292(16):1955-1960.19. Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med. 2008;149(6):391-398.20. Lazarus B, Chen Y, Wilson FP, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016;176(2):238-246. doi: 10.1001/jamainternmed.2015.7193.21. Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73(4):410-416. doi: 10.1001/jamaneurol.2015.4791.22. Ford AC, Moayyedi P, Lacy BE, et al; Task Force on the Management of Functional Bowel Disorders. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic con-stipation. Am J Gastroenterol. 2014; |109| (suppl 1):S2-S26; quiz S27. doi: 10.1038/ajg.2014.187. Review.23. Fosnes GS, Lydersen S, Farup PG. Effectiveness of laxatives in elderly-a cross sectional study in nursing homes. BMC Geriatr. 2011;11:76. doi: 10.1186/1471-2318-11-76.24. Tarumi Y, Wilson MP, Szafran O, Spooner GR. Randomized, double-blind, placebo-controlled trial of oral docusate in the management of constipation in hospice patients. J Pain Symptom Manage. 2013;45(1):2-13. doi: 10.1016/j.jpainsymman.2012.02.008.25. Hawley PH, Byeon JJ. A comparison of sennosides-based bowel protocols with and without docusate in hospitalized patients with cancer. J Palliat Med. 2008;11(4):575-581. doi: 10.1089/jpm.2007.0178.26. Ewe K, Hölker B. [The effect of a diphenolic laxative (Bisacodyl) on water- and electrolyte transport in the human colon (author’s transl)]. Klin Wochen-schr. 1974;52(17):827-833.27. Manabe N, Cremonini F, Camilleri M, Sandborn WJ, Burton DD. Effects of bisacodyl on ascending colon emptying and overall colonic transit in healthy volunteers. Aliment Pharmacol Ther. 2009;30(9):930-936. doi: 10.1111/j.1365-2036.2009.04118.x.28. Dufour P, Gendre P. Ultrastructure of mouse intestinal mucosa and changes observed after long term anthraquinone administration. Gut. 1984;25(12):1358-1363.29. Kiernan JA, Heinicke EA. Sennosides do not kill myenteric neurons in the colon of the rat or mouse. Neuroscience. 1989;30(3):837-842.30. Menees SB, Guentner A, Chey SW, Saad R, Chey WD. How do US gastro-enterologists use over-the-counter and prescription medications in patients with gastroesophageal reflux and chronic constipation? Am J Gastroenterol. 2015;110(11):1516-1525. doi: 10.1038/ajg.2015.156.
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ABSTRACT
Objectives: To characterize clinical trials supporting FDA approval of new cancer therapeutics and of supplementary indications and off-label indication inclusions on DRUGDEX, a Medicare-referenced compendium, each of which can guaran-tee reimbursement by Medicare.
Methods: Cross-sectional study using publicly available docu-ments for cancer therapeutics initially approved by the FDA from 2005-2012. Trials supporting approval were identified, characterizing randomization, blinding, comparator, end point, number of patients, and duration.
Results: Between 2005-2012, FDA approved 37 new cancer therapeutics for 39 indications, based on 50 supportive trials. These therapeutics subsequently received 21 FDA supplemen-tary indication approvals and 16 DRUGDEX off-label indication inclusions, based on 22 and 37 supportive trials, respectively. Of 109 total trials, 53.2% (95% CI, 43.9%-62.3%), 28.4% (95% CI, 20.8%-37.5%), and 53.2% (95% CI, 43.9%-62.3%) were randomized, double-blinded, and used a comparator, respectively. There was a median of 383 (interquartile range, 178 to 623) patients among aggregated supportive trials, whereas 38.2% (95% CI, 28.1%-50.6%), 69.7% (95% CI, 58.7%-78.9%), and 18.4% (95% CI, 11.3%-28.6%) were supported by at least 1 trial that lasted ≥6 months, used a comparator group, or used overall survival as a primary end point, respectively. There were few substantive differences in the aggregated clinical trial evidence supporting FDA new drug and supplementary indication approvals and DRUGDEX off-label indication inclusions.
Conclusions: The evidence supporting DRUGDEX off-label indications was similar to that used for FDA approval of new and supplementary cancer therapeutic indications, all of which had limitations for informing clinical decision making.
Am J Pharm Benefits. 2017;9(4):122-130
U nderstanding the evidence supporting new drug and supplementary indication approvals by the FDA is important for cancer care. Because many cancer patients
face life-threatening disease for which there is not necessarily an effective treatment, anecdotal evidence can exert a strong influence on clinical decisions,1 making rigorous and objective evaluation by the FDA essential. The FDA approves the use of cancer therapeutics for specific medical indications only when
“adequate and well-controlled investigations” can demonstrate the therapeutic’s safety and efficacy.2 Although physicians can use therapeutics “off-label”—that is, for an indication not specifically approved by the FDA—FDA approval guarantees an indication’s reimbursement by CMS.3 Reimbursement, in turn, may influence how cancer therapeutics are used in an era of increasingly expensive cancer treatment.4,5
For cancer therapeutics, there are 2 ways by which phar-maceutical manufacturers can ensure reimbursement for indications beyond those initially approved by the FDA. First, manufacturers can apply to the FDA for a second (or third, and so on) “supplementary indication” by providing supportive clinical evidence of a therapeutic’s efficacy and safety when used for the new indication. Second, manufacturers can seek the inclusion of off-label indications on Medicare-referenced compendia, which are comprehensive drug guides that list off-label indications deemed appropriate based on expert review of biomedical literature. The Omnibus Budget Reconciliation Act of 1993 required that CMS reimburse off-label cancer therapeutic use endorsed by these compendia.6 Because some private insurers are required to follow the same compendia per state legislation,7,8 inclusion of an off-label indication on compendia can secure coverage without FDA indication approval.
Concerns have been raised regarding the quality of clinical evidence supporting the FDA approval of new cancer therapeu-tics,5,9 particularly the reliance on surrogate markers of disease as opposed to clinical outcomes.10,11 One prior study found that new drug and supplementary indication approvals for cancer drugs were supported by trials focused on clinical outcomes with similar frequency, but that trials supporting supplementary
Cancer Therapeutic Clinical Trials Supporting FDA Approval and Compendia InclusionKevin W. Su, MD; Cary P. Gross, MD; Nicholas S. Downing, MD; Kerin B. Adelson, MD; and Joseph S. Ross, MD, MHS
ORIGINAL RESEARCH
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indication approvals more frequently used active comparators (ie, compared the new therapeutic with an available therapeutic alternative).12 However, no studies have comprehensively assessed the quality of evidence supporting the inclusion of off-label indications on compendia for cancer therapeutics, even though a 2009 review by the Agency of Healthcare Research and Quality raised concerns regarding whether compendia used consistent standards and methodologies.13 Our objective was to characterize and compare the clinical trials supporting new drug and supplementary indication approvals by the FDA and off-label indication inclusion on DRUGDEX, a Medicare-referenced compendium, focusing on trial number, size, design, duration, and end points. We used DRUGDEX, the compendium managed by Micromedex, because all of its supporting documentation is publicly available, it may list the greatest number of off-label indications among Medicare-referenced compendia,13 and its classification of indications as on-label versus off-label facilitated comparison with the FDA approval process.
