Journal of Managed Care Medicine Volume 19, Number 1 by Jeremy Williams

Vol.19, No.1, 2016

Journal of Managed Care Medicine

FEATURED ARTICLES INCLUDE: The Importance of Biosimilars and their Place in Managed Care Clinical Updates in Idiopathic Pulmonary Fibrosis Updates in the Treatment and Management of Relapsed/Refractory Multiple Myeloma

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Journal of Managed Care Medicine The Official Journal of the NAMCP MEDICAL DIRECTORS INSTITUTE A Peer-Reviewed Publication

Vol. 19, No. 1, 2016

TABLE OF CONTENTS

EDITOR-IN-CHIEF J. Ronald Hunt, MD

PUBLISHER

Jeremy Williams

ADVERTISING REPRESENTATIVE Daniel E. Davis ddavis@mrvica.com 856-768-9360

JOURNAL MANAGEMENT Douglas Murphy Communications Inc. P.O. Box 71895 Richmond, VA 23255-1895 (804) 387-7580 fax (703) 997-5842

Improving the Possibility of Remission in Major Depressive Disorder through Improved Management Mark Rosenberg, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Individualizing Treatment Strategies to Improve Patient Outcomes in the Management of Type 2 Diabetes Timothy S. Reid, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Integrating New Guidelines in the Management of Pulmonary Arterial Hypertension H. James Ford, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Clinical Updates in Idiopathic Pulmonary Fibrosis Fernando J. Martinez MD, MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

MANAGING EDITOR

Optimizing Anticoagulant Treatment Strategies in the Prevention of Stroke in Atrial Fibrillation Rajat Deo, MD, MTR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

GRAPHIC DESIGN

The Importance of Biosimilars and their Place in Managed Care Gillian Woollett, MA, DPhil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Custom Article Reprints

Advancing Clinical Care and Improving Outcomes in Psoriatic Arthritis: Payer Perspective Gary M. Owens, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Barry Barnum barry.barnum@douglasmurphy.com

Douglas Murphy Communications, Inc.

High quality reprints of individual articles are available in print and electronic formats. Contact Jeremy Williams, jwilliams@namcp.org, 804-527-1905 for reprints.

ISSN: 1094-1525. 1094-1525. The Thev Journal is published of Managed by Association Care Services Corporate and Circulation offices: Medicine Inc. is published by NAMCP Medical Directors 4435 Waterfront Drive, 101, Glen Allen,4435 VA Institute. Corporate andSuite Circulation offices: 23060; Tel (804) 527-1905; Fax (804) 747-5316. EditoWaterfront Drive, Suite 101, Glen Allen, VA 23060; rial and Production offices: 2613 N. Parham Rd., Tel (804) 527-1905; Fax 747-5316. Editorial and Suite B, Richmond, VA(804) 23294; Tel (804) 272-9100; Production offices: Advertising P.O. Box 71895, Richmond, VA Fax (804) 272-1694. offices: Jack Klose, 23255-1895; TelW. (804) 387-7580; (703) 997-5842. 804 Broadway, Long Branch, Fax NJ 07764; Tel (732) 229-8845; (856) Sloane 582-9596. Subscription Rates: AdvertisingFax offices: Reed, 4435 Waterfront one the United States; oneTel year $105 in Driveyear Ste$95 101,inGlen Allen, VA 23060 (804) 527Canada; one year $120 international. Back issues 1905, Fax (804) 747-5316. All rights reserved. Copyare available for $15 each. All rights reserved. right 2016. 2010. No part thisof publication may bemay reproCopyright Noofpart this publication be duced or transmitted in any in form by any reproduced or transmitted anyorform or means, by any means, electronic or mechanical, including photoelectronic or mechanical, including photocopy, recopy, recording, or any information storage orsysrecording, or any information storage or retrieval trieval system,written without writtenfrom consent from the tem, without consent the publisher. publisher. The publisher does not guarantee, eiThe publisher does not guarantee, either expressly ther expressly or by implication, the factual accuor by of implication, the and factual accuracy ofherein, the articles racy the articles descriptions nor and descriptions nor does the publisher does the publisherherein, guarantee the accuracy of any guarantee the accuracy ofby anythe views or opinions views or opinions offered authors of said ofarticles fered or by descriptions. the authors of said articles or descriptions. POSTMASTER: Send address changes to The POSTMASTER: Send address changes to The Journal of Managed Care Medicine, 4435 WaterJournal of Managed Waterfront Drive, Suite 101,Care GlenMedicine, Allen, VA4435 23060. front Drive, Suite 101, Glen Allen, VA 23060.

Updates in the Treatment and Management of Hemophilia: A Closer Look at Current and Emerging Strategies Julie Jaffray, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Updates in the Treatment and Management of Relapsed/Refractory Multiple Myeloma Rachid Baz, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Risk Factors for Medication Nonadherence and Acute Hospital Utilization in Medicaid Recipients Prescribed Hypoglycemics, Statins, and Antihypertensives Andrea D. Gelzer, MD, MS, FACP Wanzhen Gao, PhD David Keleti, PhD Thomas Donia, R.Ph Timothy W. Downey, MS Karen E. Michael, RN, MSN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 3

Editorial Review Board Alan Adler, MD, MS Medical Director Independence Blue Cross

Sarath Gunatilake, MD, DrPH Professor, Health Science Department California State University, Long Beach

Gary Owens, MD Principal Gary Owens Associates

Devena Alston-Johnson, MD Medical Director CIGNA

John W. Heryer, MD, FACS Medical Director Blue Cross Blue Shield of Kansas City

Philip Painter, MD Chief Medical Officer Humana

E. Paul Amundson, MD Chief Medical Officer Dakotacare

Kathy Hudson, PhD Director, Genetics and Public Policy Center Johns Hopkins University

Mary H. Pak, MD Medical Director Unity Health Plans Insurance Corporation

Linda Ash-Jackson, MD Medical Director Hometown Health

Larry L. Hsu, MD Medical Director Blue Cross Blue Shield of Hawaii (HMSA)

Paul Bluestein, MD Chief Medical Officer Connecticare

Stephen Keir, DrPH Co-Director, Center for Quality of Life Support Care Research Robert Preston Tisch Brain Tumor Center

Richard Bock, MD, MBA Chief Medical Officer Molina Health Care of California

John Knispel, MD, CPE, FACOG Regional Medical Officer Humana

Anthony Bonagura, MD Chief Medical Officer Aetna, Inc.

Karen Knowles, MD Internal Medicine Physician HCA/Emcare

Salil V. Deshpande, MD Market Medical Officer United Healthcare

Catherine Marino, MD Chief Medical Officer MagnaCare

Michael Fine, MD Medical Director Health Net John K. Fong, MD, MBA Vice President Blue Cross Blue Shield of North Carolina Stephen Friedhoff, MD Senior Vice President, National Medical Director Amerigroup/Wellpoint Ronald Y. Fujimoto, DO, FAAFP Chief Medical Officer United Healthcare Uwe G. Goehlert, MD, MSC, MPH, MBA Principal Goehlert & Associates Steven E. Goldberg, MD, MBA Vice President of Medical Affairs Coventry Health Care of Kentucky Humberto Guerra-Garcia, MD, MPH, FACP Chief Medical Officer MMM Healthcare, Inc./PMC Medicare Choice Puerto Rico

Jeff Martin, PharmD Clinical Account Director Innoviant, Inc. Monte Masten, MD, MBA, MPH Senior Consultant Health & Group Benefits, Tower Watson Wesley Mizutani, MD Director Clinical Research & Chairman Department of Rheumatology Healthcare Partners Thomas Morrow, MD Chief Medical Officer Next IT Barbara Nabrit-Stephens, MD, MBA Medical Director United Healthcare Tim Newman, MD Medical Director FirstEnergy Denis Oâ&#x20AC;&#x2122;Connell, MD Medical Director Blue Cross Blue Shield of North Carolina Arik Olson, MD, MBA Senior Medical Director CHOICE Health Plans

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Gary R. Proctor, MD Chief Medical Officer, Federal Division ValueOptions, Inc. Carlos Ramirez, MD Chief Medical Officer Valley Baptist Health Plans Paul Rein, DO Medical Director Port Warwick Ambulatory Surgery Center Kevin Roache, MD, MMM, CPE, FACPE President Medical Management Consulting, Inc. Joseph Schappert, MD Chief Medical Officer PAML Christine M. Seals, MD Medical Director Umpqua Health Alliance Jacque J. Sokolov, MD Chairman SSB Solutions Scott Spradlin, DO, FACPE, ACOI Vice President Medical Affairs/Chief Medical Officer Group Health Plan William D. Strampel, DO, FACOI Dean, College of Osteopathic Medicine Michigan State University Prentiss Taylor, MD Corporate Medical Director Advocate At Work at Advocate Health Care Pamella Thomas, MD,MPH, FACOEM Consulting Medical Director Wellness Health & Productivity Strategies Robert A. Ziff, MD, MBA, FACS, CPE Senior Corporate Medical Director, Medicare Humana

Improving the Possibility of Remission in Major Depressive Disorder through Improved Management Mark Rosenberg, MD, PhD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Major depressive disorder is significant due to its early onset, severity, likelihood of comorbidity, and overall economic and societal costs. Clinicians need to determine the most appropriate and effective interventions for patients as first-line treatment. Patients should have some input into selection of therapy. Treating the patient who does not respond to first-line treatment will require modification of the treatment plan and may require referral to a psychiatrist. Key Points • Major depressive disorder is a common and disabling illness that leads to significant reductions in quality of life and considerable cost to society. • Patient input in regard to their depression treatment choice should be considered. • When response to treatment is not optimal, medication nonadherence and correctness of the diagnosis should be considered. • Strategies to overcome treatment resistance include optimization, substitution, combination therapy, and augmentation. • Several investigational treatments are under study, including ketamine, magnetic seizure therapy, and deep brain stimulation.

IN ANY GIVEN YEAR, 19 MILLION AMERIcan adults, or 9.5 percent of the United States (U.S.) population, suffer from depressive disorders. There is a 17 percent lifetime prevalence for major depressive disorder (MDD). The average age of onset 50 years ago was 29, whereas the average age of onset today is 14.5. MDD has become a major public health concern and is responsible for significant social impairment, including the deterioration of family and interpersonal relationships, lost work productivity, general suffering, and mortality from suicide. Depression is frequently associated with, and may negatively impact other medical disorders. The morbidity related to MDD is comparable to angina and advanced coronary artery disease.1 Depression is the leading cause of disability in the U.S. and by 2020 it is projected that depression will be the leading cause of disability worldwide. Addi-

tionally, depression is the greatest cause of productivity loss among workers. Costs are especially an issue in those with both MDD and a chronic medical condition. Annual medical expenses for those with both chronic medical and behavioral health conditions cost 46 percent more than those with only a chronic medical condition. MDD is the most common psychiatric disorder in the U.S., yet few patients receive adequate treatment.2 In one study of 12-month use of mental health services in the U.S., only 19.6 percent of those with depression were receiving minimally adequate treatment.3 Inadequately treated depression may have a progressive course and may be associated with functional and structural changes in the brain.4 The changes probably perpetuate the disease. Because of the effects on the brain of a depression episode, after two to three episodes, patients probably should be treated for a lifetime.

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 5

Exhibit 1: DSM-5 Depression Criteria6

* Five or more of these symptoms must be present in order for a diagnosis of depression to be made. One of these symptoms must be either #1 or #2 Criteria 1.

Depressed mood*

Loss of interest or pleasure

Weight loss or weight gain

Sleep disturbance

Fatigue

Mood swings

Loss of concentration

Low self esteem or guilt

Suicidal ideation or thoughts of death

MDD is a costly disorder that results in significant health care resource utilization.5 In 2000, the estimated total costs were $83.1 billion. Because it is a costly disorder and can become a chronic disorder, MDD needs to be found and treated. The DSM-5 criteria for diagnosis of depression are listed in Exhibit 1.6 In primary care, physical symptoms are often the chief complaint in depressed patients. In one study, 69 percent of diagnosed depressed patients reported unexplained physical symptoms as their chief complaint.7 Once diagnosed, MDD needs to be adequately treated. For acute treatment, an initial treatment modality aimed at inducing remission of major depressive episodes and achieving a full return to baseline functions should be selected. The goal is not to just reduce symptoms. Treatment choices are outlined in Exhibit 2. The initial treatment modality should be influenced by clinical features and treatment preferences as well as take into account treatments being provided for other disorders. The acute phase of treatment lasts a minimum of six to 12 weeks. It is important to closely follow patients during this initial treatment phase because of the risk of suicide. Patient input into their depression treatment choice may have an impact on the outcome. One study found that patients did better when they were randomly assigned to the treatment they would have preferred if given a choice. In 429 patients with MDD who participated in a large multisite study comparing nefazodone, cognitive behavioral

therapy (CBT), and a combination of these two, patient preference strongly predicted outcomes over 12 weeks of treatment.8 The setting of care may also impact outcome. Receiving CBT in a setting other than a hospital, such as outdoors in the forest, may also result in better outcomes.9 Antidepressant medication is recommended as an initial treatment for patients with mild to moderate depression, and should definitely be provided to those with severe depression. Medications are generally comparable between classes, so selection will largely depend on factors such as side effects, costs, and patient preference. Once medication has been initiated, the rate of dose titration will depend on age, treatment setting, and co-occurring illness. Frequency of monitoring will be dependent upon symptom severity. If side effects occur, initial steps should be a dosage decrease or change to a medication not linked to that side effect. Approximately 30 percent of patients treated with an antidepressant will achieve remission (< 7 score on the Hamilton Depression scale). In antidepressant medication trials, up to 70 percent of depressed patients respond to treatment but fail to achieve complete remission from all their emotional and physical symptoms.10 Response is defined as a 50 percent or greater decrease in a patientâ&#x20AC;&#x2122;s depression scale score. At least four to eight weeks of therapy at an adequate dose is required before an assessment of responsiveness can be made. If minimal or no improvement is apparent, the provider should conduct an additional thorough review of contributory fac-

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Exhibit 2: Treatment Options

Pharmacologic Options

Psychotherapy

•

Serotonin Selective Reuptake Inhibitors (SSRIS)

•

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

•

Cognitive Behavioral Therapy

•

Interpersonal Therapy

•

Problem Solving Therapy

Tricyclic Antidepressants

•

Supportive Therapy

•

Monoamine Oxidase Inhibitors

•

Group Therapy

•

Adjunct Therapies

Medical Devices

= atypical antipsychotics = mood stabilizers = antiolytics

• • •

Electroconvulsive therapy Transcranial magnetic stimulation Vagus nerve stimulation

Exhibit 3: Combination/Augmentation Strategies: General Pros and Cons

Pros

Cons

• Strategy builds on therapeutic gains • Addition of second compound is generally well tolerated • More rapid onset of antidepressant effects during crucial early phase • Response rate comparable or superior to drug substitution

tors and make changes in the treatment plan. To address nonresponse, clinicians should assess the quality of the therapeutic alliance and treatment adherence. For patients in psychotherapy, clinicians should assess the frequency of sessions and if this approach is appropriately meeting the needs of the patient. Appropriate medication adjustments should be made and medication should be continued for an additional four to eight weeks to assess responsiveness. A switch in antidepressant class would be appropriate at this point. For example, the patient can be changed from a selective serotonin reuptake inhibitor (SSRI) to a tricyclic antidepressant. Between 10 and 30 percent of depressed patients taking an antidepressant are partially or totally resistant to treatment. Reasons for treatment resistance

• Increased potential of drug interaction • Reduced compliance • Increased adverse effects • Efficacy and long term effects may not yet be known in some cases

may include undiagnosed or misdiagnosed medical conditions (such as anemia), nonpsychiatric medications that can negatively impact depression, untreated comorbid conditions including eating disorders or substance abuse, and nonadherence. Nonadherence is an important reason for suboptimal treatment outcomes. Patients frequently report stopping antidepressant medication because of what they read on the Internet about it, it did not work quick enough, and it made them feel bad. Patients also frequently stop therapy once they start feeling better. Seventy-five percent of antidepressants are discontinued by month four of therapy. Interventions to reduce nonadherence include education regarding the disease and how medications and other treatments work. Common adverse effects

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of the antidepressant medication should be discussed openly with patients. Patients also need to know other medication options will be explored in case of adverse effects. It is especially important to teach patients that these medications need to be taken on a daily basis to be effective and have to be taken for a period of time before they begin to work. It can be helpful to reassure a patient that antidepressant medications are not addictive and that that continued treatment has a neuroprotective effect. Once all fixable causes of treatment resistance are resolved, a strategy for overcoming resistance will need to be implemented. Four strategies can be used to overcome resistance including optimization, substitution, combination therapy, and augmentation.11 Optimization is maximizing the dosage or duration of the therapy. An adequate duration for a trial of antidepressant therapy has been defined by some clinicians as four to six weeks. Others assert that a minimum of eight weeks is necessary. People who have not responded to traditional antidepressant therapy may benefit from drug substitution. Some studies suggest that switching to an antidepressant with a different mechanism of action is often associated with a better response rate. Studies have shown that non-responders who are switched from a tricyclic antidepressant to an alternative antidepressant class may result in a 50 to 60 percent positive response rate. Combination therapy involves the addition of a second antidepressant agent to the therapeutic regimen, such as adding trazodone, desipramine, or bupropion to fluoxetine. Therapeutic responses of combination therapy may be different than a response achieved by either drug alone, and may be potentially beneficial during the early stages of MDD. Augmentation therapy consists of adding a second agent, not routinely prescribed for depression, to the therapeutic regimen when there is a limited response to the antidepressant. Common augmentation therapy agents include lithium, atypical antipsychotics, thyroid hormone, pindolol, or buspirone. Add-on therapies based on level one evidence include aripiprazole, lithium, and olanzapine.12,13 Combination and augmentation strategies have both pros and cons (Exhibit 3). For depression resistant to medication, electroconvulsive therapy (ECT) remains an effective therapy for consideration. In patients capable of adhering to dietary and medication restrictions, an additional option is changing to a nonselective monoamine oxidase inhibitor (MAOI) antidepressant after allowing sufficient time between medications to avoid interactions. Another option for medication-resistant depression is transcranial magnetic stimulation. For patients who have not responded to four antide-

pressant trials or ECT, vagus nerve stimulation may be another treatment option. For patients with psychotherapy as their primary treatment plan, who are not achieving remission, the intensity, frequency, and duration of their treatment should be considered. A change of treatment type should also be considered. For patients utilizing psychotherapy alone, medications should be considered. Patients who have a history of poor adherence or incomplete response to single modalities may benefit from combined treatment (medication and psychotherapy). Continuation phase pharmacotherapy is strongly recommended following successful acute phase antidepressant therapy, with a recommended duration of continuation therapy of approximately four to nine months.13 The goal of continuation treatment is to prevent relapse in the vulnerable period immediately following remission. During the continuation phase of treatment, patients should be monitored with periodic symptom assessment. Patients treated successfully in the acute phase should continue whichever treatment that worked. In order to reduce the risk of a recurrent depressive episode patients who have had three or more prior episodes, or who have chronic major depressive disorder should proceed to the maintenance phase of treatment after continuation therapy. During maintenance, antidepressant medication that produced symptom remission during the acute phase and maintained remission during continuation should be continued at full dose. If therapy was the method of treatment, maintenance treatment should be considered with reduced frequency of sessions. For patients whose depressive episodes have not responded to acute or continuation treatment, but have responded to ECT, ECT maintenance should be considered. Maintenance treatment with vagus nerve stimulation is also appropriate for individuals whose symptoms have responded to that particular treatment modality. If treatment is going to be discontinued at any time, antidepressant medications have to be tapered over several weeks. A slow taper or temporary change to a longer half-life antidepressant may reduce risk of discontinuation syndrome. The patient should be informed of the potential for a depressive relapse and a plan should be established for seeking treatment in this event. After discontinuation of medication, patients should be monitored for several months, and receive another course of acute treatment if symptoms recur. Because of the importance of the mind-body connection in depression, a variety of lifestyle modifications can improve on outcomes achieved with the