METHODSData SourcesDrugs@FDA is a publicly accessible database available through the FDA’s website that lists regulatory actions, such as approvals and drug labeling changes, for all currently approved prescription therapeutics.14 The database also contains documents relevant to each therapeutic’s regulatory history, including approval letters and other correspondence, medical reviews for new drug applications and biologic license applications, and current and historical drug labels. Clinical evidence supporting each FDA-approved indication is summarized on these labels. The Drugs@FDA database was downloaded on March 6, 2015, and October 12, 2015.
Micromedex DRUGDEX® (Truven Health Analytics) is 1 of 5 compendia currently recognized by the CMS under the Omnibus Budget Reconciliation Act.15 The most recent version of the compendium is available online by subscription. Data regarding revision history were not available on request. Each therapeutic’s monograph in DRUGDEX contains information on dosing, pharmacokinet-ics, safety, and clinical applications. Clinical applications include information on both FDA-approved and off-label indications, with a description of supporting evidence reviewed. DRUGDEX monographs were downloaded on March 9, 2015, and October 12, 2015.
Study SampleWe limited our sample to novel therapeutics originally approved by the FDA between January 1, 2005, and December 31, 2012, for the treatment of cancer, as identified in a previous study (FIGURE).16 This time period allows at least 2 (and up to 10) years of follow-up for therapies to acquire supplementary indications and DRUGDEX off-label indications. Our sample excluded generic drugs, reformulations, and nontherapeutic agents, as well as non-anticancer agents (eg, plerixafor or tbo-filgrastim). Each therapeutic was categorized by original FDA approval year and as a pharmacologic or biologic agent.
Identifying Supplementary FDA IndicationsWe searched Drugs@FDA to identify supplementary indications for adults approved through March 6, 2015, and updated our search on October 12, 2015. Supplementary indications were identified by searching for regulatory decisions modifying the “Indication and Usage” section of the drug label. We included both supplementary indications approved through an additional new drug application or biologic license application, as well as those approved through an “efficacy supplement” to the therapeutic’s original new drug application or biologic license application.17 We excluded regulatory decisions that limited the scope of prior indications, or qualified or reworded a prior indication without significantly changing its scope. We excluded supplementary indica-tions that only expanded a therapeutic’s use to pediatric patients, to facilitate comparison against off-label indica-tions reimbursed by Medicare due to their inclusion on DRUGDEX.
Identifying Off-Label Indications in DRUGDEXWe last searched DRUGDEX on October 12, 2015, to identify off-label indications currently listed with a Class I, IIa, or IIb strength of recommendation or efficacy, per CMS criteria for what constitutes a “medically accepted indication.”18
PRACTICAL IMPLICATIONS■■ There are 2 ways by which pharmaceutical manufacturers can be reimbursed for cancer
therapeutics: seeking FDA approval for a new or supplementary indication or inclusion of a non-FDA approved indication on Medicare-referenced compendia.
■■ We found that the clinical trial evidence used to support inclusion of off-label indications on DRUGDEX (a Medicare-referenced compendium) was consistent with those used for FDA new drug and supplementary indication approvals for cancer therapeutics.
■■ Most indications were not supported by trials examining overall survival benefit, and nearly one-third were not supported by trials using a comparator group, raising concerns about whether the clinical evidence underlying these approvals are sufficient to inform clinical decision making.
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Indication CharacteristicsWe characterized each identified indication by approval type (FDA new drug, FDA supplementary, or DRUGDEX off-label). Indications were classified into “hematologic,”
“solid tumor, curative intent,” and “solid tumor, noncurative intent.” “Noncurative intent” refers to indications that explicitly mention metastatic or advanced disease, salvage therapy, second-line use or use after other therapies, or failure of prior therapies (eg, disease that is refractory, resistant, relapsed, or progressive after prior therapy). We also identified whether FDA supplementary and DRUGDEX off-label indications treated the same target cancer type as the original FDA indication.
Identification of Evidence Supporting Therapeutic EfficacyWe identified the clinical evidence of therapeutic efficacy supporting FDA new drug and supplementary approvals and DRUGDEX off-label indications. For FDA new drug approvals, we used medical reviews to identify “pivotal efficacy trials” supporting the indication’s approval, as described in a previous study.16 For FDA supplementary indications, medical review documents were generally not available. Instead, we included all trials listed on FDA drug labels issued at the time of an indication’s approval as supportive evidence for that indication. Per FDA guidance, labels should include “clinical studies that provide primary support for effectiveness…provide other important information about a drug’s effectiveness…and prospectively evaluate important safety end points.”19 To obtain further details for trials listed on labels, we performed literature searches to identify associated publications. For DRUGDEX off-label indications, supportive evidence and associated publications are summarized online on each
therapeutic’s monograph. We included all trials listed on the monograph as evidence of clinical efficacy, but excluded retrospective studies, review papers, and trials focused only on safety. When multiple cited publications referred to the same trial, we counted it as only 1 trial.
Characterization of Supportive EvidenceEach supportive trial was categorized by its use of randomization, double-blinding, and comparator group. Trials using “active comparators” compared the efficacy of the study therapeutic against an available therapeutic
alternative; trials using “placebo comparators” compared the study therapeutic against placebo; and trials with “no comparator” included single-arm trials and multi-arm trials comparing the study therapeutic to itself only. We classified primary end points as “overall survival” or
“surrogate marker of disease.” Using a framework based on prior literature and an Institute of Medicine report,16,20,21 surrogate markers of disease included measures of disease progression and other radiologic or pathologic markers of response. We also categorized trials by the number of overall patients and those assigned to the intervention group. We recorded the median duration of treatment for each trial, calculated as the time between when the first dose of the drug was administered and when the primary end point was measured. Median duration of exposure was used as a proxy for trial duration in trials which measured time to outcomes (such as overall survival or time to progres-sion). When the trial had multiple arms, we calculated a weighted mean of the median durations of each arm. Two investigators (NSD, JSR) performed the abstraction for FDA new drug approvals, while a third (KWS) performed the abstraction for supplementary FDA approvals and DRUGDEX off-label indications. Any abstraction for which there was uncertainty was reviewed with 2 investigators (NSD, JSR) to establish consensus.
Statistical AnalysisUsing descriptive statistics, we characterized the overall sample of supportive trials identified in our study. Next, we used descriptive statistics to characterize features of trials aggregated at the indication level (ie, summarizing all trials used to support each indication). We then used χ2 or Kruskal-Wallis tests as appropriate to examine differences
Figure. Sample Cohort of Cancer Therapeutics Approved by the FDA, 2005-2012; Associated Supplementary Indications Approved by the FDA and Off-Label Indications Included in DRUGDEX, With Associated Supportive Trials
37 novel cancer therapeutics approved by the FDA between
2005-2012
Approved for 39 indications
at initial FDA approval (across all 37 agents)
50 supportive trials cited
Approved for 21 supplementary indications with subsequent FDA regulartory decisions
(across 17 agents)
22 supportive trials cited
Approved for 16 off-label indications
with DRUGDEX (across 10 agents)
37 supportive trials cited
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among supportive trials and indications. In addition, we calculated the median time from the original FDA new drug approval to the approval of the first FDA supplementary indication; dates for off-label indication endorsement were not available within DRUGDEX. Analyses were performed using Microsoft Excel 2011 and JMP version 12 (SAS Institute, Inc; Cary, North Carolina). All statistical tests were 2-tailed and used a type I error rate of 0.01 to account for multiple comparisons across 5 therapeutic agent and indication characteristics.
RESULTSFDA New Drug ApprovalsBetween 2005 and 2012, the FDA approved 37 new cancer therapeutics, of which 21 (56.8%) were pharma-cologic agents and 16 (43.2%) were biologic agents (TABLE 1). These 37 therapeutics were originally approved for 39 indications. Fifteen (38.5%) and 24 (61.5%) of the indications were for hematologic malignancies and solid tumors, respectively, and all 24 solid tumor indications were classified as noncurative intent.
FDA Supplementary Indication ApprovalsOf the 37 novel therapeutics, 17 (45.9%) subsequently received an FDA supplementary indication approval, for a total of 21 supplementary indica-tions (Supplementary Table). Seven supplementary indications (33.3%) were for hematologic malignancies, while 14 (66.7%) were for solid tumors, and 11 of these solid tumor indications were classified as noncurative intent. Ten (47.6%) treated the same cancer type as the original FDA indication. Of these, 8 (80.0%) expanded treatment to an earlier line of therapy or changed the accompanying regimen. One of the 10 (10.0%) expanded the use of pertuzumab to the neoadjuvant setting for breast cancer, while another 1 (10.0%) expanded the use of romidepsin from cutaneous to peripheral T-cell lymphoma. A median of 920 days (interquartile range [IQR], 583-1521) passed between the original FDA new drug approval and the approval of the first supplementary indication.
Inclusion of Off-Label Indications in DRUGDEXOf the 37 novel therapeutics, 10 (27.0%) had off-label indications included on DRUGDEX, for a total of 16 off-label indications (Supplementary Table). Six off-label indications (37.5%) were for hematologic malignancies, while 10 (62.5%) were for solid tumors, and all 10 solid tumor indications were classified as noncurative intent. Six (37.5%) treated the same cancer type as the original FDA indication. Of these 6 indications, 4 (66.6%) changed the line of therapy and/or accompanying regimen, 1 (16.6%) expanded the use of nilotinib to blastic phase chronic myelogenous leukemia (in addition to chronic and accelerated phase disease), and 1 (16.6%) expanded the use of lapatinib to inflammatory breast cancer.
Table 1. Novel Cancer Therapeutics Approved by the FDA, 2005-2012, and Associated Supple-mentary Indications Approved by the FDA and Off-Label Indications Included in DRUGDEX
FDA New Drug Approval
FDA Supplementary
Indication Approval
DRUGDEX Off-Label Indication
Therapeutic agents, n 37 17 10
Therapeutic type
Pharmacologic 21 (56.8%) 13 (76.5%) 9 (90.0%)
Biologic 16 (43.2%) 4 (23.5%) 1 (10.0%)
Indications, n 39 21 16
Median indications per therapeutic agent (IQR) 1.0 (1.0-1.0) 1.0 (1.0-1.0) 1.0 (1.0-2.0)
Total supportive trials, n 50 22 37
Median supportive trials per indication (IQR) 1.0 (1.0-1.0) 1.0 (1.0-1.0) 2.0 (1.0-3.0)
Same target cancer type as initial FDA indication, n (%)
Yes - 10 (47.6%) 6 (37.5%)
No - 11 (52.4%) 10 (62.5%)
Indication approval year, n
2005 2 0 -
2006 5 0 -
2007 4 1 -
2008 2 1 -
2009 5 0 -
2010 2 4 -
2011 8 3 -
2012 11 4 -
2013 - 3 -
2014 - 3 -
2015 - 2 -
Median days from initial indication to first supplementary indication (IQR)
- 920 (583-1521) -
IQR indicates interquartile range.
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Characteristics of Supportive Trials by Approval TypeIn total, 50 trials supported new drug approvals, 22 trials supported FDA supplementary indication approvals, and 37 trials supported DRUGDEX off-label indications (TABLE 2). Of the 109 total trials identified, 53.2% (95% CI, 43.9%-62.3%) were randomized, 28.4% (95% CI, 20.8%-37.5%) were double-blinded, 53.2% (95% CI, 43.9%-62.3%) used any comparator (either active or placebo), and 19.3% (95% CI, 12.9%-27.7%) used an active comparator. Use of randomization differed by approval type (P = .01), with fewer trials supporting FDA new drug approvals and DRUGDEX inclusions using randomization than trials supporting FDA supplementary indication approvals. Similarly, use of double-blinding and any comparator differed by approval type (P = .009 and P = .01, respectively), with fewer trials supporting FDA new drug approvals and DRUGDEX inclusions using double-blinding and any
comparator than trials supporting FDA supplementary indication approvals, although there was no difference in use of an active comparator (P = .57). Surrogate markers were used in 87.2% (95% CI, 79.6%-92.2%) of trials, which did not vary by approval type (P = .22).
There were significant differences in the number of total patients and intervention patients enrolled in trials supporting FDA new drug approvals, FDA supplementary drug approvals, and DRUGDEX off-label indications (total patients, 264, 414, and 86, respec-tively; intervention patients, 191, 214, and 63, respectively; both P <.001; TABLE 3). Overall, trials had a median length of 18.4 weeks (IQR, 12.4-31.6),
and 30.3% of trials (95% CI, 22.4%-39.5%) lasted more than 6 months. Neither measure of trial duration varied by approval type (P = .32 and P = .06, respectively).