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previously discussed treatments. Physical activity and a healthy diet should be encouraged. Providers should educate patients on the importance of structure in daily life, the need to continue with activities of daily living, and the importance of avoiding spending increased time in bed. Patients need to adhere to regular sleep and wake times. It is important to involve family members early in treatment and to educate them regarding the disease process. They can provide extra support and help implement recommendations, monitor medication adherence, and provide better feedback on patient functioning. Support groups, especially outdoors or in aesthetically pleasing environments, can supplement other treatments. Several agents are under investigation for major depression. Ketamine, not yet approved by the FDA to treat depression, has provided initial fast antidepressant results, generally within hours. This may prove beneficial for patients who are suicidal. On the flip side, the effects are short-lived, generally lasting up to a week or week and a half. Experiments to date have mostly focused on patients that have treatmentresistant depression, haven’t responded to several antidepressants and have moderate to severe symptoms of depression. Side effects are initially mild. Magnetic seizure therapy (MST) is still experimental and basically sends magnetic fields to trigger a controlled seizure in the brain similar to ECT. These seizures are providing initial results of relieving symptoms of depression, and very rapidly. MST does require hospitalization. Deep brain simulation, currently used to treat Parkinson’s disease, is also in the experimental phase for depression treatment and not yet approved by the FDA. It is an invasive surgical procedure in which electrodes implanted in specific brain areas deliver a targeted electric current to relieve the symptoms of depression. Electrodes are powered by a battery pack implanted in the chest or abdomen. If ever approved, it may only be used in the very resistant cases.

outcomes. These include allowing patient preference to shape treatment, improving medication adherence, referral to a psychiatrist for management of resistant depression, and using optimization, substitution, combination therapy, and augmentation to overcome resistance. Mark Rosenberg, MD, PhD, is President of BHM Healthcare Solutions in St Louis, Mo.

References 1. Wells KB, Stewart A, Hays RD, et al. The functioning and well-being of depressed patients. Results from the Medical Outcomes Study. JAMA. 1989;262(7):914-9. 2. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-105. 3. Wang PS, Lane M, Olfson M, et al. Twelve month use of mental health services in the United States. Arch Gen Psych. 2005;62(6):629-40. 4. Bremner JD. Structural changes in the brain in depression and relationship to symptom recurrence. CNS Spectr. 2002;7(2):129-30,135-9. 5. Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64(12):1465-75. 6. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). 2013. Washington, DC: American Psychiatric Association. 7. Simon GE, VonKorff M, Piccinelli M, et al. An international study of the relation between somatic symptoms and depression. N Engl J Med. 1999;341(18):1329-35. 8. Kocsis JH, Leon AC, Markowitz JC, et al. Patient preference as a moderator of outcome for chronic forms of major depressive disorder treated with nefazodone, cognitive behavioral analysis system of psychotherapy, or their combination. J Clin Psychiatry. 2009;70(3):354-61. 9. Kim W, Lim SK, Chung EJ, Woo JM. The effect of cognitive behavior therapy-based psychotherapy applied in a forest environment on physiological changes and remission of major depressive disorder. Psychiatry Investig. 2009;6(4):245-54. 10. O’Reardon JP. Pharmacologic and therapeutic strategies in treatment-resistant depression. Introduction and clinical presentations. CNS Spectr. 2009;14(3 Suppl 4):4-6. 11. Cadieux RJ. Practical management of treatment-resistant depression. Am

Conclusion

Fam Physician. 1998;58(9):2059-62.

Major depressive disorder is a common and disabling illness that leads to significant reductions in quality of life and considerable cost to society. Treatment will usually require a combination of therapies including both medication and psychotherapy. Several strategies can lead to improved

12. Papakostas GI. Managing partial response or nonresponse: switching, augmentation, and combination strategies for major depressive disorder. J Clin Psychiatry. 2009;70 Suppl 6:16-25. 13. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition. 2010. Available at http://www.psych.org/practice/clinical-practice-guidelines.

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Individualizing Treatment Strategies to Improve Patient Outcomes in the Management of Type 2 Diabetes Timothy S. Reid, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary To improve outcomes in the management of type 2 diabetes mellitus (T2DM), it is important to individualize treatment goals, especially hemoglobin A1C (A1C) goals. There are now numerous agents for managing T2DM which have advantages and disadvantages. Achieving appropriate goals will usually require at least two medications and maybe more. For many patients, injectables such as insulin and glucagon-like peptide-1 (GLP-1) agonists are appropriate but likely underused. Key Points • Individualized treatment goals for patients with T2DM should reflect the degree of hyperglycemia, comorbid conditions, disease duration and responses to therapy. • Customized A1C goals based on individual patient characteristics are important. • Diabetes self-management education should be a covered benefit. • Numerous provider-related and patient-related barriers to the use of insulin and GLP-1 therapies exist.

DIABETES CONTINUES TO BE A MAJOR health problem in the United States (U.S.). Over 29 million people or 9.3 percent of the U.S. population has diabetes.1 Most worrisome are the 8.1 million who have disease but are undiagnosed. This is a costly disease. Total costs are estimated at $245 billion annually.1 That figure is comprised of $176 billion in direct medical costs. After adjusting for population age and sex differences, the average medical expenditures among people with diagnosed diabetes were 2.3 times higher than people without diabetes. Indirect costs of $69 billion include those related to disability, work loss, and premature death. The costs that don’t always get measured include time required to manage the disease, burden of therapy, food cost, and emotion/stress for patients and family members. There are also costs to the care

team, including complexity of care and administrative burdens. Diabetes responds poorly to cookie cutter care. Clinicians cannot start with medication A and then go to B for everyone. The American Diabetes Association (ADA) standards of medical care now focus on individualized care.2 The A1C goal for most patients is still 7% but needs to be adjusted based on the factors in Exhibit 1.2 For example, it does not make sense to be aggressive with therapy to achieve a near normal A1C in a patient who has a limited life expectancy. As noted in the Exhibit, many of these factors are not modifiable. Treatment of T2DM includes lifestyle modification, dietary management, exercise, and weight loss. Education is also an important component of treatment. Diabetes self-management education should

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Exhibit 1: Approach to the Management of Hyperglycemia1

Patient/Disease Features Risks potentially associated with hypoglycemia and other drug adverse events

More stringent

A1c 7%

Low

Less stringent

High

Disease Duration Newly Diagnosed

Long-Standing

Life Expectancy Long

Short

Usually Not Modifiable

Important Comorbidities

Established Vascular Complications Patient Attitude and expected treatment efforts Resources and Support System

Absent

Few/Mild

Severe

Absent

Few/Mild

Severe

Highly motivated, adher- Less motivated, non-adherent, excellent self-care ent, poor self care capacities capacities

Readily Available

be aimed to achieve improved diabetes knowledge, self-care behavior, clinical outcomes, and quality of life. The well-educated patient should have lower A1C, lower self-reported weight, healthy coping, and lower costs. From a managed care perspective, diabetes education should be adequately reimbursed because it will pay off in the long run. Like A1C goals, individualized treatment selection should reflect the degree of hyperglycemia, comorbid conditions, disease duration and responses to therapy. The patientâ&#x20AC;&#x2122;s expectations of therapy and their ability to pay for medications also have to be factored into therapy choice and treatment goals. Most patients are going to require medication in addition to lifestyle management. There are now nine classes of oral medications and four classes of subcutaneous medications indicated for T2DM with more new classes coming to market. Exhibit 2 illustrates the actions of the oral medications. The subcutaneous agents include insulins, pramlintide (an amylin analogue), and GLP-1 agonists (albiglutide, dulaglutide, exenatide, liraglutide). Although most patients start on oral therapy, it is important to remember that T2DM is progressive. Insulin therapy

Potentially Modifiable

Limited

will eventually be needed in most cases. Oral therapy with metformin is preferred for initial therapy if tolerated and not contraindicated. Metformin is preferred because of high efficacy, longterm experience, low hypoglycemic risk, weight neutrality, and low cost. The guidelines recommend consideration of starting initial therapy with insulin if the patient is symptomatic or blood glucose is high (>500 mg/dl). Therapy should be advanced every three months if the patient is not at goal. If metformin is not sufficient, a second agent can be added. The choice can be a sulfonylurea, thiazolidinedione, dipeptidyl peptidase-4 (DPP-4) inhibitor, glucagon like peptide-1 (GLP-1) agonist, insulin, or sodium-glucose co-transporter 2 (SGLT-2) inhibitor. Therapies can be selected with synergistic mechanisms of action and combinations with similar mechanisms should be avoided. Further glucose control can be achieved with triple therapy. If the A1C target is not achieved after approximately three months of triple therapy, therapy should again be advanced. If the patient is on an oral combination, therapy should move to injectables. The guidelines provide various options at each stage of therapy.

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Exhibit 2: Oral Diabetes Medications

↑ Insulin Secretion

↓ Hepatic Glucose Production

↓ Pancreatic Glucagon Secretion

↑ Peripheral Glucose Uptake

↓ GI CHO Absorption

↓ Renal Reabsorption of Glucose

β-cell Function

α-Glucosidase Inhibitor (acarobose, miglitol)

↔

Biguanide (metformin)

↔

Bromocriptine

Unknown

Colesevelam

Unknown

DPP-4 Inhibitor (alogliptin, linagliptin saxagliptin, sitagliptin)

Improve *

Glinide (nateglinide, repaglinide)

↔

SGLT-2 Inhibitor (canagliflozin, dapagliflozin, empagliflozin) SU (glimepiride, glipizide, glyburide

↔

TZD (pioglitazone, rosiglitazone)

Improve * In vitro and rodent data; preliminary human data

Insulins produce robust blood glucose reduction and A1C reductions of 1.5 to 3.5%. Hypoglycemia is the major concern and requires monitoring and management. There are few drug-drug interactions with most related to changes in blood glucose. There are now numerous delivery options including syringe, pens, pumps, and inhalation. Exhibit 3 compares the various insulins based on pharmacokinetic profile. Insulin is appropriate for patients with very high glucoses because it is the most effective way to lower levels and without sufficient control on oral therapy as monotherapy or in combination with oral agents. The GLP-1 agonists are incretin agents with multiple sites. They stimulate glucose-dependent insulin secretion, increase beta cell mass, and inhibit glucagon secretion in a glucose-dependent fashion. They also slow gastric emptying times and reduce hepatic glucose output by inhibiting glucagon. In the central nervous system, these agents promote sa-

tiety and reduce appetite. Exhibit 4 compares the various GLP-1 agonists. The newer agents are given at longer dosage intervals than older agents (exenatide and liraglutide). The longer-acting agents give more fasting glucose control, whereas the shorter-acting ones provide more postprandial control. In general, nausea and diarrhea are the most common adverse effects. Hypoglycemia does not usually occur with monotherapy but is more likely if GLP-1 agonists are used in combination with secretagogues. Contraindications include medullary thyroid carcinoma, hypersensitivity, and multiple endocrine neoplasia (type 2). Thyroid tumors occur in animal models because of GLP-1 receptors in the thyroid but have not been reported in humans because of fewer thyroid receptors. Many more GLP-1 agonists are on the horizon. Lixisenatide is a once-daily injectable. Oral GLP1 is under investigation. This uses low molecular weight compounds to increase lipophilicity. Com-

12 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 3: Insulin Examples/Types Type

Generic Name

Brand Name

Onset

Peak

Duration

Rapid

aspart glulisine lispro

Novolog Apidra Humalog

10 - 30 minutes

30 minutes to 3 hours

3 - 5 hours

Short

regular

various

30 - 60 minutes

2 - 5 hours

Up to 12 hours

1.5 to 4 hours

4 - 12 Hours

Up to 24 hours

0.8 to 4 hours

Minimal peak

Up to 24 hours

Intermediate Long

NPH detemir glargine

Levemir Lantus

bination formulations with insulin are being investigated by a number of companies. Very long-acting GLP-1 agonists, as an implant replaced every three, six, or 12 months, are under development. The ADA guidelines have advantages and disadvantages in guiding therapy. They provide a structured way for busy clinicians to think about the therapy available for glucose control. Unfortunately, they do not adequately address the patient population with significant comorbid conditions. The sicker the patient (significant renal dysfunction, cardiovascular disease, etc.) the more likely insulin is to be the better therapy. Additionally, the guidelines give no direction regarding when to discontinue medication and potentially promote polypharmacy. Despite all the effective medications, patients with T2DM are still not reaching appropriate goals. One reason is clinical inertia-the failure to initiate or intensify therapy in a defined time among patients who have not attained clinical goals and who would likely benefit from intensification. In a retrospective cohort study based on 81,573 people with T2DM, in patients taking one, two or three oral agents, the median time from treatment initiation to intensification with an oral agent or insulin exceeded the maximum follow-up time of 7.2 years.3 Many people in this study were at A1C values greater than 8% for years, which is unacceptable. Clinical inertia results from provider and patient barriers. Physician barriers to intensifying therapy include the time it takes to educate patients and get them started on injectable agents, fears of hypoglycemia, concerns about weight gain, personal inadequacy, and feelings of futility.4,5 Patient barriers include perceptions of insulin as a marker of endstage disease, aversions to injections, and cultural issues. Culturally, some groups think insulin means

that they have very advanced disease and are likely to die soon. Overcoming barriers requires a multipronged approach. Clinicians need to identify personal obstacles, help patients restore sense of personal control, enhance self-efficacy, and address emotional issues. It is also helpful to discuss the risks of hypoglycemia and injection fears and reinforce the positive aspects of insulin use. It is important to help patients understand the benefits of following through with treatment. Patients should be referred for diabetes self-management education for ongoing support.6 Because this is a lifelong disease, it requires lifelong support. The future of T2DM therapy includes additional classes of medications. This includes glucokinase activators, ultra-long-acting insulins, ultra-rapidacting insulins, biosimilar insulins, very long-acting GLP-1 agonists, and additional products combining different classes. If there is any hope of fighting the diabetes epidemic, numerous changes to the environment, physical activity levels, and food supplies need to become the cultural norm. The rate of diabetes in adults is a major issue, but the real problem is the rate in children and adolescents. That population is getting a head start on all the complications of the disease. Conclusion

Clinical practice guidelines can give us important insights into the management of our patients with T2DM. It is important to consider patient specific factors when choosing therapy and glucose goals for our patients. There are many newer classes of medications for T2DM, including GLP-1s that need to be considered. There are important patient and provider barriers to identify when choosing injection therapy for our patients. Our understanding of diabetes continues to evolve, the number of tools that

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 13

Exhibit 4: GLP-1 Agonists Name

Dosing Schedule

Dosing

Smallest Needle Size

Use with Basil Insulin

Auto Injector

A1c Reduction (Monotherapy

Fasting Blood Sugar Reduction

Albiglutide (Tanzeum)

30 mg, 50 mg

29-guage 5mm thin-walled needle

Yes

30 mg = -0.7% 50 mg = -0.9%

30 mg = -16 mg/dl 50 mg = -25 mg/dl

Dulaglutide (Trulicity)

0.75 mg, 1.5 mg

Built into device 29-guage, 5mm needle

No (Studies are currently evaluating)

Yes

0.75 mg = -0.7% 1.5 mg = -0.8%

0.75 mg = -26 mg/dl 1.5 mg = -29 mg/dl

Exenatide (Byetta)

BID

5 mcg, 10 mcg

32-guage, 4mm needle

Yes

5 mcg = -0.7% 10 mcg = -0.9%

5 mcg = -17 mg/dl 10 mcg = -19 mg/dl

Exenatide extended release (Bydureon Kit)

2 mg

23-guage 8mm needle

No (Studies are currently evaluating)

2 mg = -1.6%

2 mg = -25 mg/dl

Exenatide extended release (Bydureon Pen)

2 mg

23-guage 7mm needle

No (Studies are currently evaluating)

2 mg = -1.6%

2 mg = -25 mg/dl

Liraglutide (Victoza)

06, 1.2, 1.8 mg

32-guage, 4mm needle

Yes

1.2 mg = -0.8% 1.8 mg = -1.1%

1.2 mg = 115 mg/dl 1.8 mg = -26 mg/dl

we have continue to grow, and the environment in which we care for our patients continues to change. Thus, clinicians have to keep up.

2. American Diabetes Association. Summary of Revisions. In Standards of Medical Care in Diabetes â&#x20AC;&#x201C; 2015. Diabetes Care. 2015;38 Suppl :S4. 3. Khunti K, et.al. Clinical Inertia in People with Type 2 Diabetes. Diabetes Care. 2013; 36:3411-7.