Characterization of Aggregate Trial Features Support-ing Approved Indications, by Approval TypeFDA new drug approvals, FDA supplementary indication approvals, and DRUGDEX off-label indication inclusions were supported by a median of 1.0 trial (IQR, 1.0-1.0), 1.0 trial (IQR, 1.0-1.0), and 2.0 trials (IQR, 1.0-3.0) per indication, respectively (TABLE 4). All indications had at least 1 sup-portive trial. FDA new drug and supplementary indication approvals cited 1 or 2 trials each, with the exception of the original approval of dasatanib, which cited 6. DRUGDEX off-label indication inclusions cited a median of 2 trials (IQR, 1-3), with a maximum of 7 trials for the first-line use of bendamustine for non-Hodgkin lymphoma.
Table 2. Design of Supportive Trials Providing the Basis for FDA Approval of 37 Cancer Therapeutics, 2005-2012; Supplementary Indication Approvals; and Off-Label Indications Included in DRUGDEX
Approval type
Trial design, (%) [95% CI] Comparator, (%) [95% CI] End point, (%) [95% CI]
Randomized Double-blinded Placebo Active Any Surrogate marker Overall survival
Pa .01 .009 <.001 .57 .01 .22 .22aP value for difference across approval type: FDA new drug approval, FDA supplementary indication approval, and DRUGDEX indication inclusion.
Table 3. Median Number of Patients and Duration of Supportive Trials Providing the Basis for FDA Approval of 37 Cancer Therapeutics, 2005-2012; Supplementary Indication Approvals; and Off-Label Indications Included in DRUGDEX
Approval type
Median Patients, n (IQR) Trial Duration
TotalIntervention
GroupMedian, week
(IQR)≥6 months (%),
[95% CI]
All trials(n = 109)
171(73-488)
148(63-289)
18.4(12.4-31.6)
33 (30.3)[22.4-39.5]
FDA new drug (n = 50)
264 (93-615)
191 (93-372)
22.1(11.4-31.7)
17 (34.0)[22.4-47.8]
FDA supplementary(n = 22)
414(161-673)
214 (108-343)
24.0(14.3-41.3)
9 (40.9)[23.3-61.3]
DRUGDEX off-label(n = 37)
86(40-268)
63(39-156)
17.0(12.5-24.5)
7 (18.9)[9.5-34.2]
Pa <.001 <.001 .32 .06
IQR, interquartile rangeaP value for difference across approval type: FDA new drug approval, FDA supplementary indication approval, and DRUGDEX indication inclusion.
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Indications were supported by total and intervention group patient populations of 383 (IQR, 178-623) and 239 (IQR, 153-397) across aggregated supportive trials, neither of which varied by approval type (P = .47 and .31, respectively). Only 38.2% (95% CI, 28.1%-50.6%) and 6.6% of indications (95% CI, 2.8%-14.5%) were supported by trials lasting more than 6 and 12 months, respectively. This did not vary by approval type (P = .95 and .81, respectively). Patient-time exposure among aggregated supportive trials was 8516 patient-weeks (IQR, 2645-15,744), which did not vary by approval type, either (P = .14).
While 69.7% of indications (95% CI, 58.7%-78.9%) were supported by a trial with any comparator (either active or placebo), only 26.3% of indications (95% CI, 17.7%-37.2%) were supported by a trial with an active comparator. Neither use of any nor an active comparator varied by approval type (P = .09 and .04, respectively). Only 18.4% of indications
(95% CI, 11.3%-28.6%) were supported by a trial using overall survival as a primary end point: 23.1% (95% CI, 12.6%-38.3%) of FDA new drug approvals, 14.3% (95% CI, 5.0%-34.6%) of FDA supplementary indication approvals, and 12.5% (95% CI, 3.5%-36.0%) of DRUGDEX off-label indications. This did not vary by approval type (P = .56). No hematologic indications were supported by a trial using overall survival as a primary end point.
DISCUSSIONOur study characterized and compared the clinical trial evidence underlying the original FDA approval of new cancer therapeutics, the subsequent FDA approval of supplementary indications for these therapeutics, and the inclusion of off-label indications for these therapeutics on the Medicare-referenced compendium, DRUGDEX. Some may consider the quality of evidence supporting cancer
Table 4. Number of Trials, Number of Patients, and Characteristics of Trials Providing the Basis for FDA Approval of 37 Cancer Therapeutics, 2005-2012; Supplementary Indication Approvals; and Off-Label Indications Included in DRUGDEX
Approval type
Median supportive
trials,a n (IQR)
Patients in aggregated cited trials,
median (IQR)Patient-weeks
aggregated cited trials,b median (IQR)
Indications approved on basis of at least 1 trial that met criteria below (%) [95% CI]
Trial duration Comparator End point
TotalIntervention
group≥6
months ≥12
months Placebo Active AnyOverall survival
All indications(n = 76)
1.0 (1.0-1.0)
383 (178-623)
239 (153-397)
8516 (2645-15,744)
31 (40.8) [30.4-52.0]
5 (6.6) [2.8-14.5]
33 (43.4) [32.9-54.6]
20 (26.3) [17.7-37.2]
53 (69.7)[58.7-78.9]
14 (18.4) [11.3-28.6]
FDA new drug (n = 39)
1.0 (1.0-1.0)
397 (169-643)
277 (163-419)
9108 (3412-15,975)
16 (41.0) [27.1-56.6]
2 (5.1) [1.4-16.9]
14 (35.9) [22.7-51.6]
9 (23.1) [12.6-38.3]
23 (59.0)[43.4-72.9]
9 (23.1)[12.6-38.3]
Heme (n = 15)
1.0 (1.0-2.0)
167 (102-288)
154 (102-266)
3140 (2057-8786)
5 (33.3) [15.2-58.3]
1 (6.7) [1.2-29.8]
0 (0.0) [0.0-0.0]
2 (13.3) [3.7-37.9]
2 (13.3)[3.7-37.9]
0 (0.0) [0.0-0.0]
Solid (n = 24)
1.0 (1.0-1.0)
615 (347-767)
378 (230-504)
12,884 (6177-23,455)
11 (45.8) [27.9-64.9]
1 (4.2) [0.7-20.2]
14 (58.3) [38.8-75.5]
7 (29.2) [14.9-49.2]
21 (87.5)[69.0-95.7]
9 (37.5) [21.2-57.3]
FDA supplementary (n = 21)
1.0 (1.0-1.0)
417 (189-690)
221 (122-361)
10,316 (3918-17,073)
9 (42.9) [24.5-63.5]
2 (9.5) [2.7-28.9]
15 (71.4) [50.0-86.2]
3 (14.3)[5.0-34.6]
18 (85.7)[65.4-95.0]
3 (14.3) [5.0-34.6]
Heme (n = 7)
1.0 (1.0-10)
447 (178-792)
221 (165-396)
15,792 (1800-40,608)
5 (71.4) [35.9-91.8]
1 (14.3) [2.6-51.3]
3 (42.9) [15.8-75.0]
2 (28.6) [8.2-64.1]
5 (71.4)[35.9-91.8]
0 (0.0) [0.0-0.0]
Solid (n = 14)
1.0 (1.0-1.0)
414 (192-673)
227 (105-365)
9244 (4123-14,607)
4 (28.6) [11.7-54.6]
1 (7.1) [1.3-31.5]
12 (85.7) [60.0-96.0]
1 (7.1) [1.3-31.5]
13 (92.9)[68.5-98.7]
3 (21.4) [7.6-47.6]
DRUGDEX off-label(n = 16)
2.0 (1.0-3.0)
269 (143-520)
177 (88-296)
3466 (1664-12,237)
6 (37.5) [18.5-61.4]
1 (6.3) [1.1-28.3]
4 (25.0) [10.2-49.5]
8 (50.0) [28.0-72.0]
12 (75.0)[50.5-89.8]
2 (12.5) [3.5-36.0]
Heme (n = 6)
2.0 (1.0-4.0)
155 (53-406)
120 (53-289)
2294 (61-7827)
4 (66.7) [30.0-90.3]
1 (16.7) [3.0-56.4]
0 (0.0) [0.0-0.0]
3 (50.0) [18.8-81.2]
3 (50.0)[18.8-81.2]
0 (0.0) [0.0-0.0]
Solid (n = 10)
2.0 (1.0-3.0)
348 (240-547)
260 (161-304)
6119 (2254-14,563)
2 (20.0) [5.7-51.0]
0 (0.0)[0.0-0.0]
4 (40.0) [16.8-68.7]
5 (50.0) [23.7-76.3]
9 (90.0)[59.6-98.2]
2 (20.0) [5.7-51.0]
Pc <.001 .47 .31 .14 .95 .81 .007 .04 .09 .56