Timothy S. Reid, MD, is a Diabetes and Metabolic Specialist at the

4. Koerbel G, Korytkowski M. Insulin-Therapy Resistance. Practical Diabetolo-

Mercy Diabetes Center in Janesville, Wis.

gy. June 2003:36-40. 5. Magwire ML. Addressing barriers to insulin therapy: the role of insulin pens.

References

Am J Ther. 2011;18(5):392-402.

1. Centers for Disease Control. National Diabetes Report 2014. Available at:

6. Funnell MM, Brown TL, Childs BP, et al. National standards for diabetes

http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-

self-management education. Diabetes Care. 2012;35(Suppl 1):S101-8.

web.pdf

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Integrating New Guidelines in the Management of Pulmonary Arterial Hypertension H. James Ford, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title

Summary Because symptoms are nonspecific and treatments can worsen other types of pulmonary hypertension, pulmonary arterial hypertension (PAH) requires right heart catheterization for an accurate diagnosis. There are several PAH medications which can be used to improve symptoms and survival in this devastating disease. Care in a referral center is important for optimal management. Key Points • PAH can be heritable; secondary to drugs and toxins; associated with connective tissue diseases, HIV infection, portal hypertension, congenital heart diseases, or schistosomiasis; or idiopathic. • Right heart catheterization is necessary for diagnosis of PAH. • The major consequence of PAH is right-sided heart failure. • Several oral, inhaled, subcutaneous, and intravenous therapies are available for reducing symptoms and improving survival. • Combination therapy is acceptable and may become the recommended initial step.

SEMANTICS ARE IMPORTANT WHEN DIScussing pulmonary arterial hypertension (PAH); one must distinguish between pulmonary hypertension (PH) and PAH. Pulmonary hypertension is a general term used to describe elevated pressure in the pulmonary vascular bed, not describing where the “lesion” is, and is defined as a mean pulmonary artery pressure ≥ 25 mmHg as measured by right heart catheterization. PAH is elevated pressure in the pulmonary vasculature due to disease limited to the arteries/arterioles (i.e. due to an intrinsic abnormality in the pulmonary arterial bed). It is defined by mean pulmonary artery pressure ≥ 25 mmHg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, pulmonary vascular resistance ≥ 3 Wood Units, and a transpulmonary gradient (normal < 12 mmHg).

PAH can be heritable (bone morphogenetic protein receptor (BMPR2) mutations); secondary to drugs and toxins; associated with connective tissue diseases (lupus, scleroderma, etc.), HIV infection, portal hypertension, congenital heart diseases, or schistosomiasis; or idiopathic.1 In the United States (U.S.), amphetamines are the most common drugrelated cause of PAH. One to 2 percent of patients with HIV will develop PAH during the course of their disease. Schistosomiasis is the most common cause of PAH worldwide but is rarely seen in the U.S. Idiopathic PAH is relatively rare. PAH is more common in women but also affects many men and affects a wide age range. Unfortunately the majority (69 to 75%) of patients are not diagnosed until they have functional Class III or IV disease.2,3 The median time between

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 15

Exhibit 1: PAH Specific FDA-Approved Therapies (in the U.S.) 7 Oral Therapies •

Bosentan - improvements in 6MWT, time to clinical worsening functional class, hemodynamics

•

Ambrisentan - improvements in 6MWT, time to clinical worsening, functional class

•

Macitentan - improvement in morbidity and mortality

•

Sildenafil - improvements in 6MWT, functional class, hemodynamics

•

Tadalafil - improvements in 6MW, functional class, time to clinical worsening

•

Riociguat - improvement in 6MWT, functional class

•

Treprostinil - improvement in 6MWT

2 Parental Therapies •

Epoprostenol - improvements in survival, 6MWT, hemodynamics

•

Treprostinil (subcutaneous also) - improvement in 6MWT, hemodynamics

2 Inhaled Therapies •

Iloprost - improvement in 6MWT, hemodynamics

•

Treprostinil - improvement in 6MWT, hemodynamics

6MWT = six-minute walk test

symptom onset and diagnosis is 14 months. The vagueness of the symptoms, particularly early in the disease process, is one of the causes of diagnosis delays. A wide range of signs and symptoms are suggestive of PAH. Dyspnea on exertion is the most common presenting complaint. Fatigue, weakness, angina, and syncope can also occur. Lower extremity edema, jugular venous distension, and ascites are signs of more severe disease and right heart failure. Echocardiograms are recommended for screening when PAH is suspected. One should be ordered for screening selected groups even if PAH is not suspected. These groups include first-degree relatives of those with idiopathic PAH or with known BMPR2 mutation and those with scleroderma, coronary heart disease (particularly uncorrected left to right shunts), or being evaluated for liver transplant. Echocardiography is used to estimate pulmonary pressures and identify enlargement of the right side of the heart but should not be used to make the diagnosis. Right heart catheterization is important for diagnosing PAH and determining whether PAH therapy is appropriate. Unfortunately, many managed care plans do not require right heart catheterization data before approving use of oral PAH therapies. For intravenous medication approval, catheterization is usually required. Many patients who have

had PAH diagnosed based on echocardiography get treated with oral PAH therapy which is frequently inappropriate. There is an extremely low morbidity and mortality with right heart catheterization. A retrospective/ prospective analysis of 7,200 elective procedures found only four deaths; this equates to a 0.055 percent mortality.4 A vasodilator challenge can be done with injectable epoprostenol or adenosine or inhaled nitrous oxide during the right heart catheterization procedure to determine if vasodilator therapy with calcium channel blockers is appropriate. Vasodilator testing is only useful in IPAH and drug-induced PAH; it is not indicated in someone with advanced PAH or right heart failure because the vasodilators are not effective. A positive vasodilator challenge is defined as a drop in mean pulmonary artery pressure by 10 mm Hg to a value of 40 mm Hg or less. A positive vasodilator challenge does have prognostic value; responders have better longer-term survival. Once diagnosed, patients with PAH require several general care measures. Women with PAH need to avoid pregnancy because of the high maternal mortality rate (30 to 60%) and teratogenicity of many PAH medications. Thus, all fertile women with PAH require counseling on pregnancy avoidance and reliable contraception. Because respiratory

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illnesses can worsen the disease, all those with PAH should receive influenza and pneumonia vaccinations. Those with heart failure need to be counseled to minimize Valsalva maneuvers because of an increased risk of syncope. Oxygen therapy may be required in these patients because hypoxic vasoconstriction aggravates PAH. It is important to keep patients’ oxygen saturation at 90 percent or greater. Nocturnal desaturation should be ruled out with overnight oximetry and concomitant obstructive sleep apnea and hypoventilation syndromes which cause significant pulmonary artery pressure elevations also need to be identified. Pulmonary rehabilitation is also recommended because it can significantly improve functional ability as measured by the six-minute walk test (6MWT, distance walked in 6 minutes). There are seven oral, two parenteral, and two inhaled PAH specific therapies (Exhibit 1). New York Heart Association (NYHA) Functional Classification can be used to determine which PAH therapy to choose. Patients classified as NYHA Class I have no symptoms or impact on their function from their disease. NYHA Class II patients have shortness of breath when performing ordinary activities, whereas NYHA Class III includes those with shortness of breath with less than usual activity levels. Class IV signs and symptoms include shortness of breath at rest, syncope, and right heart failure. Endothelin receptor antagonists (ETRAs) target relative excess of endothelin-1 by blocking receptors on the endothelium and vascular smooth muscle. The available agents are bosentan (Tracleer ®), ambrisentan (Letairis®), and macitentan (Opsumit®). All agents in this class are oral and teratogenic. All women on an ETRA must have a monthly negative pregnancy test to continue these agents. In studies, bosentan led to improvements in 6MWT, time to clinical worsening, functional class, and hemodynamics. There is larger clinical experience with bosentan compared with the other ETRA but it has the potential to cause serious liver injury (including very rare cases of unexplained hepatic cirrhosis after prolonged treatment). Monthly liver function monitoring is required and significant drug interactions can occur. Ambrisentan, a selective agent given orally, has been shown to lead to improvements in 6MWT, time to clinical worsening, and functional class. This agent has several advantages over bosentan – it is given once daily versus twice, no transaminase monitoring is required, and there are no known significant drug interactions. Macitentan, the most recently agent approved, is a tissue-targeting ETRA. The trial evaluating

this agent was landmark in PAH study design. The SERAPHIN trial enrolled 742 subjects and continued for two years, a much larger sample size and trial duration compared with prior PAH studies. At the highest dose, this agent reduced morbidity and mortality by 40 percent.5 Post hoc analyses of the trial data showed that both low and high dose macitentan resulted in reduced hospitalizations and hospital days compared to placebo.6 Phosphodiesterase (PDE-5) inhibitors augment the bioavailability of nitrous oxide in the pulmonary arteries which has vasodilatory and antiproliferative actions and is relatively deficient in patients with PAH. Sildenafil (Revatio®) was the first FDAapproved PDE-5 inhibitor. The FDA approved dose is 20 mg three times daily but higher doses (80 to 100 mg tid) have been shown in trials to improve hemodynamic findings. Tadalafil (Adcirca®), with an FDA-approved dose of 40 mg qd, has similar efficacy to sildenafil. Its once-daily dosing is a slight advantage over sildenafil. PDE-5 inhibitors do cause more adverse effects than the ETRAs. Many of the adverse effects are related to vasodilation and include headaches, epistaxis, hypotension (transient), gastroesophageal reflux, dyspepsia, diarrhea, and myalgia. Nonarteritic anterior ischemic optic neuropathy and sudden hearing loss have also been reported. The last class of PAH-specific agents are the prostacyclin analogues - epoprostenol, treprostinil, and iloprost. These agents provide vasodilation, platelet inhibition, anti-proliferative effects, and inotropic effects. Trials have shown improvements in 6 MWT over 12 weeks, hemodynamics, and survival. Epoprostenol (Flolan®, Veletri®) was the first PAH specific therapy available in the mid-1990s. This agent has a very short half-life (2 minutes) so it is delivered via continuous parenteral infusion. Because of the continuous infusion requirement, there are significant costs and difficulties with giving this agent. The cost is approximately $100,000/year, but it is the only PAH therapy with a demonstrated pure mortality benefit versus placebo, not just a combined mortality/morbidity benefit. Administration issues include infusion-related adverse effects, complex daily preparation, individualized dosing requirements, need for keeping the Flolan formulation cold even while infusing, catheter complications, pump malfunctions, embolization, and infection. Therapy with epoprostenol requires a savvy, teachable patient or caregiver to manage the regimen. The side effects that occur with prostacyclin analogues tend to improve as the patient adjusts to the therapy but include headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, anxiety/nervousness, and erythroderma.

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 17

Treprostinil (Remodulin®) results in hemodynamic and 6MWT improvements. It is available as subcutaneous or intravenous continuous infusion and has a longer half-life than epoprostenol (4 hours). This longer half-life provides a theoretical reduced risk of rapid fatal deterioration if the infusion is stopped accidentally. Significant pain at the infusion site limits use of subcutaneous infusion. More than 10 percent of patients will discontinue this agent because of site pain, despite efforts to treat the pain. This agent causes the same basic adverse effects and administration issues as epoprostenol. Iloprost (Ventavis®), an inhaled prostacyclin analogue, results in improvements in 6MWT, functional class, and hemodynamics. Safety and side effects are similar to the infused agents, but there are some unique adverse effects with inhalation including cough and pharyngitis. Morning syncope has been reported with this agent because it is only given during the daytime. Patients have to remember to inhale a dose before they leave the bed to prevent syncope. Ideally, this agent is administered nine times daily, with each inhalation taking five to eight minutes. Inhaled treprostinil (Tyvaso®) is dosed four times daily. Initially the patient inhales three breaths four times daily then the dose is titrated to at least nine breaths four times daily. Doses higher than the FDA approved nine breaths four times daily are used. Each ampule of the medication provides up to 21 breaths four times daily without any additional cost. This agent has been shown to provide improvements in 6MWT at peak and trough when co-administered with an ETRA or a PDE-5 inhibitor. Oral treprostinil (Orenitram®) was recently approved and clinicians are still trying to determine its place in therapy. It is a sustained-release formulation with plasma concentrations significant over eight to10 hours (10 to 12 hours with high fat/calorie meal). In two trials, this oral formulation did improve 6MWT when used as monotherapy and as add-on to ETRA or sildenafil. The major issue with this formulation is gastrointestinal adverse effects, which are typical with prostacyclin analogue therapy magnified by giving an oral agent. Slow titration of the dose may help mitigate the GI problems. The place for this therapy is likely for the patient on lowdose parenteral therapy and normal right ventricle who can be transitioned to the oral therapy. Generally speaking, prostacyclin analogues are reserved for the sickest patients, particularly the infused agents. This includes those with marked elevation in right atrial pressure, depressed cardiac output/index, syncope, pericardial effusion, or evidence of advancing right ventricle therapy failure

despite oral therapy. Riociguat is a new class of medication– soluble guanylate cyclase stimulator. It is approved in both PAH and PH secondary to chronic thromboembolic disease. It improved 6 MWT in both types of PH. The clinical management guidelines for PAH recommend that diagnosis of PAH be done or confirmed in a PH center with right heart catheterization.1,7 If a patient has vasoreactivity on catheterization, they should be tried on a calcium channel blocker if their cardiac output is sufficient. Durability of the efficacy of CCB has to be assessed periodically. Functional Class should be improved by therapy. In general, those with functional Class II and III are usually treated with oral therapies. Those with Class IV will need inhaled or infused therapy. Combination therapy is indicated when monotherapy is not sufficient; this recommendation may change to early use of combination therapy based on some ongoing trials. A trial of ambrisentan and sildenafil found that initial combination therapy improved hospitalization rates and 6MWT compared to either agent alone.8 Lung transplant is considered once a patient has failed all the available medications. Other medications are under investigation. Selexipag is a selective prostacyclin receptor agonist which will hopefully have fewer prostacyclin-related adverse effects. In one trial, patients were treated for up to 4.3 years, with median exposure to study treatment of 63.1 weeks. At enrollment, 80 percent of patients were already receiving therapy for PAH, with 15 percent receiving ERA monotherapy, 32 percent PDE-5 inhibitor monotherapy and 33 percent receiving a combination of both.9 Statistically significant increases in 6MWT of 12 meters were seen in the entire patient population (p=0.0027), with an improvement of 34 meters in PAH-treatment-naïve patients (p=0.0002). Referral to a PH care center is important for optimal management of those patients who require very expensive treatment. One important role of PH care centers is confirming diagnosis. The multicenter RePHerral study demonstrated the volume of pulmonary arterial hypertension (PAH) misdiagnosis. In an analysis of PH referrals to three tertiary care centers, 51 percent of patients had a change in diagnosis after a complete, evidence-based workup by the receiving center. Thirty percent of patients evaluated by the tertiary care centers were already on PAH therapy and, after a full workup, 45 percent of those on PAH-targeted therapy were classified as “non-PAH”.10 Thus, a significant percentage of patients who are not seen in referral centers are misdiagnosed and on inappropriate therapy, which is not only the wrong, expensive therapy but can

18 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

also worsen other types of PH.

2. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med.

Conclusion

2006;173(9):1023-30.

The preferred screening test for PH is the echocardiogram, but the diagnosis of PAH can only be made via right heart catheterization. The proper classification of PH is crucial for appropriate therapy choices. There are multiple new and emerging therapies for PAH patients, with increasingly rigorous and robust clinical trial design. This has led to the need for frequent updates in treatment guidelines for PAH. Multidisciplinary, accredited, PH center-based care is becoming the new standard of care.

3. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376-873. 4. Hoeper MM, Lee SH, Voswinckel R, et al. Complications of right heart catheterization procedures in patients with pulmonary hypertension in experienced centers. J Am Coll Cardiol. 2006;48(12):2546-52. 5. Said K. Macitentan in pulmonary arterial hypertension: The SERAPHIN trial. Glob Cardiol Sci Pract. 2014;2014(2):26-30. 6. Channick RN, Delcroix M, Ghofrani HA, et al. Effect of macitentan on hospitalizations: results from the SERAPHIN trial. JACC Heart Fail. 2015;3(1):1-8. 7. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment

H. James Ford, MD, is an Assistant Professor of Medicine and the

algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1

Director of the Pulmonary Hypertension Program at the University of

Suppl):S78-84.

North Carolina at Chapel Hill, in the Division of Pulmonary and Critical

8. AMBITION study 2014. First-line combination of ambrisentan and tadalafil

Care Medicine.

reduces risk of clinical failure compared to monotherapy in pulmonary arterial hypertension outcomes study. Abstract 2916. Presented at the European Respi-

References

ratory Society International Congress, Munich, Germany, 8th September 2014.

1. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert

9. McLaughlin VV, Channick R, Chin K et al. Effect of selexipag on morbidity/

consensus document on pulmonary hypertension: a report of the American

mortality in pulmonary arterial hypertension: results of the GRIPHON study.

College of Cardiology Foundation Task Force on Expert Consensus Docu-

J Am Coll Cardiol. 2015;65. http://dx.doi.org/10.1016/S0735-1097(15)61538-8

ments and the American Heart Association: developed in collaboration with the

10. DeaĂąo RC, Glassner-Kolmin C, Rubenfire M, , et al. Referral of Patients with

American College of Chest Physicians, American Thoracic Society, Inc., and

Pulmonary Hypertension Diagnoses to Tertiary Pulmonary Hypertension Cen-

the Pulmonary Hypertension Association. Circulation. 2009;119(16):2250-94.

ters: The Multicenter RePHerral Study. JAMA Intern Med. 2013;173(10)887-93.

NAMCP works to improve patient outcomes by providing medical directors with education, evidence-based tools and resources. Go to www.namcp.org or contact Jeremy Williams at (804) 527-1905 or jwilliams@namcp.org. AAIHDS is at the forefront of provider integration and population health management. Members are executives from ACOs, CIOs, IDS, PHOs, & IPAs. Contact RenĂŠ Enders at renders@aaihds.org, (804) 747-5823 or visit www.aaihds.org.

American Association of

Integrated Healthcare Delivery Systems

AAMCN is a nursing association focused on managed care and improving patient outcomes. Visit www.aamcn.org or contact April Snyder to learn more. (804) 747-9698 asnyder@aamcn.org.