IQR, interquartile range; Heme indicates hematologic malignancy; solid indicates solid tumor malignancy.aSupportive trials include pivotal efficacy trials for FDA new drug approvals; evidence listed on drug label at time of indication’s approval for supplementary FDA indications; and publications cited by DRUGDEX for DRUGDEX off-label indications.bFor each trial, patient-week exposure was calculated by multiplying median duration of treatment by overall number of patients (intention to treat). Trial-level patient-weeks were summed to obtain patient-weeks for each indication.cP value for difference across approval type: FDA new drug approval, FDA supplementary indication approval, and DRUGDEX indication inclusion.
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therapeutic approvals to have limitations for informing clinical decision making, as only 70% of indications were supported by a trial using an active or placebo comparator, 30% by a trial lasting more than 6 months, and 18% by a trial using overall survival as a primary end point. However, when viewed in aggregate, new drug and supplementary indication approvals by the FDA and off-label indication inclusions by DRUGDEX were generally supported by similar bodies of clinical trial evidence.
At the individual trial level, we found some differences across approval types, potentially suggesting that the trials supporting FDA supplementary indication approvals were of higher quality, as they had the highest rates of randomization, double-blinding, and use of any comparator, and had the largest patient populations and duration of study. While these differences were not significant on aggregate, it does suggest that once a cancer therapeutic is originally approved for use, the FDA evidentiary standards for supplementary indication approvals are higher than those used by DRUGDEX for off-label indication inclusions. Further studies should examine the standards used by other compendia. If their standards are lower, from an evidentiary standpoint, the decision to allow experts outside of FDA to determine indications for which Medicare will pay for therapy may be eroding incentives to produce rigorous evidence that supports FDA supplementary indication approvals.
The strength of clinical evidence supporting these indications has important implications for informing cancer care clinical decision making. Although oncologists routinely use cancer therapeutics for indications outside those approved by the FDA or included on compendia,22-24 the formal endorsement of new indications through these pathways provides an additional expert review of safety and efficacy, and defines the prevailing standard of cancer care by helping secure reimbursement. The vast majority of indications in our study were only supported by trials using surrogate markers of disease, as opposed to overall survival, even though recent research has cast doubt on the mortality benefit of cancer therapeutics approved on the basis of surrogate markers.10,11 Moreover, no trial in our sample used patient-reported outcomes as a primary end point. Our finding that nearly one-third of indications lacked support by a trial using a comparator group further highlights weaknesses in the quality of trials used as sup-portive evidence. Nearly three-fourths of indications also lacked active comparator data, raising questions regarding the comparative effectiveness of these treatments, though some may have targeted disease for which no therapeutic alternative exists. FDA and Medicare should consider whether supplementary indication approvals and compendia
off-label indication inclusions should be permitted on the basis of evidence that is focused on surrogate markers of disease or without active or placebo comparator; given that these medications are already approved for use by patients, higher standards could be required.
The development of new indications for already-approved therapeutics, whether it be through the approval of supple-mentary indications by the FDA or inclusion of off-label indications on compendia, may complement the costly process of new drug development, particularly for advanced or rare diseases. Indeed, more than half of the new indica-tions in our study expanded therapeutics’ use to a different target cancer type, and most of them treated advanced disease. As clinical trials begin to systematically match already-approved therapeutics to different target cancers based on tumor genomic abnormalities,25 supplementary indications and compendia off-label indications will likely play an increasingly important role in defining the standard of care. However, both the FDA and compendia review processes, as well as the reimbursement policies referencing their decisions, must balance the urgency of identifying new treatments with the need to ensure drug safety and efficacy. Prior work has highlighted the FDA’s flexible standards for the approval of new cancer therapeutics.16,26,27 This flexibility may be beneficial when the cancers being treated are life-threatening and lack other effective treatment options, but it also invites criticism that the evidentiary threshold for approval is too low, especially given concerns that some new and expensive treatments offer only marginal benefits over existing therapies.9 Our findings suggest that similar uncertainties may apply to FDA supplementary indications and compendia off-label indications.
Ultimately, it is vital that the pharmaceutical industry produces data that matter for patients. Stringent postmarket-ing requirements could theoretically ensure that the industry conducts rigorous studies evaluating whether FDA-approved indications improve survival.28 Unfortunately, recent studies suggest that these requirements are not consistently enforced and completed on a timely basis,29 that one-third of FDA cancer therapeutic approvals based on surrogate markers have not been followed up with a study examining overall survival,11 and that less than 5% of FDA approvals based on surrogate markers, across all indications, have not been followed up with a randomized, double-blind study demonstrating improved clinical outcomes.30 Furthermore, no external regulatory mechanisms currently exist to evaluate off-label therapeutic use endorsed by compendia. Some authors have proposed expanded use of “coverage-under-evidence development” as a solution,31 in which CMS reimburses off-label therapeutic use on the
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condition that treated patients are enrolled into a clinical trial evaluating the therapeutic’s safety and efficacy.
LimitationsOur study has several limitations. First, we only characterized the inclusion of off-label indications on DRUGDEX, 1 of several CMS-referenced compendia. While the National Cancer Comprehensive Network (NCCN) compendium probably exerts greater influence on clinical decision-making, it does not clearly label endorsed indications as off-label or list any supportive evidence, making direct comparison against FDA approvals difficult. Although the NCCN guidelines (upon which the compendium is based) may cite relevant studies in its discussion section, study citation is not uniform and systematic, precluding its use for this study.
Second, we identified supportive evidence differently for each approval type, due to the varying regulatory information available: We used medical review documents for FDA new drug approvals, drug labels for FDA supplementary approvals (as has been done previously12,32), and trials cited by DRUGDEX online for endorsed off-label indications. We likely identified the strongest evidence considered for FDA approvals, as we found a median of 1 supportive trial for both new drug and supplementary indications. However, we may have overstated DRUGDEX’s evidentiary standards, as we had access to the supportive evidence currently listed online, but not the evidence listed at the time an off-label indication was first endorsed.
Third, we did not assess measures of evidentiary quality other than trial design, such as effect sizes or safety, nor did we assess factors that might reasonably change the evidentiary threshold for approval, such as the severity of the target cancer and the availability of other effective treatments.
Fourth, because the vast majority of solid tumor indica-tions were classified as noncurative intent, across approval types, we were unable to compare evidentiary quality supporting indications with curative and noncurative intent. Finally, despite studying 8 years of approvals, our small sample size may have limited us from detecting statistically significant differences among approval types. Additionally, on this same point, because our study was limited to FDA approvals between 2005 and 2012, our results may not be generalizable to cancer therapeutics approved prior to this period.
CONCLUSIONSAlthough there was some variation in the strength of the clinical trials supporting the FDA approval of new cancer therapeutics, the FDA approval of supplementary indications, and DRUGDEX off-label indication inclusions,
in aggregate the 3 approval types are supported by similar bodies of clinical trial evidence. Most indications were not supported by trials examining overall survival benefit, and nearly one-third were not supported by trials using a comparator group. These are levels of evidence that some may consider to be limited for informing clinical decision making for cancer treatment.
Author Affiliations: Department of Medicine, Boston Medical Center (KWS), Boston, MA; Section of General Medicine and Robert Wood Johnson Foundation Clinical Scholars Program (CGP, JSR), and Section of Medical Oncology (KBA), Department of Medicine, Yale University School of Medicine, New Haven, CT; Center for Cancer Outcomes, Practice and Policy Evaluation Research, Yale Cancer Center (CGP, KBA, JSR), New Haven, CT; Department of Medicine, Brigham & Women’s Hospital (NSD), Boston, MA; Center for Outcomes Research and Evaluation, Yale-New Haven Hospital (NSD, JSR), New Haven, CT; Department of Health Policy and Management, Yale University School of Public Health (JSR), New Haven, CT.
Source of Funding: None.
Author Disclosures: Mr Su is supported by the Yale University School of Medicine Office of Student Research. Dr Gross receives research funding from 21st Century Oncology. Drs Gross and Ross receive support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing. Dr Ross receives support through Yale University from CMS to develop and maintain performance measures that are used for public reporting; from Medtronic, Inc, and the FDA to develop methods for postmarket surveillance of medical devices; from the Blue Cross Blue Shield Association to better understand medical technology evaluation; and from the Laura and John Arnold Foundation to support the Collaboration on Research Integrity and Transparency at Yale. The funders had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Authorship Information: Concept and design (KWS, JSR, CG); acquisition of data (KWS, NSD); analysis and interpretation of data (KWS, NSD, KA, JSR); drafting of the manuscript (KWS); critical revision of the manuscript for important intellectual content (JSR, NSD, CG, KA); statistical analysis (KWS); and supervision (JSR).
Address Correspondence to: Joseph S. Ross, MD, MHS, Section of General Medicine, Yale University School of Medicine, PO Box 208093, New Haven, CT 06520-8093. E-mail: [email protected].
REFERENCES 1. Pfister DG. Off-label use of oncology drugs: the need for more data and then some [published correction appears in J Clin Oncol. 2012;30(10):1149]. J Clin Oncol. 2012;30(6):584-586. doi: 10.1200/JCO.2011.38.5567.2. US Food and Drug Administration. Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. 1998; www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid-ances/ucm078749.pdf. Accessed May 29, 2015.3. Mason A, Drummond M, Ramsey S, Campbell J, Raisch D. Comparison of anticancer drug coverage decisions in the United States and United Kingdom: does the evidence support the rhetoric? J Clin Oncol. 2010;28(20):3234-3238. doi: 10.1200/JCO.2009.26.2758.4. Kantarjian HM, Fojo T, Mathisen M, Zwelling LA. Cancer drugs in the United States: justum pretium—the just price. J Clin Oncol. 2013;31(28):3600-3604. doi: 10.1200/JCO.2013.49.1845.5. Mailankody S, Prasad V. Five years of cancer drug approvals: innova-tion, efficacy, and costs. JAMA Oncol. 2015;1(4):539-540. doi: 10.1001/jamaoncol.2015.0373.6. H.R. 2264: Omnibus Budget Reconciliation Act of 1993. 103rd Congress ed 1993.7. Bach PB. Limits on Medicare’s ability to control rising spending on cancer drugs. [published correction appears in N Engl J Med. 2009;360(9):944] N Engl J Med. 2009;360(6):626-633. doi: 10.1056/NEJMhpr0807774.