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 19

Clinical Updates in Idiopathic Pulmonary Fibrosis Fernando J. Martinez MD, MS For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Appropriate diagnosis of idiopathic pulmonary fibrosis (IPF) is difficult but vital. Unfortunately, patient survival is very poor. Treatment of IPF has changed dramatically in the last year with the approval of two agents which slow the progression of the disease. Key Points • IPF is a progressive disease with poor survival. • Diagnosis of IPF is difficult. • Triple therapy with prednisone, azathioprine, and N-acetylcysteine (NAC) increases risk of death and hospitalization. • Two treatments have been approved and reduce progression, but they are very expensive.

INTERSTITIAL LUNG DISEASES ARE DIFFIcult because they are a diverse group of disorders (130+), having similar symptoms, physiology, and radiology, difficult nomenclature, and limited, often toxic, treatments. Idiopathic pulmonary fibrosis (IPF) is one of the many interstitial lung diseases. IPF is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and limited to the lungs. It is characterized by progressive worsening of dyspnea and lung function and is associated with a poor prognosis. An estimated 89,000 people have diagnosed IPF in the United States (U.S.). Thirty-four thousand cases are diagnosed each year. The majority of cases are in those over 75.1 Five-year survival of IPF, at 25 percent, is worse than most cancers.2 Diagnostic criteria for IPF include exclusion of other known causes of diffuse parenchymal lung dis-

ease and usual interstitial pneumonia (UIP) pattern on high resolution computed tomography (HRCT) without surgical biopsy or definite/possible UIP pattern on HRCT with a surgical lung biopsy showing definite/probable UIP.3 For patients who have the classic interstitial pneumonia pattern on HRCT, a lung biopsy is not required. Clinical history can identify other causes of lung disease such as infection, systemic disorders (particularly connective tissue disease), and exposures (inhaled or oral). HRCT allows detailed evaluation of the lung parenchyma and is optimal for interstitial lung disease. Unfortunately, many patients do not have a clear pattern for diagnosis. Because survival is worst in IPF compared to other interstitial lung diseases, it is very important that an accurate diagnosis be made. Communication among the multidisciplinary team (clinician, pathologist, and radiologist) is essential to the ac-

20 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 1: Disease Progression in IPF is Variable and often Unpredictable 5

Respiratory Functions/Symptoms

Slow Decline

Acute Exacerbation

Rapid Decline

Years

curate diagnosis. Multidisciplinary interactions have been shown to improve diagnostic agreement and confidence for IPF and are now considered the standard of care.4 Even experts do not do a good job on making the diagnosis in isolation. Initial symptoms in IPF are cough and dyspnea. As the disease progresses, hypoxemia develops and eventually pulmonary hypertension. As patients progress, they will have increasing disability. Death can result from end-stage pulmonary hypertension. Disease progression in IPF is variable and often unpredictable. Patients can have a slow, stair-step, or rapid decline (Exhibit 1).5 There is not currently a good way to predict the course a patient will have. Men typically do worse and the older the patient the worse the prognosis. Degree of lung function is also predictive of prognosis. In IPF patients, exacerbations are frequent and commonly result in hospitalization. The treatment options for IPF are limited to best supportive care, medical treatment, and lung transplantation. Lung transplantation, which has been shown to definitively improve survival, is an option for a minority of patients. As shown in Exhibit 2, many therapies have been tried but few have significant scientific data supporting their use.3 Oxygen, lung transplantation, and pulmonary rehabilitation for symptomatic patients are the only ones that were recommended. Since these guidelines were published in 2011, a few IPF treatment trials have been published. Gastro-esophageal reflux is frequently seen in pa-

tients with IPF and a series of studies have shown that anti-reflux medication treatment is associated with improved survival. The trials have not been randomized, placebo controlled, but there is strong clinical support for treating reflux symptoms. A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used in the past as a treatment for idiopathic pulmonary fibrosis. Unfortunately, in a recent well-designed study, as compared with placebo, this triple combination offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild to moderate impairment in lung function and actually increased risk of death and hospitalization.6 A study of NAC alone in the same patient population found no benefit compared to placebo.7 Thus, triple therapy and NAC are no longer recommended for IPF treatment. Unfortunately, many managed care plans require that patients have failed the triple combination before being approved for the two new agents discussed below. These policies need to change based on the new data on the triple combination. Pirfenidone (Esbriet速) is an oral antifibrotic therapy FDA approved for treating IPF in October 2014. It works by reducing lung fibrosis through downregulation of the production of growth factors and procollagens I and II. In the pivotal trial used for approval, pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fi-

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 21

Exhibit 2: Management of IPF3 Treatment

Strong For

Weak For

Weak Against

Strong Against

Corticosteroid

Colchicine

Cyclosporine A

Interferon Îł 1b

Bosentan

Etanercept

NAC/Azathioprine/Prednisone

NAC

Anticoagulation

Mechanical ventilation

Pulmonary rehab

Long-term oxygen

Lung transpantation

Exhibit 3: Comparing Patients in the IPF Phase III Trials 8,9

ASCEND

INPULSIS

68 yr, 79% men 64% smokers

67 yr, 79% men 72% smokers

95% definite UIP pattern on HRCT [FEV1/FVC > 0.8] 30% SLB performed

97% HRCT consistent with IPF 40% emphysema at HRCT [FEV1/FVC > 0.7]

FVC 685 pred. DLCO 44% pred.

FVC 82% pred. DLCO 47% pred.

35% patients screened enrolled

70% patients screened enrolled

brosis.8 Nausea, rash, and modest weight loss are the most common adverse effects. Nintedanib (OFEVÂŽ), an intracellular inhibitor that targets multiple tyrosine kinases, was also approved by the FDA for IPF in 2014. It slowed the decline in FVC over time.9 It is frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5 percent of patients. Nausea can also occur. Exhibit 3 compares the patient populations in the pirfenidone and nintedanib Phase III trials. In the pirfenidone trial, the subjects had a confident diagnosis of IPF by a panel of experts. They had relatively well-preserved lung function and did not

have significant chronic obstructive lung disease. The benefits of pirfenidone are proven in a narrow population. In the nintedanib study, the CT criteria were a little less stringent so it was easier to get patients enrolled. COPD was allowed in the nintedanib study. Because these two agents can cost $60 to $100 thousand annually, patients need to be selected carefully. There are many other agents under study for IPF. It is hoped several of these will prove beneficial. Optimal management of IPF patients should include referral to an IPF center. These centers have diagnostic expertise and do standardized assessment to confirm the diagnosis. They also have manage-

22 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

ment expertise in oxygen prescription, pulmonary rehabilitation, attention to obesity and sarcopenia/ frailty, and transplant evaluation. Centers also offer the potential for enrollment in a clinical trial. Delays in referral to expert care is associated with higher mortality rates.10 Lung transplantation is a treatment possibility. It can be considered when histopathologic or radiographic evidence of usual interstitial pneumonitis (UIP), abnormal lung function: FVC < 80% predicted or DLCO < 40% predicted , any dyspnea or functional limitation attributable to lung disease, and any oxygen requirement, even if only during exertion.11 Urgent lung transplantation is the only effective treatment for acute exacerbation-related decline.

References 1. Raghu G, Weycker D, Edelsberg J, et al. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174(7):810-6. 2. Vancheri C, Failla M, Crimi N, Raghu G. Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology. Eur Respir J. 2010;35(3):496-504. 3. Raghu G, Collard HR, Egan JJ, et al. An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. Am J Respir Crit Care Med. 2011;183:788-824. 4. Flaherty KR, King TE Jr, Raghu G, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med. 2004;170(8):904-10. 5. Kim DS, Collard HR, King TE Jr. Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc. 2006;3(4):285-92. 6. Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ, et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-77.

Conclusion

7. Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez FJ, de

IPF is a form of chronic, progressive fibrosing interstitial pneumonia of unknown cause that occurs primarily in older adults and is limited to the lungs. The diagnostic process is centered on excluding systemic diseases or exposures and identifying a pattern of UIP on HRCT or surgical lung biopsy. Standard immunosuppressive therapy is no longer felt to be indicated. Pirfenidone and nintedanib were recently approved to treat IPF and can slow the progress of the disease.

Andrade JA, et al. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2093-101. 8. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-92. 9. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-82. 10. Lamas DJ, Kawut SM, Bagiella E, et al. Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study. Am J Respir Crit Care Med. 2011;184(7):842-7.

Fernando J. Martinez, MD, MS, is the Gladys and Roland Harriman

11. Weill D, Benden C, Corris PA, et al. A consensus document for the selection

Professor of Medicine and Executive Vice Chair, Joan and Sandy Weill

of lung transplant candidates: 2014--an update from the Pulmonary Transplan-

Department of Medicine at Weill Cornell Medical College. He is also a

tation Council of the International Society for Heart and Lung Transplantation.

Professor of Medicine at the University of Michigan.

J Heart Lung Transplant. 2015;34(1):1-15.

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 23

Optimizing Anticoagulant Treatment Strategies in the Prevention of Stroke in Atrial Fibrillation Rajat Deo, MD, MTR For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Stroke prophylaxis must be considered in every patient with atrial fibrillation (AF). The choice of therapy will depend on the other risk factors for stroke, risk factors for bleeding present in the patient, and other concomitant conditions such as kidney dysfunction. New anticoagulants offer the promise of improved risk reduction with similar or lower risk of bleeding complications compared with warfarin. • • • •

Key Points Stroke prophylaxis is very important in patients with AF. Stroke risk scores are used for selecting therapy. Warfarin is still indicated for many patients. Newer anticoagulants are alternatives to warfarin but have not been compared directly to each other.

ATRIAL FIBRILLATION (AF), THE MOST common arrhythmia in clinical practice, affects over three million Americans. Because of population aging, AF is estimated to affect 16 million Americans by 2050. In patients with AF, it is important to prevent thromboembolic events. AF-related thromboembolism is the reason for one in five strokes in the United States (U.S.). Ninety percent of thromboembolism cases in AF originate in the left atrial appendage. Unfortunately, only 50 percent of those with AF receive some type of thromboembolic prevention. An individual’s risk of stroke can be estimated and is used for selecting therapy. CHADS2 scoring is a system for establishing the risk of stroke in patients with nonrheumatic AF.1 Points are given for presence of heart failure, hypertension, age over 75, diabetes mellitus, and previous stroke or transient ischemic attack. CHA 2DS2VASc is a refinement of

the older CHADS2 score, which includes additional stroke risk factors and puts greater emphasis on age as a risk factor.2 Exhibit 1 compares the two scoring systems. With either system, the risk of stroke increases with increasing score. Generally, they result in similar treatment recommendations. The most recent update of the American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/ HRS) guidelines recommend the use of CHA 2DS2VASc for assessing stroke risk in nonrheumatic AF.3 When taken appropriately, warfarin is effective in reducing stroke risk, but monitoring is required to ensure therapeutic dosing and many foods and many medications interact with warfarin. Despite efficacy, warfarin exposes patients to bleeding risks (e.g., intracranial hemorrhage and hemorrhagic stroke). Warfarin tops the list for emergency hospitalizations for adverse drug events in older Americans.4 Addi-

24 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 1: How do CHADS2 and CHAD2S2VASc Compare? Where they are the same: •

Both CHADS systems assign 1 “point” each for presence of congestive heart failure (any), hypertension and diabetes

•

Both CHADS systems assign 2 points for prior TIA or stroke

Where they differ •

CHA 2DS2VASc puts greater emphasis on age, assigning 1 point for age between 65-74 years, and 2 points for age > 75 years. CHADS2 only assigns one point for age > 75 years

•

CHA 2DS2VASc adds 1 point each for presence of any vascular disease and female gender, which are not included in the CHADS2 score

tionally, warfarin use represents a challenge when patients need surgery and there are high rates of discontinuation and nonadherence to therapy. Because of all these issues, warfarin is underprescribed in AF and researchers have sought better anticoagulants. Dabigatran (Pradaxa®), rivaroxaban (Xarelto®), apixaban (Eliquis®), and edoxaban (Savaysa®), are new novel anticoagulants FDA approved in recent years as alternatives to warfarin. There have been single trials comparing each of the new agents with warfarin but no trials comparing them to each other. Rivaroxaban, apixaban, and edoxaban all work by inhibiting factor Xa, whereas dabigatran is a direct thrombin inhibitor. Each of the novel anticoagulants is given orally; dabigatran and apixaban are dosed twice daily, rivaroxaban and edoxaban once daily. Doses of dabigatran, rivaroxaban, and edoxaban must be adjusted for renal dysfunction. Dosage regimens and the need for dose adjustments are part of agent selection. For the novel agents, no standard monitoring for anticoagulation activity is recommended. Unlike warfarin, there is not a standard way to determine if a patient is actually taking one of these agents as prescribed. An activated partial thromboplastin time (aPTT) can be checked but is not yet validated as a measure of efficacy. A value 2.5 times normal may indicate over-anticoagulation. The RE-LY trial, a noninferiority trial, compared dabigatran and warfarin.5,6 This trial showed that dabigatran 150mg bid is superior to warfarin in low to moderate risk patients. For reversing over-anticoagulation with dabigatran, it is recommended that adequate diuresis be maintained. The agent is 60 percent dialyzable. Bleeding can be managed with fresh frozen plasma, packed red blood cells, prothrombin complex concentrates, or recombinant factor VIIa. Similar strat-

egies can be used to manage bleeding secondary to the other novel agents. A monoclonal reversal agent for dabigatran has been submitted to the FDA for approval. As an alternative anticoagulant, dabigatran has its limitations and safety concerns. A high rate of dyspepsia leads to intolerance and discontinuation. In the RE-LY trial, dabigatran caused more gastrointestinal (GI) bleeds but fewer intracranial hemorrhages (ICH) than warfarin.5,6 Overall, the numbers of serious bleeding episodes with either dabigatran or warfarin were very low. There is also a potential for accumulation in the presence of renal dysfunction. Most clinicians choose not to use dabigatran in patients with renal dysfunction because it has not been prospectively studied in this population. Lastly, the need for twice-a-day dosing may negatively impact adherence. Rivaroxaban has been approved by the FDA for treatment of nonvalvular AF. In comparison to warfarin, it was equivalent in the ROCKET AF trial which enrolled patients with nonvalvular AF at moderate to high risk of stroke.7,8 The clinical population in the ROCKET AF trial had a higher risk of stroke than those in the RE-LY trial or in other trials of novel anticoagulants. The study population had an average CHADS2 score of 3.47. This agent also has a similar safety profile to dabigatran – higher rate of GI bleeds, lower rate of ICH – compared with warfarin. Major and nonmajor bleeding events were similar and not statistically different between the rivaroxaban and warfarin treatment groups. Dosage adjustments for renal dysfunction have been prospectively tested for rivaroxaban. Once daily dosing with rivaroxaban may increase adherence to treatment and patient preference over dabigatran. Rivaroxaban is best absorbed when taken with food and the current labeling recommends taking the

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 25

Exhibit 2: Recommended Stroke Prophylaxis in AF3 Recommended Agent

Notes

AF and mechanical heart valves

Warfarin

INR = 2.0 - 3.0 or 2.5 - 3.5 depending on type and location of valve

Nonvalvular AF with CHA 2DS2VASc score of 0

None

Nonvalvular AF with CHA 2DS2VASc score of 1

None, aspirin or anticoagulant

Nonvalvular AF with prior stroke, transient ischemic attack (TIA), or a CHA 2DS2VASc score 竕･ 2

Warfarin, dabigatran, rivaroxaban or apixaban

INR 2.0 - 3.0 for warfarin. Novel agent recommended if unable to maintain therapeutic INR

Nonvalvular AF with a CHA 2DS2-VASc score 竕･ 2 and end stage chronic kidney disease (creatinine clearance <15 mL/min) or are on hemodialysis

Warfarin

INR 2.0 - 3.0

INR = international normalized ratio

daily dose with the evening meal. Apixaban and warfarin were compared in the ARISTOLE trial in AF patients with an average CHADS2 score of 2 (similar to RE-LY trial).9 The rate of any stroke or systemic embolism was 1.27 percent in the apixaban group versus 1.67 in the warfarin group, a 22 percent reduction in risk. Major bleeding occurred in 2.3 percent of the apixaban group versus 3.09 percent of warfarin patients. Intracranial hemorrhage was 0.33 percent per year with apixaban and 0.8 percent per year with warfarin. Overall, the rate of any bleeding was 25.8 percent per year in the warfarin group and 18.1 percent in the apixaban group for an absolute reduction of 7.7 percentage points. Fatal bleeding occurred in 34 patients in the apixaban group and 55 patients in the warfarin group. This is the first of the new medications that shows a lower risk of overall bleeding, but this difference was not statistically different; again noninferiority with warfarin was shown. The dose of apixaban should be decreased from 5 mg twice daily to 2.5 mg twice daily when two of the following factors are present - age greater than 80, weight less than 60 kg or creatinine greater than 1.5. Apixaban is given twice a day, which may result in lower adherence. Edoxaban, the most recently approved novel anticoagulant, is approved for the prevention of stroke and non窶田entral-nervous-system systemic embolism in patients with nonvalvular AF. In the ENGAGEAF TIMI trial comparing this agent to warfarin, low-dose and high-dose edoxaban was noninferior

to warfarin and was associated with significantly lower rates of bleeding and death from cardiovascular causes.10 High-dose edoxaban resulted in more GI bleeding versus warfarin and low-dose edoxaban. Overall, dabigatran, rivaroxaban, apixaban, and edoxaban have demonstrated safety and efficacy in clinical trials. However, real-world and longterm efficacy, safety, and drug interactions are not yet known and are being investigated. While new oral anticoagulants may avoid the burden of regular INR monitoring, bleeding risks and high rates of nonadherence are still a problem. A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require longterm patient adherence. Exhibit 2 outlines the recommended stroke prophylactic agents based on the CHA 2DS2VAS score.3 Edoxaban was approved by the FDA after these guidelines were published. Antiplatelet therapy with aspirin is indicated in AF patients at low risk of stroke (score of 1). For those with higher risk (score of 2 or more), anticoagulation is recommended. Conclusion

Protecting patients from stroke is vitally important but many AF patients, who should be anticoagulated, are not being treated. All patients with AF need to be assessed for stroke risk and prescribed appropriate preventive therapies. A variety of anticoagulants can be used to protect against thromboembolic risk in AF. The newer anticoagulants provide clinicians with additional choices for anticoagulation and

26 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

should be available for selection.

izations for adverse drug events in older Americans. N Engl J Med. 2011;365(21):2002-12.

Rajat Deo, MD, MTR, is the Director of Translational Research in Car-

5. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in

diac Arrhythmias in the Division of Cardiology, Electrophysiology Sec-

patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51.

tion at the University of Pennsylvania.

6. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363(19):1875-6.

References

7. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Com-

1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classifica-

mittee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in

tion schemes for predicting stroke: results from the National Registry of Atrial

nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91.

Fibrillation. JAMA. 2001;285(22):2864-70.

8. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct fac-

2. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for

tor Xa inhibition compared with vitamin K antagonism for prevention of stroke

predicting stroke and thromboembolism in atrial fibrillation using a novel risk

and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET

factor-based approach: the euro heart survey on atrial fibrillation. Chest.

AF study. Am Heart J. 2010;159(3):340-7.

2010;137(2):263-72.

9. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in

3. January CT, Wann LS, Alpert JS, Calkins H, et al. 2014 AHA/ACC/HRS

patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-92.

Guideline for the Management of Patients with Atrial Fibrillation: Executive

10. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in

Summary. J Am Coll Cardiol. 2014: S0735-1097(14)01739-2.

patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-104..

4. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospital-

Abbott Vascular AbbVie Acelity (KCI) Actelion Acorda Therapeutics Allergan Amarin Corporation Ambry Genetics AmerisourceBergen/Premier Source Amgen Inc. AssureRx Health Astellas Pharma US Baxalta Bayer HealthCare Pharmaceuticals Biodesix Biofire Diagnostics, LLC Biogen Bioventus, LLC Boehringer Ingelheim Boston Scientific Bristol-Myers Squibb CVS Caremark CardioDx Celgene Corporation Counsyl DiaTech Oncology, LLC Eisai Exact Sciences Corporation Foundation Medicine GE Healthcare Genentech Genomic Health

Genoptix Gilead Sciences HeartFlow InSightec Incyte Corporation Intarcia Therapeutics J & J Health Care Systems KalĂŠo Lilly Oncology Lilly USA, LLC Merck & Co. Merrimack Myriad Genetic Laboratories NanoString Technologies NantOmics Natera Novartis Pharmaceuticals Novo Nordisk, Inc. Omeros Osiris Therapeutics, Inc. Pfizer Inc PharMedQuest Purdue Pharma, L.P. Sandoz Pharmaceuticals Seattle Genetics Sunovion Pharmaceuticals Taiho Oncology Takeda Oncology Teva Pharmaceuticals Tolmar Pharmaceuticals VITAS Healthcare Corporation Veracyte Vermillion

Thank You For Your Continued Support!

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 27

The Importance of Biosimilars and their Place in Managed Care Gillian Woollett, MA, DPhil For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary The debate about biosimilars continues in the United States (U.S.) and around the world, and the approval process for these agents continues to evolve in the U.S. Interchangeability of biosimilars is not yet solidified nor is the process of how this will happen. The first biosimilars have been approved and more are likely to hit the market in the next few years. Key Points • Commercialization of a biologic is done on a case-by-case basis. • In the U.S., the available options for biologic approvals may have already discouraged biosimilars. • Without extrapolation between indications, the U.S. biosimilars pathway has questionable value. • Return on investment from an individual biologic will be impacted by interchangeability and the reimbursement environment.

MEDICINES WORK, BUT HEALTH SYSTEMS determine the incentives. Available medicines are largely created by commercial enterprises. Variations in regulatory decision-making govern what is available in a given jurisdiction, but even once approved, access can be variable within a country because of cost and health care programs. Thus, commercial enterprises develop products, but this type of development does not ensure access. Pharmaceutical product development, particularly for biologic medications, is no longer compartmentalized the way it used to be; in the past, a company would decide to develop a product, market it, and see if the health care system adopted use of the product. There are a lot more voices throughout the stages of development that now have to be considered. There

are also changes in how products are coming to the market. Product sponsors now need to anticipate a whole slew of different types of evidence for product approval, which varies greatly from country to country. These types of evidence have to be integrated in the beginning of development almost before a company decides what the product actually is and how it may be used. Sponsors integrated market access strategy must align multidisciplinary goals. Patient access is also a major factor in market access strategy. Patient access, although always considered in the past, has become a much stronger factor because of patient advocacy groups. There are struggles within the approval process at the FDA of how to accommodate patient access voices. All the changes in how products come

28 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 1: Highly Regulated and Emerging Markets for Biologics

Europe 0.31

Largely have and expect access

Brazil 0.19 Russia 0.14

U.S. 0.30

India 1.22 China 1.34

ICH plus others

Canada 0.03

Japan 0.12

Mexico 0.10 BRIC-MT plus others

Australia 0.02

Rest of the World Limited health care infrastructure Population is in billions ICH = International Conference on Harmonisation BRIC-MT = (Brazil, Russia, India, China, Mexico and Turkey)

Turkey 0.07

See products and want greater access

Little knowledge and even less access

World Population Total 6.9

to market are particularly relevant for biologics. Biologics, medicines made in living systems, are not new. The first vaccine for small pox was approved in the early 1800s. The FDA has licensed more biologics, especially biotechnology, than most regulatory authorities in other countries. Late in the 20th century, there was a huge amount of progress in biologics and biotechnology. During this time, there was a proliferation of blockbuster small molecule drugs, the emergence of the biotechnology industry, the beginning of the generic revolution and competition as the stimulus to innovation, and globalization of manufacturing. Additionally, international naming conventions were established and the human genome was mapped. Early in the 21st century, biotechnology became mainstream. There are now multiple special regulatory programs in the highly regulated markets, a patent cliff where many products patents are due to expire in the highly regulated markets, and globalization in demands for access. The special regulatory programs such as orphan drugs counter market pressures and prioritize development for products that perhaps benefit the

fewest people. Quality, in terms of good manufacturing practices, has been in the spotlight and has contributed to some product shortages worldwide. In the beginning, biotechnology was a way to manufacture follow-ons to naturally-sourced biologics. For example, 250,000 pigs were replaced by one 300 liter fermenter to produce insulin. The products are life-saving and life-enhancing but are not dependent on limited natural sources (live animals or dead people) and carry less risk of endogenous infectious agents. Biotechnology products have more consistent purity, potency, and identity. Biotechnology can create products that do not occur in nature. Biotechnology products do require significant initial investment in manufacturing facilities because production of biotechnology products is much more complicated than traditional medications. Often this is a single site, but this is cost effective on a unit basis for a global market. Manufacturing continues to innovate with the potential to significantly reduce the cost of goods, but needs to be able to upgrade facilities as a regulatory matter.

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 29

Exhibit 2: Global versus Regional Considerations for all Medicines – What Governs Market Entry? 2

GLOBAL

REGIONAL/NATIONAL

ACCESS Patients are everywhere

Regulations are regional with some harmonization for drugs, and innovator biologics

SCIENCE Essentially global

IP varies, and getting a little better harmonized, but barely

Companies DEVELOP AND MANUFACTURE for more than one market

Healthcare systems vary Determines commercialization (ROI, primary and secondary markets)

NAMING Historically have had global norms IP = intellectual property regulations; ROI = return on investment

Historically, there has been no head-to-head competition for biologics. In the U.S., there are separate statutes for approval – one for drugs and one for biologics – which has helped maintain separation and issues with biosimilars. As shown in Exhibit 1, Europe, the U.S., and Japan, are part of the International Committee on Harmonization (ICH) and have standardized approaches to product approval. The required evidence dossiers are different among countries, but the required data are similar and acceptable across jurisdictions. Canada and Australia are not formally part of the ICH but adopt the same approaches. These five areas of the world are considered the highly regulated markets and account for 15 percent of the world population. The U.S. alone has 5 percent of the world’s population but accounts for almost 50 percent by value of the biologics market. The highly regulated markets have and expect access to biologics. Brazil, Russia, India, China, Mexico, and Turkey (BRIC-MT) are the fastest growing markets and regulators in these countries have imposed certain requirements, including the need for local clinical studies, for registration of biologics.1 The regulatory landscape in these countries is rapidly evolving, which necessitates an up-to-date understanding of their individual requirements. These emerging markets account for 45 percent of the world’s population and know these products are out there and want better access. These countries have historically waited

for the highly regulated market to approve products before adopting them. The rest of the world beyond the highly regulated markets and the emerging markets has less knowledge about and less access to biologics. These countries are largely dependent on donations for biologic access, which is primarily limited to vaccines. Exhibit 2 outlines the global and regional/national factors that govern market entry.2 Overall, patient access is determined by regulatory approval plus competition based on value within an individual country. Generics are products of the same quality with the same clinical value at a lower price. Generics offer high quality drugs for established treatments at an affordable cost and thereby free up health care funds for new innovative drug development. Innovative drugs offer improved treatment outcomes and fewer adverse effects and thereby replace older/ less effective medications. The brand name/generic drug model requires companies to continue to innovate as their product patents expire. Biosimilars, essentially generic biologics, are expected to offer the same value at a lower cost than branded biologics. But, lower price and uptake by the market of biosimilars is a big assumption. In the U.S., health care payers are concerned about price and trends in the use of biologics. Payers and providers in the U.S. are looking to control specialty product costs because the trend they are

30 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 3: Originator Biologic Drug Approvals Have Increased and are Expected to Rise3,4 In Development (NDA and BLA)

Approvals (NDA and BLA) 12

1000 900

10 8

800

Non-orphan Orphan

700 600

500 400

300 200

100 0 19 82 19 84 19 86 19 88 19 90 19 92 19 94 19 96 19 98 20 00 20 02 20 04 20 06 20 08 20 10 20 12 20 14

19 82 19 84 19 86 19 88 19 90 19 92 19 94 19 96 19 98 20 00 20 02 20 04 20 06 20 08 20 10 20 12 20 14

NDA = new drug application; BLA = biologic license application

seeing is unsustainable. The success of biotechnology is showing; payers are looking at the cost and use of these agents. This trend should support the uptake of biosimilars. What is the future? Originator biologic drug approvals have increased and are expected to continue to rise and are expected to dramatically increase the total costs of biologics. Exhibit 3 compares the products which have been approved by the FDA over about 30 years and those in development over those same years. 3,4 There are a tremendous number of products in clinical trials (900 in 2012) but only 12 products were approved in 2014. This suggests either the wrong products are being studied or there is an issue with FDA approval, which will worsen as biosimilars come up for approval. Although there is a strong pipeline of biotech products, if the FDA cannot approve even innovator products, we do not have to worry too much about biosimilars. The consistency of regulatory expectations becomes very important as to whether a biosimilar market is even feasible. It is questionable whether biosimilars can ever be approved in the U.S. with the assurance of purity, safety, and potency comparable to the innovator product. The one biosimilar that has been recently approved was supported by European data in seven million patients. A significant number of biologic patents are soon to expire. Products with over $70 billion in sales are due to go off patent by 2017.5 The top six compa-

nies with biologics include Roche, Amgen, Novo Nordisk, Sanofi, AbbVie, and Johnson & Johnson. These companies are going to have to do something about product lifecycle management to maintain their market share. For example, AbbVie sought and had approved an orphan indication for Humira速 (adalimumab), which means a biosimilar cannot meet that same indication for seven years. No one is going to pursue a biosimilar for an unsuccessful product, but companies with successful products do have the opportunity to invest significantly in lifecycle management with additional indications and patent protections. Europe has 21 biosimilars approved from 13 development programs. There have been substantial savings and increases in access through this affordability without unusual or unexpected adverse events. The Biologics Price Competition and Innovation Act of 2009 (BPCIA) was enacted as part of the Patient Protection and Affordable Care Act (ACA) with the expectation of significant savings to the federal government. The BPCIA, Title VII of ACA, created a distinct approval pathway for interchangeable biologics, the 351(k) pathway, in 2010 but no applications have yet been filed through this pathway. Sponsors can elect the pathway (Exhibit 4) they wish to pursue when seeking biologic approval. In the U.S., a few biologics are approved and regulated as drugs, including growth hormone, insulin, and a few others.

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Exhibit 4: Biologic and Drug Approval Pathways

PATHWAY New Drug Application (NDA) 505 (b) (1) and 505 (b) (2) 510k and PMA

STATUTE U.S. Food, Drug and Cosmetic Act

Abbreviated NDA (505 (j) or ANDA) Biologic License Application (BLA) or “Standalone” 351 (a)

U.S. Public Health Service Act

BIOSIMILAR 351 (k) (can be interchangeable)

The standalone biologic pathway has some benefits for sponsors in the U.S. These include data exclusivity for 12 years (+), patents are independently litigated, and known payer/physician/consumer perceptions regarding new entrants in a product class. The biosimilar pathway results in limited exclusivity (1 year for first in class), regulatory uncertainty, and unknown payer/physician/ consumer perceptions. It may be easier to get a product into the U.S. market as a standalone; then the company can rely on payers to push their product over others based on cost and off label use. Although this is not the best avenue, it will likely occur because of the FDA process. Exhibit 5 illustrates the difference in the approval process for a standalone biologic versus a biosimilar.6 For a standalone biologic, the clinical trials in Phase I, II, and III have to be done. For a biosimilar, analytics are the basis for establishing biosimilarity. Analytics head-to-head with the innovator product establish “High Similarity/ Similarity”; functional studies support this conclusion. The developer of the biosimilar does not have access to anything in the originator’s dossier. The developer is referring to the prior FDA approval decision and establishing the match with its own analytics. This means the developer has to extensively analyze the reference product to know where to start in making the new product. Developers have to buy the commercially available product in the jurisdiction where it will be marketed (i.e., a U.S. approved product with U.S. approved labeling must be used to establish biosimilarity for the U.S. market). Studies may have to be repeated for each market, which may make biosimilars not cost effective and limit a company’s ability

to develop a product. Targeted clinical trials confirm biosimilarity and reduce residual uncertainty. The FDA approved the first biosimilar in March of 2015 - Zarxio® (filgrastim-sndz). The biosimilar received full extrapolation of five U.S. indications of the reference product (Neupogen) at the time of approval. Amgen has since added an indication for their product that will not automatically be on the label for the biosimilar. The indications can be different in different countries. In Europe, the biosimilars have all the same indications as the reference products without individual clinical trials for each indication. Interchangeability is not a global concept. In the U.S., the FDA can designate biologics as interchangeable so they can be substituted for the reference product. The term ‘interchangeable’ or ‘interchangeability’, in reference to a biological product that is shown to meet the standards, means that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.7,8 In the U.S., where there is the opportunity for interchangeability, the FDA would like, but the federal statutes do not require, for the biosimilar to have all the same indications as the reference before there is interchangeability. Designation of Zarxio as an interchangeable biologic was not sought. The FDA expected up to 10 biosimilar 351(k) applications by the end of 2015, so the issue of interchangeability will need to be resolved. Biosimilars share aspects of traditional originator pharmaceuticals and generics (Exhibit 6).6 These similarities and differences may lead to business

32 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 5: The Regulatory Concept of Biosimilarity6

351(a) Standalone BLA

Switching Studies

351 (k) Biosimilar

Confirmation of biosimilarity • Establish Safety, Purity and Potency a priori Clinical

Clinical

• Clinical Phase 1, 2, and 3 Studies

ClinPharm

• Comparator is current standard of care

Non-Clinical

Analytical: establish high similarity

ClinPharm Non-Clinical R and D: Lead Selection

Every stage is head-to-head comparison of the biosimilar candidate and the reference originator

Every stage is standalone

models that span the two areas of treating biosimilars as generics or brands. A new business model for biosimilars/interchangeable biologics will likely emerge. Previously, brand name products could command a high price for being new and innovative but were initially prescribed in low volume and generic products were competitive based on price with a low margin but high volume. Biosimilars are going to have to be somewhere in-between. The cost to patients will depend on the development costs for market access and payer uptake (market share). Initial development costs, which can be substantial, are decided by the extent and cost of studies the FDA requires for product approval; details for biosimilars remain uncertain. Another issue with biologics and biosimilars is manufacturing changes. These changes are common with already approved products where a manufacturer alters the way the product is produced. Each manufacturing change is approved by the regulators in the jurisdictions where the product is approved. A product that is “highly similar” has the “same” active ingredient, and the clinical outcome is expected to be the “same” and while the mechanism of action may or may not be known there is complete extrapolation between all indications, interchange-

ability, and the patient or health care practitioner is not informed of the change because the label on the product does not change. The nonproprietary name stays the same when high similarity is established. There is tremendous experience in what is highly similar and the basis for determining this. Thus, all reference products that undergo manufacturing changes are biosimilars to themselves. Developers of biosimilars have to know that these changes occur in order to make sure they are using the right reference product in doing their analytics. As a scientific matter, comparability and biosimilarity are the same. As a regulatory matter, they are the same in the European Union but that is less clear in the U.S. There is a greater proof burden for biosimilars in the U.S. than what has been historically applied for manufacturing changes in already approved products. Manufacturing-changed products are always interchangeable. The absence of an interchangeability designation may be a commercial constraint. Two outstanding issues in the U.S. are that both the reference product used in biosimilar development and the study design need to be agreed amongst regulators. A single global source of the reference product is relevant and already known to

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 33

Exhibit 6: Biosimilars Share Aspects of Originator Products and Generics 6

Novel Molecular Entity

Biosimilar/Interchangeable Biologic

Small Molecule Generic

Unmet Need: Lack of therapeutic options

Already therapeutic options, but may be lack of access through affordability challenges

Often novel mechanism of action (MOA)

Established MOA

Routine analytics

Exceptional analytics (‘fingerprint-like”)

Routine analytics

Broad clinical development program

Tailored clinical studies to confirm biosimilarity

Limited confirmatory clinicals (BE)