130 The American Journal of Pharmacy Benefits® | July/August 2017
Su et al
8. American Society of Clinical Oncology. Reimbursement for cancer treatment: coverage of off-label drug indications. J Clin Oncol. 2006;24(19):3206-3208.9. Fojo T, Mailankody S, Lo A. Unintended consequences of expensive cancer therapeutics—the pursuit of marginal indications and a me-too mentality that stifles innovation and creativity: the John Conley Lecture. JAMA Otolaryngol Head Neck Surg. 2014;140(12):1125-1236. doi: 10.1001/jamaoto.2014.1570.10. Prasad V, Kim C, Burotto M, Vandross A. The strength of association between surrogate end points and survival in oncology: a systematic review of trial-level meta-analyses. JAMA Intern Med. 2015;175(8):1389-1398. doi: 10.1001/jamainternmed.2015.2829.11. Kim C, Prasad V. Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of US Food and Drug Administration approvals. JAMA Intern Med. 2015;175(12):1992-1994. doi: 10.1001/jamainternmed.2015.5868.12. Wang B, Kesselheim AS. Characteristics of efficacy evidence supporting approval of supplemental indications for prescription drugs in United States, 2005-14: systematic review. BMJ. 2015;351:h4679. doi: 10.1136/bmj.h4679.13. Abernethy AP, Raman G, Balk EM, et al. Systematic review: reliability of compendia methods for off-label oncology indications [published cor-rection appears in Ann Intern Med. 2009;150(8):571]. Ann Intern Med. 2009;150(5):336-343. Review.14. US Food and Drug Administration. Drugs@FDA: FDA approved drug products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed March 6, 2015.15. Tillman K, Burton B, Jacques LB, Phurrough SE. Compendia and anticancer therapy under Medicare. Ann Intern Med. 2009;150(5):348-350.16. Downing NS, Aminawung JA, Shah ND, Krumholz HM, Ross JS. Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012. JAMA. 2014;311(4):368-377. doi: 10.1001/jama.2013.282034.17. DiMasi JA. Innovating by developing new uses of already-approved drugs: trends in the marketing approval of supplemental indications. Clin Ther. 2013;35(6):808-818. doi: 10.1016/j.clinthera.2013.04.004. 18. Centers for Medicare & Medicaid Services. Thomson Micromedex Drugdex® Compen-dium Revision Request - CAG-00391. CMS website. http://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=16&McdName=Thomson+Micromedex+DrugDex+%C2%AE+Compendium+Revision+Request+-+CAG-00391&mcdtypename=Compendia&MCDIndexType=6&bc=AAAEAAAAAAAAAA%3D%3D&. Published February 19, 2008. Accessed April 8, 2015.
19. US Food and Drug Administration. Guidance for industry: clinical studies section of labeling for human prescription drug and biological products — con-tent and format. 2006:2-3. 20. Institute of Medicine. Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. Washington, DC: National Academies Press; 2010.21. Clement FM, Harris A, Li JJ, Yong K, Lee KM, Manns BJ. Using effectiveness and cost-effectiveness to make drug coverage decisions: a comparison of Brit-ain, Australia, and Canada. JAMA. 2009;302(13):1437-1443. doi: 10.1001/jama.2009.1409.22. Conti R, Veenstra DL, Armstrong K, Lesko LJ, Grosse SD. Personalized medicine and genomics: challenges and opportunities in assessing effective-ness, cost-effectiveness, and future research priorities. Med Decis Making. 2010;30(3):328-340. doi: 10.1177/0272989X09347014.23. Kalis JA, Pence SJ, Mancini RS, Zuckerman DS, Ineck JR. Prevalence of off-label use of oral oncolytics at a community cancer center. J Oncol Pract. 2015;11(2):e139-e143. doi: 10.1200/JOP.2014.001354.24. Laetz T, Silberman G. Reimbursement policies constrain the practice of oncology. JAMA. 1991;266(21):2996-2999.25. McNeil C. NCI-MATCH launch highlights new trial design in precision-medi-cine era. J Natl Cancer Inst. 2015;107(7).26. Johnson JR, Williams G, Pazdur R. End points and United States food and drug administration approval of oncology drugs. J Clin Oncol. 2003;21(7):1404-1411.27. Kesselheim AS, Myers JA, Avorn J. Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer. JAMA. 2011;305(22):2320-2326. doi: 10.1001/jama.2011.769.28. Institute of Medicine. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: National Academies Press; 2006.29. Fain K, Daubresse M, Alexander GC. The Food and Drug Administration Amendments Act and postmarketing commitments. JAMA. 2013;310(2):202-204. doi: 10.1001/jama.2013.7900.30. Pease AM, Krumholz HM, Downing NS, Aminawung JA, Shah ND, Ross JS. Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review. BMJ. 2017;357:j1680. doi: 10.1136/bmj.j1680.31. Sox HC. Evaluating off-label uses of anticancer drugs: time for a change. Ann Intern Med. 2009;150(5):353-354.32. Shea MB, Roberts SA, Walrath JC, Allen JD, Sigal EV. Use of multiple end-points and approval paths depicts a decade of FDA oncology drug approvals. Clin Cancer Res. 2013;19(14):3722-3731.
Vol. 9, No. 4 | The American Journal of Pharmacy Benefits® 131www.ajpb.com
N ews about potential breakthrough treatments that cure diseases or dramatically improve patient health compete with news that highlights how
drug pricing and insurance access rules make it harder for patients to obtain new therapies.
These competing headlines set up one of the most important challenges for biopharmaceutical manufactur-ers, payers, and policy makers: how to create a healthcare system of economic incentives that encourage innovation and improve broad-based affordability and access.
It is important to remember that the past 5 decades have seen tremendous progress in patient health. Death rates attributed to cancer, diabetes, heart attack, and stroke have declined dramatically, including by more than 75% for deaths from stroke.1
We have seen curative drugs for hepatitis C, important progress in the fight against cancer, and new treatments that give patients with multiple sclerosis greater ability to function and remain at work.
But we have yet to truly sort out just how much these advancements are worth. What if we had a drug that slowed the progression of Alzheimer’s disease? The one-time costs would be large, but the benefit to patients, their caregivers, and society overall would be profound.
For payers and biopharmaceutical companies, talking about value is not always straightforward—there are some parameters about what they can discuss, along with other regulatory concerns. These conversations often require real-world evidence, which are data and studies that show how (and whether) a particular drug performs in typical patients and usual care settings. This data frequently provides complementary information beyond the traditional randomized clinical trials used for product approval.
Payers and biopharmaceutical companies are using real-world evidence in their development of value-, or outcomes-based, contracts, which are growing in use. Through these contracts, payers and biopharmaceutical
companies tie the cost of the medication to parameters based on how well the treatment performs in a given population or how the treatment impacts the total costs of care.
Insurance plans are increasingly looking favorably on these types of arrangements, according to a recent survey. One-quarter of the plans surveyed had value-based contracts in place, another 30% were negotiating at least 1, and 70% of the plans viewed them favorably.2
Payers also are testing indication-based pricing, under which the cost of the medication differs when it is used to treat different conditions. For example, a treatment that improves survival for patients with breast cancer might have a lower cost when the treatment is used to treat lung cancer, where it might not be as effective.
Standing in the way of more progress on the value-and-price front and testing these types of innovative contracts are regulatory hurdles that restrict communications between payers and manufacturers, as well as other barriers that currently create disincentives to paying for value.
Manufacturers and payers must be able to communicate about a drug’s potential benefits and risks. Those com-munications might need to be broader than the specifics included on a drug’s label. For example, understanding the projected budget impact of a treatment or whether medication use is associated with fewer emergency room visits or hospital readmissions is typically part of product approval. Yet, these conversations are especially needed to enable a drug maker and a payer to set benchmarks for the terms included in an outcomes-based contract.