Demonstration de novo efficacy and safety

Relies on prior finding of safety and efficacy of reference

Expertise in therapeutic area fundamental

Clinical expertise unnecessary

Quality Manufacturing Essential (cGMP)

regulators. Without a single global source of the reference product, manufacturers may have to do multiple studies. Regulators from the highly regulated markets (e.g., FDA, European Medicines Agency, Health Canada) are largely consistent scientifically, but reference to each other as a regulatory matter continues to be difficult. The result for manufacturers is cumulative requirements. Harmonization of regulatory requirements is essential for incenting global development. The FDA has stated that to repeat unnecessary clinical studies would be unethical, and also would like access to non-U.S. data on products being considered for submission in the U.S. European Medicines Agency is allowing use of appropriately justified, non- EU-sourced reference product. Canada can allow the use of a non-Canadian reference product. Consistent clinical study design is as important as recognition of studies with foreign reference product if global development is to be feasible. The need for doing clinical studies in every country where a biologic would be marketed increases product marketing costs. Nonproprietary naming confusion of biosimilars continues in the U.S. The one approved product is named filgrastim-sndz to designate it from the fil-

grastim reference product. The ending is a temporary placeholder indicating the manufacturer. This violates United States Pharmacopeia (USP) guidelines on matching names and is a big issue for databanks given a name that does not match and a name that may change. The USP has naming authority so the placeholder ending required by the FDA is resulting in mislabeled and misbranded products which makes manufacturers uncomfortable. It is unknown if this situation will change. The FDA may decide to drop the company reference placeholder or go back and rename old products to add manufacturer designation. Under the Medicaid Rebate Program, manufacturers must enter into rebate agreements with states to have drugs covered by Medicaid. For covered outpatient drugs, the rebate to Medicaid has two components: the basic rebate and the additional rebate. For brand drugs, the basic rebate is the greater of 23.1 percent of the average manufacturer price (AMP) or the difference between the AMP and the best price extended to any buyer. For generic drugs, the basic rebate is equal to 13 percent of each product’s AMP. For brand drugs, additional rebates are required when a product’s price increases faster than the Consumer Price Index – Urban (CPI-U). The

34 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

additional rebate equals the excess amount by which the AMP exceeded the CPI-U. For generic drugs, there is no additional rebate for excessive price increases. According to the Centers for Medicare & Medicaid Services (CMS), biosimilar biological products fall within the definition of single source drugs requiring sponsors offer 23.1 percent rebates.9 The first biosimilar approved for each biologic will receive a Healthcare Common Procedure Coding System (HCPCS) code separate from the reference product. This first biosimilar will be paid at its own average sale price (ASP) plus 6 percent of the reference product’s ASP. Until the ASP is available, the biosimilar will be paid at 106 percent of its own wholesale acquisition cost. It is unknown whether all biosimilars to the same reference product will share the same code. Whether payment for all biosimilars to the same reference product will be based on weighted average ASP of all of the biosimilars plus 6 percent of the reference product’s ASP. Overall, biosimilars are considered brand drugs for purposes of the Medicaid Rebate calculation. The CMS recommends that states take steps to encourage use of biosimilars. It is unknown when and if Medicaid agencies will aggressively promote biosimilars. Biosimilars and reference biologics are not considered different for satisfying two-drug formulary requirements. Midyear addition of a biosimilar and removal of a reference biologic will be considered a non-maintenance change, which requires CMS approval on a case-by-case basis. Pharmacy and Therapeutics committees must review newly approved biosimilars according to existing formulary management requirements, which include making coverage decisions within 180 days, or 90 days for drugs in the protected classes. Part D plan sponsors must treat a biosimilar and its reference biologic as different drugs for the purposes of transition fills. Biosimilars do not meet the definition of a multiple-source drug; therefore, biosimilars are subject to higher low income subsidy (LIS) maximum copayments. Similar to generic drugs, biosimilars are excluded from the coverage gap discount program (CGDP) by the ACA, and are therefore considered non-applicable drugs; consequently, non-LIS beneficiaries will not receive the 50 percent discounts from manufacturers in the coverage gap. It is unknown whether or not plans must cover both a biosimilar and reference product in a protected drug class, or if a plan may substitute the biosimilar for

the reference product as is the case with generics. Marketing to prescribers will have to detail how biosimilars are interchangeable. Very specific analysis of the prescribing incentives, reimbursement, and other factors for each indication will be needed to determine the way to get both these products approved and prescribed. Already in certain settings, a biosimilar can be treated as both a generic and a brand name product. Conclusion

Commercialization of any biologic is done on a caseby-case basis but in the U.S. the available options may have already discouraged biosimilars. Sponsors weigh the risks and benefits of each pathway for each product to decide which path will present the greatest potential return on investment in each market. Without extrapolation between indications, the U.S. biosimilars pathway has questionable value. Return on investment will be impacted by interchangeability and the reimbursement environment. Gillian Woollett, MA, DPhil, is a Senior Vice President at Avalere Health.

References 1. Damle B, White R, Wang HF. Considerations for clinical pharmacology studies for biologics in emerging markets. J Clin Pharmacol. 2015;55 Suppl 3:S116-22. 2. World Health Organization. WHO Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). Available at http://www.who.int/biologicals/en/. 3. FDA. Drug and Biologic Approval Reports. Available at http://www.fda. gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/default.htm. 4. PhRMA. Biotechnology Research Promises to Bolster the Future of Medicine with More Than 900 Medicines and Vaccines in Development. Available at http://www.phrma.org/sites/default/files/pdf/biologics2013.pdf. 5. Lanthier M, Behrman R, Nardinelli C. Economic issues with follow-on protein products. Nature Reviews Drug Discovery 2008;7:733-737. 6. McCamish M., Pakulski J., Sattler C, Woollett G. Toward interchangeable biologics. Clin Pharmacol Ther. 2015;97: 215–17. 7. Biologics Price Competition and Innovation Act of 2009 (sections 7001 through 7003 of the Patient Protection and Affordable Care Act). 8. Committee for Medicinal Products for Human Use (CHMP). Guideline on Similar Biological Medicinal Products. 2005. Available at http://www.ema. europa.eu/docs/en_GB/document_library/Scientif ic_guideline/2009/09/ WC500003517.pdf. 9. Center for Medicare and Medicaid. MLN Matters Number SE1509. Available at

http://www.cms.gov/Outreach-and-Education/Medicare-Learning-Net-

work-MLN/MLNMattersArticles/Downloads/SE1509.pdf.

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 35

NOW FDA APPROVED The First FDA-approved Therapy for Use in Combination for Patients with Metastatic Pancreatic Cancer After Disease Progression Following Gemcitabine-based Therapy1,2

PROVEN TO EXTEND OVERALL SURVIVAL1 ONIVYDETM (irinotecan liposome injection)/5-FU/LV demonstrated a statistically significant increase in median OS vs 5-FU/LV alone: 6.1 months vs 4.2 months (log-rank p=0.014; HR=0.68 [95% CI: 0.50, 0.93])1

Probability of Survival

1.0

Median (95% CI) OS, months

0.9

ONIVYDE/5-FU/LV

6.1 (4.8, 8.5)

0.8

5-FU/LV

4.2 (3.3, 5.3)

â&#x20AC;˘ ONIVYDE/5-FU/LV achieved an increase in median progressionfree survival (PFS) vs 5-FU/LV: 3.1 months vs 1.5 months (HR=0.55 [95% CI: 0.41, 0.75])

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

ONIVYDE/5-FU/LV:

117

5-FU/LV:

119

# at risk:

6 9 12 Time from randomization (months)

*NAPOLI-1 was a global Phase 3, randomized, open-label, multicenter trial in patients (N=417) with metastatic adenocarcinoma of the pancreas whose disease has progressed following gemcitabine-based therapy. Patients were initially randomized to receive ONIVYDE (100 mg/m2 q3w) or 5-FU/LV. After 63 patients were enrolled, a third arm, ONIVYDE (70 mg/m2 q2w)/5-FU/LV, was added. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint, OS, was assessed with 2 pair-wise comparisons: ONIVYDE (n=151) vs 5-FU/LV (n=149) and ONIVYDE/5-FU/ LV (n=117) vs 5-FU/LV (n=119, post-protocol amendment). There was no improvement in OS for ONIVYDE vs 5-FU/LV (HR=1.00, p=0.97 [two-sided log-rank]).1,3

5-FU, fluorouracil; CI, confidence interval; HR, hazard ratio; LV, leucovorin; OS, overall survival.

INDICATION AND IMPORTANT SAFETY INFORMATION INDICATION ONIVYDE is indicated, in combination with fluorouracil (5-FU) and leucovorin (LV), for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas. WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil (5-FU) and leucovorin (LV). Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with 5-FU/LV. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity.

Please see additional Important Safety Information for ONIVYDE on the next page and Brief Summary of full Prescribing Information at the end of this advertisement.

INDICATION AND IMPORTANT SAFETY INFORMATION (CONT’D) CONTRAINDICATION ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl. WARNING AND PRECAUTIONS Severe Neutropenia ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In a clinical study, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving ONIVYDE, occurring in 1/117 patients in the ONIVYDE/5-FU/LV arm and 1/147 patients receiving ONIVYDE as a single agent. Severe or lifethreatening neutropenia occurred in 20% of patients receiving ONIVYDE/5-FU/LV vs 2% of patients receiving 5-FU/LV. Grade 3/4 neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving ONIVYDE/5-FU/LV, and did not occur in patients receiving 5-FU/LV. In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia was higher among Asian (18/33 [55%]) vs White patients (13/73 [18%]). Neutropenic fever/neutropenic sepsis was reported in 6% of Asian vs 1% of White patients. Severe Diarrhea ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to patients with bowel obstruction. Severe and life-threatening late-onset (onset >24 hours after chemotherapy) and early-onset diarrhea (onset ≤24 hours after chemotherapy, sometimes with other symptoms of cholinergic reaction) were observed. An individual patient may experience both early- and late-onset diarrhea. In a clinical study, Grade 3/4 diarrhea occurred in 13% of patients receiving ONIVYDE/5-FU/LV vs 4% receiving 5-FU/LV. Grade 3/4 lateonset diarrhea occurred in 9% of patients receiving ONIVYDE/5-FU/ LV vs 4% in patients receiving 5-FU/LV; the incidences of early-onset diarrhea were 3% and no Grade 3/4 incidences, respectively. Of patients receiving ONIVYDE/5-FU/LV, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea. Interstitial Lung Disease (ILD) Irinotecan HCl can cause severe and fatal ILD. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD. Severe Hypersensitivity Reactions Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction. Embryo-fetal Toxicity Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for 1 month after ONIVYDE treatment. ADVERSE REACTIONS • The most common (≥20%) adverse reactions in which patients receiving ONIVYDE/5-FU/LV experienced a ≥5% higher incidence of any Grade vs the 5-FU/LV arm, were diarrhea (any 59%, 26%; severe 13%, 4%) (early diarrhea [any 30%, 15%; severe 3%, 0%], late diarrhea [any 43%, 17%; severe 9%, 4%]), fatigue/asthenia (any 56%, 43%; severe 21%, 10%), vomiting (any 52%, 26%; severe 11%, 3%), nausea (any 51%, 34%; severe 8%, 4%), decreased appetite (any 44%, 32%; severe 4%, 2%), stomatitis (any 32%, 12%; severe 4%, 1%), pyrexia (any 23%, 11%; severe 2%, 1%).

• Of less common (<20%) adverse reactions, patients receiving ONIVYDE/5-FU/LV who experienced Grade 3/4 adverse reactions at a ≥2% higher incidence of Grade 3/4 toxicity vs the 5-FU/LV arm, respectively, were sepsis (3%, 1%), neutropenic fever/neutropenic sepsis (3%, 0%), gastroenteritis (3%, 0%), intravenous catheter-related infection (3%, 0%), weight loss (2%, 0%), and dehydration (4%, 2%). • The laboratory abnormalities in which patients receiving ONIVYDE/5-FU/LV experienced a ≥5% higher incidence vs the 5-FU/LV arm, were anemia (any 97%, 86%; severe 6%, 5%), lymphopenia (any 81%, 75%; severe 27%, 17%), neutropenia (any 52%, 6%; severe 20%, 2%), thrombocytopenia (any 41%, 33%; severe 2%, 0%), increased alanine aminotransferase (any 51%, 37%; severe 6%, 1%), hypoalbuminemia (any 43%, 30%; severe 2%, 0%), hypomagnesemia (any 35%, 21%; severe 0%, 0%), hypokalemia (any 32%, 19%; severe 2%, 2%), hypocalcemia (any 32%, 20%; severe 1%, 0%), hypophosphatemia (any 29%, 18%; severe 4%, 1%), hyponatremia (any 27%, 12%; severe 5%, 3%), increased creatinine (any 18%, 13%; severe 0%, 0%). • ONIVYDE can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early-onset diarrhea. Grade 1/2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients. • Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of ONIVYDE administration were reported in 3% of patients receiving ONIVYDE or ONIVYDE/5-FU/LV. • The most common serious adverse reactions (≥2%) of ONIVYDE were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia. DRUG INTERACTIONS Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme–inducing therapies ≥2 weeks prior to initiation of ONIVYDE. Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to starting therapy. USE IN SPECIFIC POPULATIONS Pregnancy and Reproductive Potential Advise pregnant women of the potential risk to a fetus. Advise males with female partners of reproductive potential to use effective contraception during and for 4 months after ONIVYDE treatment. Lactation Advise nursing women not to breastfeed during and for 1 month after ONIVYDE treatment. Pediatric Safety and effectiveness of ONIVYDE have not been established in pediatric patients. DOSAGE AND ADMINISTRATION The recommended dose of ONIVYDE is 70 mg/m2 intravenous (IV) infusion over 90 minutes every 2 weeks, administered prior to LV and 5-FU. The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by IV infusion over 90 minutes. There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. Premedicate with a corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE. Withhold ONIVYDE for Grade 3/4 adverse reactions. Resume ONIVYDE with reduced dose once adverse reaction recovered to ≤Grade 1. Discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction and in patients with a confirmed diagnosis of ILD. Do not substitute ONIVYDE for other drugs containing irinotecan HCl.

Please see Brief Summary of full Prescribing Information for ONIVYDE beginning on the next page. Reference: 1. ONIVYDE™ (irinotecan liposome injection) [package insert]. Cambridge, MA: Merrimack Pharmaceuticals, Inc.; October 2015. 2. Data on file. Merrimack Pharmaceuticals, Inc. 3. Wang-Gillam A, Li CP, Bodoky G, et al; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. Published online November 22, 2015. doi: 10.1016/S0140-6736(15)00986-1. [Epub ahead of print].

ONIVYDE is a trademark of Merrimack Pharmaceuticals, Inc.

ONIVYDE™ (irinotecan liposome injection) for intravenous use The following is a Brief Summary; refer to full Prescribing Information for complete product information. WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or lifethreatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil (5-FU) and leucovorin (LV). Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. (2.2, 5.1) Severe diarrhea occurred in 13% of patients receiving ONIVYDE/5-FU/LV. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2–4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity. (2.2, 5.2) 1. INDICATIONS AND USAGE ONIVYDE™ is indicated, in combination with 5-FU/LV, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas (see Clinical Studies, 14). 2. DOSAGE AND ADMINISTRATION 2.1 Important Use Information: DO NOT SUBSTITUTE ONIVYDE for other drugs containing irinotecan HCl. 2.2 Recommended Dose: Administer ONIVYDE prior to LV and 5-FU (see Clinical Studies, 14). • The recommended dose of ONIVYDE is 70 mg/m2 administered by intravenous (IV) infusion over 90 minutes every 2 weeks. • The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by IV infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m2 as tolerated in subsequent cycles. • There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal (see Adverse Reactions, 6.1; Clinical Studies, 14). 2.2 Recommended Dose, Premedication: Administer a corticosteroid and an antiemetic 30 minutes prior to ONIVYDE infusion. 2.3 Dose Modifications for Adverse Reactions: Table 1: Recommended Dose Modifications for ONIVYDE Toxicity Occurrence ONIVYDE adjustment Patients homozygous for in patients receiving UGT1A1*28 without previous NCI CTCAE v4.0† 70 mg/m2 increase to 70 mg/m2 Withhold ONIVYDE. Initiate loperamide for late onset diarrhea of any severity. Administer IV or subcutaneous atropine 0.25–1 mg (unless clinically contraindicated) for early-onset diarrhea of any severity. Grade 3 or 4 adverse Upon recovery to ≤Grade 1, resume ONIVYDE at: reactions First 50 mg/m2 43 mg/m2 Second 43 mg/m2 35 mg/m2 Third Discontinue ONIVYDE Discontinue ONIVYDE Interstitial Lung First Discontinue ONIVYDE Discontinue ONIVYDE Disease (ILD) Anaphylactic First Discontinue ONIVYDE Discontinue ONIVYDE Reaction †NCI CTCAE v 4.0=National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0. For recommended dose modifications of 5-FU or LV, refer to the full Prescribing Information (see Clinical Studies, 14).

4 CONTRAINDICATIONS ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl. 5 WARNINGS AND PRECAUTIONS 5.1 Severe Neutropenia: ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In Study 1, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving ONIVYDE, occurring in 1/117 patients in the ONIVYDE/5-FU/LV arm and 1/147 patients receiving single-agent ONIVYDE. Severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE/5-FU/LV compared to 2% of patients receiving 5-FU/LV. Grade 3/4 neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving ONIVYDE/5-FU/LV, and did not occur in patients receiving 5-FU/LV. In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia was higher among Asian patients (18/33 [55%]) vs White patients (13/73 [18%]).

Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients vs 1% of White patients (see Clinical Pharmacology, 12.3). Monitor complete blood cell counts on Days 1 and 8 of every cycle and more frequently if clinically indicated. Withhold ONIVYDE if the absolute neutrophil count (ANC) is below 1500/mm3 or if neutropenic fever occurs. Resume ONIVYDE when the ANC is 1500/mm3 or above. Reduce ONIVYDE dose for Grade 3–4 neutropenia or neutropenic fever following recovery in subsequent cycles (see Dosage and Administration, 2.2). 5.2 Severe Diarrhea: ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to patients with bowel obstruction. Severe or life-threatening diarrhea followed one of two patterns: late-onset diarrhea (onset ˃24 hours following chemotherapy) and early-onset diarrhea (onset ≤24 hours of chemotherapy, sometimes occurring with other symptoms of cholinergic reaction) (see Cholinergic Reactions, 6.1). An individual patient may experience both early- and late-onset diarrhea. In Study 1, Grade 3/4 diarrhea occurred in 13% receiving ONIVYDE/5-FU/LV vs 4% receiving 5-FU/LV. The incidence of Grade 3/4 late-onset diarrhea was 9% in patients receiving ONIVYDE/5-FU/LV vs 4% in patients receiving 5-FU/LV. The incidence of Grade 3/4 early-onset diarrhea was 3% in patients receiving ONIVYDE/5-FU/LV vs none in patients receiving 5-FU/LV. Of patients receiving ONIVYDE/5-FU/LV in Study 1, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea. Withhold ONIVYDE for Grade 2–4 diarrhea. Initiate loperamide for late-onset diarrhea of any severity. Administer IV or subcutaneous atropine 0.25–1 mg (unless clinically contraindicated) for earlyonset diarrhea of any severity. Following recovery to Grade 1 diarrhea, resume ONIVYDE at a reduced dose (see Dosage and Administration, 2.2). 5.3 Interstitial Lung Disease (ILD): Irinotecan HCl can cause severe and fatal ILD. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD. 5.4 Severe Hypersensitivity Reaction: Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction. 5.5 Embryo-Fetal Toxicity: Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman. Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan exposures lower than those achieved with ONIVYDE 70 mg/m2 in humans, administered to pregnant rats and rabbits during organogenesis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONIVYDE and for1 month following the final dose (see Use in Specific Populations, 8.1, 8.3; Clinical Pharmacology, 12.1). 6 ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: • Severe Neutropenia (see Warnings and Precautions, 5.1; Boxed Warning) • Severe Diarrhea (see Warnings and Precautions, 5.2; Boxed Warning) • Interstitial Lung Disease (see Warnings and Precautions, 5.3) • Severe Hypersensitivity Reactions (see Warnings and Precautions, 5.4) 6.1 Clinical Trials Experience The safety data described below are derived from patients with metastatic adenocarcinoma of the pancreas previously treated with gemcitabine-based therapy who received any part of protocol-specified therapy in Study 1, an international, randomized, active-controlled, open-label trial. Protocol-specified therapy consisted of ONIVYDE 70 mg/m2 with LV 400 mg/m2 and 5-FU 2400 mg/m2 over 46 hours every 2 weeks (ONIVYDE/5-FU/LV; n=117), ONIVYDE 100 mg/m2 every 3 weeks (n=147), or LV 200 mg/m2 and 5-FU 2000 mg/m2 over 24 hours weekly for 4 weeks followed by 2 week rest (5-FU/LV; n=134) (see Clinical Studies, 14). Serum bilirubin within the institutional normal range, albumin ≥3 g/dL, and Karnofsky Performance Status (KPS) ≥70 were required for study entry. The most common adverse reactions (≥20%) of ONIVYDE were diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common, severe laboratory abnormalities (≥10%, Grade 3/4) were lymphopenia and neutropenia. The most common serious adverse reactions (≥2%) of ONIVYDE were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia. Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions resulting in discontinuation of ONIVYDE were diarrhea, vomiting, and sepsis. Dose reductions of ONIVYDE for adverse reactions occurred in 33% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia. ONIVYDE was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia.

Table 2: Adverse Reactions with Higher Incidence (≥5% Difference for Grades 1–4* or ≥2% Difference for Grades 3–4) in the ONIVYDE/5-FU/LV Arm ONIVYDE/5-FU/LV 5-FU/LV n=117 n=134 Adverse Reaction Grades Grades Grades Grades 1–4 (%) 3–4 (%) 1–4 (%) 3–4 (%) Gastrointestinal disorders Diarrhea Early diarrhea† Late diarrhea‡ Vomiting Nausea Stomatitis§

59 30 43 52 51 32

13 3 9 11 8 4

26 15 17 26 34 12

4 0 4 3 4 1

Infections and infestations

4 3 Neutropenic fever/neutropenic sepsis♠ Gastroenteritis 3 Intravenous catheter-related infection 3 General disorders and administration site conditions

3 3 3 3

2 1 0 0

1 0 0 0

Fatigue/asthenia Pyrexia Metabolism and nutrition disorders

56 23

21 2

43 11

10 1

Decreased appetite Weight loss Dehydration Skin and subcutaneous tissue disorders Alopecia

44 17 8

4 2 4

32 7 7

2 0 2

Sepsis

*NCI CTCAE v4.0. †Early diarrhea: onset ≤24 hours of ONIVYDE administration. ‡Late diarrhea: onset >1 day after ONIVYDE administration. §Includes stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation. ♠Includes febrile neutropenia.

Cholinergic Reactions: ONIVYDE can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early-onset diarrhea. In Study 1, Grade 1/2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients. Six of these 12 patients received atropine and in 1 of the 6 patients, atropine was administered for cholinergic symptoms other than diarrhea. Infusion Reactions: Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of ONIVYDE administration, were reported in 3% of patients receiving ONIVYDE or ONIVYDE/5-FU/LV. The following laboratory abnormalities were reported (NCI CTCAE v4.0, worst grade shown) with higher incidence (≥5% difference Grades 1–4 [any] or ≥5% difference Grades 3–4 [severe] according to NCI CTCAE v4.0) for patients receiving ONIVYDE/5-FU/LV (n=117) vs 5-FU/LV (n=134). Percentages were based on the number of patients with a baseline and at least 1 post-baseline measurement. Hematology: anemia (any 97%, 86%; severe 6%, 5%), lymphopenia (any 81%, 75%; severe 27%, 17%), neutropenia (any 52%, 6%; severe 20%, 2%), thrombocytopenia (any 41%, 33%; severe 2%, 0%). Hepatic: increased alanine aminotransferase (any 51%, 37%; severe 6%, 1%), hypoalbuminemia (any 43%, 30%; severe 2%, 0%). Metabolic: hypomagnesemia (any 35%, 21%; severe 0%, 0%), hypokalemia (any 32%, 19%; severe 2%, 2%), hypocalcemia (any 32%, 20%; severe 1%, 0%), hypophosphatemia (any 29%, 18%; severe 4%, 1%), hyponatremia (any 27%, 12%; severe 5%, 3%). Renal: increased creatinine (any 18%, 13%; severe 0%, 0%). 7 DRUG INTERACTIONS 7.1 Strong CYP3A4 Inducers: Following administration of non-liposomal irinotecan (ie, irinotecan HCl), exposure to irinotecan or its active metabolite, SN-38, is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin and strong CYP3A4 inducers. Avoid the use of strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, St. John's wort) if possible. Substitute nonenzyme inducing therapies ≥2 weeks prior to initiation of ONIVYDE therapy (see Clinical Pharmacology, 12.3). 7.2 Strong CYP3A4 or UGT1A1 Inhibitors: Following administration of nonliposomal irinotecan (ie, irinotecan HCl), patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Co-administration of ONIVYDE with other inhibitors of CYP3A4 (eg, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (eg, atazanavir, gemfibrozil, indinavir) may increase systemic exposure to

irinotecan or SN-38. Avoid the use of strong CYP3A4 or UGT1A1 inhibitors if possible. Discontinue strong CYP3A4 inhibitors ≥1 week prior to starting ONIVYDE therapy (see Clinical Pharmacology, 12.3). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy, Risk Summary: Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman (see Clinical Pharmacology, 12.1). There are no available data in pregnant women. Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan exposures lower than those achieved with ONIVYDE 70 mg/m2 in humans, administered to pregnant rats and rabbits during organogenesis (see Data in the full Prescribing Information). Advise pregnant women of the potential risk to a fetus. 8.2 Lactation, Risk Summary: There is no information regarding the presence of irinotecan liposome, irinotecan, or SN-38 (an active metabolite of irinotecan) in human milk, or the effects on the breastfed infant or on milk production. Irinotecan is present in rat milk (see Data in the full Prescribing Information). Because of the potential for serious adverse reactions in breastfed infants from ONIVYDE, advise a nursing woman not to breastfeed during treatment with ONIVYDE and for 1 month after the final dose. 8.3 Females and Males of Reproductive Potential, Contraception, Females: ONIVYDE can cause fetal harm when administered to a pregnant woman (see Use in Specific Populations, 8.1). Advise females of reproductive potential to use effective contraception during treatment with ONIVYDE and for 1 month after the final dose. Males: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with ONIVYDE and for 4 months after the final dose (see Nonclinical Toxicology, 13.1). 8.4 Pediatric Use: Safety and effectiveness of ONIVYDE have not been established in pediatric patients. 8.5 Geriatric Use: Of the 264 patients who received single-agent ONIVYDE or ONIVYDE/5-FU/LV in Study 1, 49% were ≥65 years old and 13% were ≥75 years old. No overall differences in safety and effectiveness were observed between these patients and younger patients. 10 OVERDOSAGE There are no treatment interventions known to be effective for management of overdosage of ONIVYDE. 17 PATIENT COUNSELING INFORMATION Severe Neutropenia: Advise patients of the risk of neutropenia leading to severe and life-threatening infections and the need for monitoring of blood counts. Instruct patients to contact their healthcare provider immediately if experiencing signs of infection, such as fever, chills, dizziness, or shortness of breath (see Warnings and Precautions, 5.1). Severe Diarrhea: Inform patients of the risk of severe diarrhea. Advise patients to contact their healthcare provider if they experience persistent vomiting or diarrhea; black or bloody stools; or symptoms of dehydration such as lightheadedness, dizziness, or faintness (see Warnings and Precautions, 5.2). Interstitial Lung Disease (ILD): Inform patients of the potential risk of ILD. Advise patients to contact their healthcare provider as soon as possible for new onset cough or dyspnea (see Interstitial Lung Disease, 5.3). Hypersensitivity to Irinotecan HCl or ONIVYDE: Advise patients of the potential risk of severe hypersensitivity and that ONIVYDE is contraindicated in patients with a history of severe allergic reactions with irinotecan HCl or ONIVYDE. Instruct patients to seek immediate medical attention for signs of severe hypersensitivity reaction such as chest tightness; shortness of breath; wheezing; dizziness or faintness; or swelling of the face, eyelids, or lips (see Contraindications, 4; Warnings and Precautions, 5.4). Females and Males of Reproductive Potential, Embryo-Fetal Toxicity: Inform females of reproductive potential of the potential risk to a fetus, to use effective contraception during treatment and for 1 month after the final dose, and to inform their healthcare provider of a known or suspected pregnancy (see Warnings and Precautions, 5.5; Use in Specific Populations, 8.1, 8.3). Contraception: Advise male patients with female partners of reproductive potential to use condoms during treatment with ONIVYDE and for 4 months after the final dose (see Females and Males of Reproductive Potential, 8.3). Lactation: Advise women not to breastfeed during treatment with ONIVYDE and for 1 month after the final dose (see Use in Special Populations, 8.2). To report SUSPECTED ADVERSE REACTIONS, contact Merrimack Pharmaceuticals, Inc. at 1-844-441-6225 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Manufactured for: Merrimack Pharmaceuticals, Inc. Cambridge, MA 02139 ONIVYDE is a trademark of Merrimack Pharmaceuticals, Inc. ©2015 Merrimack Pharmaceuticals, Inc. 11/15

PP-ONV-US-0073

Advancing Clinical Care and Improving Outcomes in Psoriatic Arthritis: Payer Perspective Gary M. Owens, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Psoriatic arthritis causes significant pain and functional impairment. For patients with moderate to severe disease, reducing symptoms and preventing joint damage requires disease-modifying antirheumatic drugs (DMARDs). Because of the expense of biologic agents, most managed care plans use different strategies to manage the cost of these agents. Key Points • Psoriasis and pstoriatic arthritis are chronic, immune inflammatory diseases which cause significant morbidity and health care costs. • Biologic DMARDs, nonbiologic DMARDs, and oral small molecules are used to manage psoriatic arthritis. • These agents have significant acquisition costs. • Managed care payers are instituting many different strategies to manage the growing cost of managing psoriatic arthritis.

PSORIASIS IS A CHRONIC, IMMUNE-MEDIated inflammatory disease that affects about 2 percent of the population.1 It can manifest at any age, but there are two general peak age groups – 20 to 30 and 50 to 60 years. Plaque psoriasis occurs in 85 to 90 percent of all cases and is driven by extensive inflammation and altered keratinocyte differentiation. More than one-third of patients with psoriasis have moderate to severe disease. Moderate to severe psoriasis is associated with significant morbidity. These patients often require therapies beyond topical treatments. Those with moderate to severe disease are significantly more likely to have comorbidities, including psoriatic arthritis, cardiovascular disease, depression, diabetes, hypertension, and obesity compared with those with mild psoriasis. Those with moderate to severe psoriasis also consume more health care resources than those with mild disease. One comorbidity of psoriasis is psoriatic arthritis. It is most commonly a seronegative oligoarthritis,

which affects the spine, joints and entheses (areas where tendons, ligaments and joint capsule attach to bone).1 Psoriatic arthritis develops in 5 to 10 percent of patients with psoriasis. Psoriatic arthritis not only causes functional impairment, but also increases mortality risk of patients. Psoriasis appears to precede the onset of psoriatic arthritis in 60 to 80 percent of patients; however, in the rest, arthritis appears before the psoriasis. Occasionally, arthritis and psoriasis appear simultaneously. Signs and symptoms of psoriatic arthritis include enthesopathy or enthesitis (inflammation at tendon or ligament insertions), dactylitis (thickening of fingers), and skin lesions. The Achilles tendon and the plantar fascia to the calcaneus are common sites of enthesopathy. Dactylitis is seen in as many as 35 percent of patients. The most characteristic radiological finding indicative of psoriatic arthritis is bone destruction and proliferation with an asymmetrical distribution. Distal interphalangeal joints are typically involved.

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Exhibit 1: EULAR Treatment Recommendation3

• NSAIDs for musculoskeletal signs and symptoms • Disease-modifying agents (methotrexate, sulfasalazine, and leflunomide) at an early stage for patients with active disease ◦ Agents that are also effective against psoriasis are preferred if concomitant psoriasis • TNF-inhibitor therapy is considered when: ◦ Failure of 1 or more synthetic, disease-modifying antirheumatic medications ◦ Active enthesitis and/or dactylitis without sufficient response to NSAIDs or local steroid injections ◦ Active, predominantly axial disease that does not respond sufficiently to NSAIDs ◦ Very severe disease

Periostitis and interspinous or anterior ligament calcification are also commonly seen, but bone density is usually preserved. Genetic factors play an important role in susceptibility to psoriasis and psoriatic arthritis. Several psoriatic arthritis susceptibility loci have been identified, including HLA-B7, HLA-B27, HLA-DR4, HLA-38, and HLA-DR7. Several other genetic loci have also been shown to be disease progression predictors. These include HLA-B39, HLA-B27 in the presence of HLA-DR7, and HLA-DQ3 in the absence of HLA-DR7. Certain gene polymorphisms are also associated with psoriasis and psoriatic arthritis. Tumor necrosis factor (TNF)-alpha promoter, caspase-activating recruitment domain, and the interleukin (IL)-12/ IL-23p40 and IL-23 receptor are some of the ones identified. All of these play a role in immune system activity and are targets for pharmacotherapy. Fibroblasts from the skin and synovia of patients with psoriatic arthritis have an increased proliferative activity and the capability to secrete increased amounts of interleukin one (IL-1), IL-6, and platelet-derived growth factors. Several studies suggest that cytokines secreted from activated T cells and other mononuclear proinflammatory cells induce proliferation and activation of synovial and epidermal fibroblasts. Overall, psoriatic arthritis is a T cell-mediated inflammatory autoimmune disease. The immune issues in psoriatic arthritis has some similarities to rheumatoid arthritis but also differences. Both have synovial-lining cell hyperplasia and mononuclear infiltration. Synovial-lining hyperplasia is less, macrophages are fewer, and vascularity is greater in psoriatic arthritis than in rheumatoid.

Most medications approved for psoriatic arthritis are also approved for rheumatoid arthritis. There are several challenges in managing those with this disease. Patients present with a broad spectrum of symptoms and severity. Some have very minor disease and others experience significant joint deformity and functional impairment. Associated psoriasis is common and must be addressed. Lastly, a variety of treatment options are available and must be tailored to meet the needs of the patients. The goals of therapy are to gain initial rapid control of the disease, maintain the patient in long-term remission, avoid relapse, avoid adverse effects as much as possible, and improve the patient’s quality of life.2 The European League Against Rheumatism (EULAR) has published management guidelines for psoriatic arthritis (Exhibit 1).3 Nonsteroidal antiinflammatory drugs (NSAIDs) are recommended for the relief of musculoskeletal signs and symptoms, but not many patients are maintained long term on these agents because of the adverse effects. Treatment with nonbiologic disease-modifying antirheumatic drugs (DMARDs, methotrexate, sulfasalazine, and leflunomide) can be considered at an early stage for patients with active disease. DMARDs may relieve more severe symptoms and attempt to slow or stop joint/tissue damage and the progression of psoriatic arthritis. If a patient with active psoriatic arthritis also has clinically relevant psoriasis, preference should be given to treatment with methotrexate or other disease-modifying drugs that are also effective against psoriasis. If active psoriatic arthritis fails to adequately respond to one or more nonbiologic DMARDs, biologic therapy with tumor ne-

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Exhibit 2: Anti-TNF Therapy Safety Considerations • Do not start or continue anti-TNF therapy in patients with serious active infection; use caution in those at high risk of infection • Screen all patients for infection with mycobacteria, human immunodeficiency virus (HIV), hepatitis B (HBV), and hepatitis C (HCV) before starting anti-TNF therapy • Consider prophylactic vaccination for tuberculosis and HBV in high-risk patients before initiating anti-TNF therapy • In patients with HIV, HBV, or HCV, initiate anti-TNF therapy only in those with well-controlled disease and appropriate monitoring; appropriate antiviral therapy for patients with HBV is also important • Avoid anti-TNF treatment in patients with a current or previous history of malignancy, unless there is a high likelihood of cure or the malignancy was diagnosed and treated more than 10 years ago • Regularly screen for skin cancers in patients who are receiving anti-TNF therapy and who have a history of current or previous malignancy • Discontinue anti-TNF therapy prior to pregnancy; restart anti-TNF treatment following the end of lactation or delivery if the mother is not breastfeeding

crosis factor (TNF)-inhibitors should be employed. TNF-inhibitor therapy should also be considered if a patient with active enthesitis and/or dactylitis does not show sufficient response to NSAIDs or local steroid injections. Additionally, TNF-inhibitor therapy should be considered if a patient has active, predominantly axial disease that does not respond sufficiently to NSAIDs. Initial use of a TNF-inhibitor therapy may be considered if a very active patient is disease-modifying ̶ treatment naïve. If a TNF-inhibitor produces an inadequate response, consideration should be given to replacing it with another TNF-inhibitor or another biologic with a different mechanism of action. Anti-TNF agents approved for psoriatic arthritis treatment include etanercept (Enbrel®), adalimumab (Humira®), infliximab (Remicade®), certolizumab (Cimzia®), and golimumab (Simponi®). TNF-inhibitor biologics may slow or stop joint damage and the progression of psoriatic arthritis. There are several important safety considerations with anti-TNF therapy which are outlined in Exhibit 2. If adjustments are made in a patient’s therapy, then comorbidities, safety concerns, and other considerations beyond the psoriatic arthritis itself should be factored into the change. Beyond anti-TNF therapy, ustekinumab (Stelera®), an interleukin-12/23 inhibitor, is approved for the treatment of active psoriatic arthritis in adults who have not responded adequately to previous treatment with nonbiologic DMARDs. Apremilast (Otezla®) is an oral nonbiologic small molecule op-

tion which was approved in 2014 for treatment of active psoriatic arthritis. It is a phosphodiesterase-4 (PDE4) inhibitor that is specific for cAMP, resulting in increased intracellular cAMP levels. Both of these agents are effective in managing psoriatic arthritis. Secukinumab (Cosentyx ®) targets IL-17A and is the most recently approved agent for treating moderate to severe plaque psoriasis in adult patients. It has not yet been FDA approved specifically for psoriatic arthritis but is under study for this indication. Tofacitinib, an oral Janus kinase ( JAK) inhibitor currently approved for rheumatoid arthritis, is being studied for psoriasis and psoriatic arthritis. There are also numerous other agents with many different mechanisms of action under investigation. Management of psoriatic arthritis and other inflammatory conditions present several payer challenges. Specialty pharmacy spend for biologics continues to increase. It used to be around 5 percent of total pharmacy spend and is now around 35 percent. Treatment of inflammatory conditions, including psoriatic arthritis, is the largest category of specialty medication spending. According to ESI, inflammatory conditions were the most expensive specialty therapy indication for the fifth year in a row.4 The TNF-inhibitors make up the majority of use but use of the other classes are growing. The per-memberper-year (PMPY) spend for this category was $63.31 in 2013, up 21.8 percent from 2012. There are also new indications for many of the biologics which are already approved and more biologics are being approved every year.