The rationale for those restrictions make sense, as regulators want to ensure that discussions about a drug’s benefits and risks are consistent with what the FDA approved.
But in today’s world, with new discussions about linking reimbursement to a drug’s benefits and the real-world evidence to inform those conversations, more detailed communications are needed to shape care delivery, improve system efficiencies, and achieve better health outcomes.
Value Depends on Real-World EvidenceDan Leonard, President, National Pharmaceutical Council
NPC
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Leonard
In a survey the National Pharmaceutical Council (NPC) conducted with Xcenda, payers and providers told us that communications that are not specifically on the FDA-approved label, but are consistent with its content, would yield benefits that were more important than the risks. In fact, the types of information payers consider when making treatment decisions (eg, ability of a product to help achieve health quality measures; information comparing treatments in everyday use) often extend beyond what is included on the product’s label.3
The bipartisan 21st Century Cures Act broadened the rules that govern these manufacturer–payer communica-tions, allowing for clinical assumptions in addition to health economic analyses to be communicated if the audience is payer-related or making coverage decisions for populations of patients rather than individuals. Draft guidance subsequently released by the FDA in January provides greater clarity but has yet to finalized.
This kind of communication is especially critical when it comes to the new specialty treatments or product indications that garner headlines. Given the cost of those treatments, a payer–manufacturer exchange of information is needed, not after the drug is approved, but at least 12 to 18 months before.
Such advance communication would help health plans that submit rate proposals for regulatory approval each spring for the subsequent year. If an insurance plan incorrectly forecasts the costs or use of a new drug because a treatment is approved for a new condition during the following year, the financial impact could be significant. If product use is underestimated, the health plan could lose money. However, it is even more problematic if costs are overestimated and result in higher health premiums for consumers.
It’s not difficult to see the potential benefits for both payers and manufacturers. A preapproval exchange of information prior to the recent introduction of hepatitis C cures may have better prepared payers for the coming demand for treatment. With that information in hand, appropriate budgeting could have occurred in a more timely way.
Payers aren’t just waiting for real-world evidence to be shared with them, however. They are already utilizing their own databases to develop real-world evidence to improve
care and make health systems more efficient. Their usage sophistication varies, ranging from predictive analytics to determine which treatments work best to basic utilization management and medication adherence programs.4 But conducting these analyses requires the high-quality data and good research methods that will ensure the integrity of the results. It can be challenging for payers and other healthcare decision makers to sift through these outside studies and determine which ones are most applicable to the decision at hand.
That’s why the NPC, along with the Academy of Managed Care Pharmacy and the International Society for Pharmacoeconomics and Outcomes Research, formed the CER Collaborative to help insurance plans and others assess the relevance and credibility of studies. To date, the collaborative’s online tools and training program have been used by thousands of people interested in assessing the quality, credibility, and relevance of real-world evidence and related studies.
The value of the new information is lost if it cannot get into the hands of the end user—the health plan setting up the guidelines for coverage and reimbursement for patients. If we can work with regulators and policy makers to reduce the barriers to the alignment of a drug’s value and price, and use good methods to understand what works in the real world, the public’s interest in health and safety will be well served. The promise of a more affordable and healthier future depends on it.
REFERENCES1. Ma J, Ward EM, Siegel RL, Jemal A. Temporal trends in mortality in the United States, 1969-2013. JAMA. 2015;314(16):1731-9. doi: 10.1001/jama.2015.12319. 2. Choe SH, Learch C. Health plans are actively exploring outcomes-based con-tracts. Avalere Health website. avalere.com/expertise/life-sciences/insights/health-plans-are-actively-exploring-outcomes-based-contracts. Published May 30, 2017. Accessed June 27, 2017.3. National Pharmaceutical Council. Comment from National Pharmaceuti-cal Council on the Food and Drug Administration (FDA) proposed rule: manufacturer communications regarding unapproved uses of approved or cleared medical products; availability of memorandum; reopening of the comment period. Regulations.gov website. regulations.gov/document?D=FDA-2016-N-1149-0102. Published April 20, 2017. Accessed June 27, 2017.4. Avalere Health and National Pharmaceutical Council. Health plan use of patient data: from the routine to the transformational. National Pharmaceutical Council website. npcnow.org/publication/health-plan-use-patient-data-routine-transformational. Published April 25, 2017. Accessed June 27, 2017.
• Circulation to over 20,000 pharmacy benefit decision makers
• An expedited review process
• Exposure through Web and print publication opportunities
•
OUR JOURNAL BOASTS:
2017 TOPICS:
AJPB® is continually seeking submissions on a variety of topics. Areas of particular interest include utilization management, outcomes research on
Medicare Part D, analysis of drug therapies, cost utility analyses, and more.
FROM THE EDI TORFollow the Numbers: A Focus on Anti-Inflammatory Medications
In addition to having a major impact on patient health outcomes, medications can have significant cost implications for all stakeholders; insurers and employers need to work with their pharmacy benefit managers to ensure that the right patients are getting the right medications at the right time.Berger
NAT IONAL PHARMACEU T ICAL COUNCILHow Can We Address Barriers to Accessing Needed Care?Adherence and access to higher-value care can make a big difference in reducing costs for patients and our healthcare system; however, the financial burden of high-deductible health plans and out-of-pocket costs must also be considered.Dubois
Translating Evidence-Based Research into Value-Based Decisions®
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The American Journal ofPHARMACY BENEFITS
ORIG INAL RESE ARCHLarge-Scale, Community-Based Trial of a Personalized Drug-Related Problem Rectification System
A controlled trial of a system for rectifying and preventing drug-related problems was conducted to evaluate improvement in the efficiency of resource utilization.Kahan, Waitman, Berkovitch, Yosselson Superstine, Glazer, Weizman, and Shiloh
ORIG INAL RESE ARCHTelephone-Based Cardiovascular Medication Therapy Management in Medicare Part D Enrollees With Diabetes A telephonic pharmacist-delivered medication therapy management intervention is an effective method for increasing the use of guideline-recommended cardiovascular therapies in high-risk Medicare patients with diabetes.
Caplan, Guy, Chang, and Boesen
ORIG INAL RESE ARCHGeneric Use Under Changing Co-Payments: Implications for Those With Multiple Chronic ConditionsPatients with multiple chronic conditions are less likely to use generic drugs, even when facing lower co-payments.
Buttorff
• Circulation to over 20,000 pharmacy benefit decision makers
• An expedited review process
• Exposure through Web and print publication opportunities
•
OUR JOURNAL BOASTS:
2017 TOPICS:
AJPB® is continually seeking submissions on a variety of topics. Areas of particular interest include utilization management, outcomes research on
Medicare Part D, analysis of drug therapies, cost utility analyses, and more.