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Overall, managed care still needs to make sure the right therapy for the right patient is available while being fiscally responsible. Management strategies include step therapy through nonbiologic DMARDs before biologicals, prior authorization of biological agents, preferred biological agents, limited prescribing of biologicals to appropriate specialists, and managing site of service. Most payers are going to prior authorized biologic agents to ensure the patient has been tried on or has contraindications to nonbiologic DMARDs. Additionally, most payers now have a preferred TNF-inhibitor based on contracting. Managing site of service has become more prominent recently. There are infused agents such as infliximab which have to be given in an infusion center or doctorâ&#x20AC;&#x2122;s office and injectable or oral agents for patient self-administration. Many payers are managing away from infusion agents because of the additional costs related to site of service. Other payer strategies in 2015 and beyond are newer benefit designs with multiple tiers of specialty benefit, consideration of the emerging biosimilar marketplace, specialty specific formularies, and alignment of physician incentives. Newer benefit designs include having four or more tiers of prescription copays rather than fewer. Specialty product tiers with biosimilar/high value products having lower out-of-pocket costs are likely to grow as more biosimilar products get FDA approved. Some payers even have a non-covered tier beyond the preferred branded and non-preferred branded tiers. Payers are still struggling with what is going to happen in the biosimilar arena. One biosimilar has been approved and more are likely to come in next year. In Norway,

the introduction of a biosimilar infliximab resulted in a price war and a 60 to 70 percent reduction in cost. The impact of biosimilars on the U.S. market place is unknown, but payers are looking at this in their long-term strategies. Payers are also looking at physician payment arrangements that may shift the financial decisions for biologics and other pharmacotherapy from the health plan to the physicians. Conclusion

Several biologics are available for treating psoriatic arthritis. Because of the cost of these agents, managed care plans are developing specialty tiers with preferred biologics that have lower out-of-pocket costs to drive use. Managed care has implemented many different strategies to manage the costs of psoriatic arthritis and other inflammatory conditions, and these strategies continue to evolve with the evolving biologic marketplace. Gary M. Owens, MD, is President of Gary Owens and Associates.

References 1. Liu JT, Yeh HM, Liu SY, Chen KT. Psoriatic arthritis: Epidemiology, diagnosis, and treatment. World J Orthop. 2014;5(4):537-43. 2. National Psoriasis Foundation. Psoriatic Arthritis. Available at https://www. psoriasis.org/psoriatic-arthritis. 3. Gossec L, Smolen JS, Gaujoux-Viala C, et al. European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. Ann Rheum Dis. 2012;71(1):4-12. 4. ESI Drug Trend Report 2013. Available at http://lab.express-scripts.com/ drug-trend-report/therapy-class-review/therapy-class-review-specialty-medications/specialty-spend-rank-1-inflammatory-conditions.

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Updates in the Treatment and Management of Hemophilia: A Closer Look at Current and Emerging Strategies Julie Jaffray, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary The complications of hemophilia cause significant joint destruction and disability. Factor replacement is used episodically to treat bleeding episodes and prophylactically to prevent bleeding and reduce joint damage. New extended-release factors are available that reduce the dosing interval. Additional products are under study, which should continue to improve treatment of this disorder. Key Points • Hemophilia is a serious bleeding disorder that without treatment will lead to permanent, debilitating joint damage in severe patients. • Prophylactic treatment is time consuming and costly but reduces bleeding episodes and joint damage. • Those with severe disease and some with moderate will require prophylactic treatment. • Several factor replacement innovations are under study.

HEMOPHILIA IS THE TERM USED TO DEscribe deficiencies of factors VIII and IX (coagulation proteins). It is also known as hemophilia A and B, respectively. Deficiencies of factors VIII and IX are inherited in an X-linked recessive pattern, and the majority of affected patients are male. Some women who are carriers of the hemophilia gene where the abnormal X gene predominates over the normal gene can be symptomatic and require treatment. Patients can have mild, moderate, or severe disease based on levels of factor deficiencies. Exhibit 1 compares the clinical and laboratory manifestations of mild, moderate, and severe disease. Based on severity, patients will present at different ages. Those with severe disease will typically present as infants, whereas those with mild or moderate disease may not be diagnosed until they have surgery or experience significant trauma. The major complications of hemophilia are bleeding and joint arthropathy. Exhibit 2 shows the typical bleeding locations by age. Joint arthropathy is painful destruction of joints related to bleeding

inside the large joints. It is a major cause of disability in these patients and a reason to give factor replacement. Hemophilia treatment can be episodic (on-demand when bleeding occurs) or preventative (prophylaxis). Medications include factor replacement, desmopressin (DDAVP), and antifibrinolytic therapy. Factor replacement is providing the missing clotting factor. DDAVP, given by IV or intranasally, is used for mild factor VIII deficiency to increase release of von Willebrand factor and naturally produced factor VIII. It is used before dental procedures. Antifibrinolytic therapy can be used for stabilizing clots and is used after dental procedures. On-demand treatment is appropriate for mild and most moderate hemophilia patients. Treatment with factor replacement is given when bleeding episodes occur. This approach to treatment does not prevent bleeds or joint disease, but the incidence of joint damage is lower in the mild and moderate patients than those with severe disease. Prophylaxis with regular administration of factor

44 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 1: Clinical and Laboratory Manifestations

Severe

Moderate

Mild

Factor level

< 1%

1 - 5%

5 - 40%

Age at presentation

Birth - 3 years*

2 - 10 years*

5 - > 21 years*

Presentation

• Family history (pre- or postnatal screening)

• Neonatal bleeding (circumcision, heel sticks)

• Neonatal bleeding (less likely than severe)

• Bruising (< 1 year)

• Vaccine-related bleed

• Vaccine related bleed

• Mucosal bleed

• Joint bleed

• Post traumatic bleed • Post surgical bleed

• Joint bleed Risk for inhibitor development Risk for hemophilic arthropathy

~25% in FVIII ~5% in FIX Universal without prophylaxis

~1 - 2% Very common without prophylaxis

Very rare

Rare

*Age at presentation is highly variable

prevents bleeding and hemophilic arthropathy. Primary prophylaxis is initiation of factor prior to any joint bleeding (or after 1 to 2 joint bleeds before any obvious joint disease). Secondary prophylaxis is initiation of factor replacement after the onset of joint disease in order to prevent further bleeding. Ideally, clinicians prefer to start replacement before any joint damage occurs. Prophylaxis is generally used in severe hemophilia to prevent hemophilic arthropathy and to reduce the rate of bleeding. In the United States (U.S.), severe hemophilia patients should start prophylaxis no later than after their second joint bleed, but it can be started prior to any joint bleeds. Moderate hemophilia patients who bleed frequently should also be on prophylaxis. In a trial comparing prophylaxis to episodic factor replacement in 65 boys less than 30 months of age with severe FVIII deficiency, prophylaxis significantly reduced the rate of arthropathy. At 6 years of age, 93 percent in the prophylaxis group had normal joints on MRI compared with 55 percent in the episodic group.1 A significant portion (~25%) of those with severe factor VIII deficiencies develop antibodies to factor replacement (inhibitors) and thus factor replacement is no longer effective. Inhibitor development only occurs in about 5 percent of those with factor VIX deficiency. Once the factor VIX patient develops an

inhibitor they can never receive this factor again because they will have an anaphylactic reaction. Risk of developing inhibitors is significantly less with moderate and mild disease. There are drawbacks to factor replacement – all the products are given intravenously, most recipients will require central line placement for the infusions, parents have to cause pain to their young child, and the infusions have to be given multiple times weekly. The first few years of factor replacement in young children are very hard for the families. As children age, they should begin to take on the responsibility of doing their own infusions, which does not always work so well. The parents and the boys have to be taught how to start an IV. The infusions should be given early in morning so the child is protected during the day, but this can cause issues with family schedules. Factor replacement can be done with plasmaderived, recombinant, or extended half-life factor. Plasma-derived factor is high-purity and virally inactivated. In the 1980s, HIV was a huge issue and infected 80 percent of the patients who were given factor before a process to eliminate it from the products was developed. Both plasma-derived (pd) FVIII and pdFIX products are available. Currently, pdFVIII products are mostly used for patients with von Willebrand disease and patients with inhibitors.

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 45

Exhibit 2: Typical Bleeding Locations by Age

Age

Site

Frequency

Neonatal

Post-circumcision Heel sticks Intracranial

Common in severe (less so in other types) Common in severe (less so in other types) Uncommon (~1-5% in severe)

4 weeks - 1 year

Bruising Post-vaccination Joint (elbow, knee, ankle) Intracranial

All severe, most moderate, less in mild Occasional in severe (less so in other types) Infrequent in severe, rare in other types Rare (1% or less)

Joint (elbow, knee, ankle) Muscle

Nearly all severe patients will have a joint/muscle bleed, very common in moderate and rare in mild

Mucosal

Universal in all types with trauma

5 - 13 years

Joint (elbow, knee, ankle) Muscle Post-trauma

All severe and most moderates will have joint/muscle bleeds All types will have post-traumatic bleeding

13 - 21 years

Joint (elbow, knee, ankle) Muscle Post-trauma

All severe and most moderates will have joint/muscle bleeds All types will have post-traumatic bleeding

1 year - 5 years

Some clinicians think the plasma-derived factors have a better chance of eliminating inhibitors. pdFIX is rarely used in the U.S. Recombinant factor is free of human or animal sourced proteins and also virally inactivated. Recombinant factor (r) FVIII and rFIX products are available. These are the most commonly used factors currently in the U.S. rFVIII has a half-life of around eight to 12 hours and prophylaxis is given three times a week. Some patients require an every other day schedule to maintain adequate trough factor levels. rFIX has a half-life of about 18 hours and is given twice a week. The goal with factor replacement is to have a factor trough level of 1 to 2 percent. This is essentially turning a severe hemophilia patient into a moderate one and is sufficient to prevent spontaneous bleeding. Extended-release factors are the most recent innovation in hemophilia management. These factors are fusion products that have long half-lives. The Fc domain of human IgG is fused to the rFVIII or rFIX molecule. Fc-fused proteins are protected from lysosomal degradation through intracellular IgG recycling. Extended half-life factor products are available for both factor VIII and IX (rFVIIIFc and rFIXFc). Exhibit 3 compares the pharmacokinetic profile of recombinant factor administration multiple times

per week with extended-release factor. With recombinant factor administration, there are high peaks of factor with rapid drop off between doses. With extended-release factor, there is one peak during the week and a prolonged tail of the curve.2 Whether the long duration at low factors levels is best for an active child or young adult is unknown. The extended-release factors may be better for older patients who are more sedentary. In a trial of the extended-release factor versus recombinant factor in adults, no serious bleeding events occurred and no subjects developed an inhibitor.3 Factor half-life in this study was 18.8 hours for rFVIIIFc versus 11-12.2 hrs. for rFVIII. Another trial found the time to 1 percent factor levels was 4.9 days with rFVIIIFc compared with 3.3 days with rFVIII.4 This trial also found that when used episodically, one infusion of the extended-release factor resolved 87.3 percent of bleeding episodes. Ninety-eight percent of episodes were controlled with two or fewer infusions. Recommended prophylactic dosing for extendedrelease factor rFVIIIFc is 50 IU/kg every four days for adults and 25 IU/kg alternating 50 IU/kg twice weekly for children. rFIXFc has an even longer half- life and prophylactic dosing is 50 IU/kg once weekly or 100 IU/kg every 10 or 14 days. Trough factor levels can be done to determine individual-

46 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 3: Example of FVIII Activity with Recombinanty Factor Prophylaxis Dosing Versus Extended Half Life Dosing

FVIII

FVIII 1% Mon

Weds

Fri

ized dosing intervals for each type of factor. An rFVIII-SingleChain is under study. This is an rFVIII with increased stability through covalent bond linking light and heavy chains with an increased affinity to the von Willebrand factor. The half-life of rFVIII is very dependent on the half-life of the von Willebrand factor. Only animal study results have been published. Pegylated rFVIII is also under investigation. Pegylation enhances half-life by increasing molecular size and decreasing renal clearance. This formulation should also be less susceptible to proteolytic cleavage and degradation. Animal and human data have been presented or published. A third product in development is recombinant albumin fused to the c-terminus of rFIX (rIX-FP). It is proposed that there will be decreased immune response with this product since albumin is a natural protein. This product has a half-life of over 90 hours. As more and more factor products reach the market, choosing the right product is becoming more difficult. Adequate dosing is also an issue. Studies are looking at the benefits of achieving a higher trough goal above 1 percent to further minimize bleeding episodes. Quality of life in this disease is important. Decreased needle sticks, fewer infusions, and the elimination of need for a central line would improve both patient and parent quality of life. Cost is also an

Sat

Sun

issue with factor replacement. Currently, the overall price of recombinant (rFIX twice a week) and the extended-release products (rFIXfc once a week) are similar but substantial. Conclusion

Hemophilia is a serious bleeding disorder that without treatment will lead to permanent, debilitating joint damage in severe patients. Prophylactic treatment is time consuming and costly but reduces bleeding episodes and joint damage. There are many new and emerging treatments which will hopefully continue to improve treatment. Julie Jaffray, MD, is a pediatric Hematologist-Oncologist in Los Angeles, Calif.

References 1. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-44. 2. Collins PW, Fischer K, Morfini M, et al. Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia. Haemophilia. 2011;17(1):2-10. 3. Powell JS, Josephson NC, Quon D, et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood. 2012;119(13):3031-7. 4. Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014;123(3):317-25.

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 47

Updates in the Treatment and Management of Relapsed/Refractory Multiple Myeloma Rachid Baz, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Although considered incurable, multiple myeloma (MM) can be treated for several years with novel therapies. Once a patient relapses or fails to respond to initial therapy, there are now many different treatment choices, including some which are oral therapies. The first monoclonal antibody to treat this disease was recently approved. Key Points • Relapsed/refractory MM can be treated with multiple lines of treatment but the response declines with each subsequent treatment. • Three new agents were recently FDA approved for relapsed/refractory MM, including the first monoclonal antibody. • Additional agents are on the horizon.

MULTIPLE MYELOMA (MM) IS AN INCURable plasma cell malignancy, which causes significant morbidity due to organ damage and bone tissue destruction. Relapses are inevitable with patients going through several lines of therapy before reaching the refractory stage. The effectiveness of therapies declines with each relapse. The management of relapsed/refractory disease has changed dramatically over the last 10 years with many new agents being introduced. Relapse is defined as a new plasmacytoma or new bone metastatic site, increase in bone/plasmacytoma site of greater than one centimeter, hyperkalemia, progressive anemia, new or recurrent renal dysfunction, or reappearance/rise in M protein level or doubling of M protein at two consecutive time points. Refractory myeloma is defined as no response to

therapy, progression of disease on therapy, or recurrence of disease within two months of stopping therapy. There are several considerations in selecting therapy for relapsed/refractory disease. Types of previous therapy, response to previous therapy, patient characteristics, and disease features all must be considered. The first factor to consider is whether the patient is having a biochemical or a symptomatic relapse. Patients with asymptomatic rise in M protein (biochemical relapse) can be observed to determine the rate of rise and nature of relapse. Aggressiveness of previous relapse, risk of organ damage, and magnitude of M protein increase all play into the decision to treat a biochemical relapse. Patients with known aggressive or high-risk disease are considered for salvage treatment, even in the setting of

48 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 1: Relapsed/Refactory Myeloma: Preferred Regimens1 • NCCN Category 1 – Bortezomib – SC vs IV administration – Bortezomib/pegylated liposomal doxorubicin – Carfilzomib/lenalidomide/ dexamethasone – Panobinostat/bortezomib/ dexamethasone – Lenalidomide/dexamethasone

biochemical relapse. Patients with a symptomatic relapse are treated. The main disease-related factor is the duration of response to initial therapy and risk type of disease. Treatment-related factors include previous therapy exposure and toxicity of prior regimens. Availability of oral agents has helped make therapy easier for many patients. Relapsed/refractory MM is primarily treated with the so called novel agents - proteasome inhibitors (bortezomib, carfilzomib), immunomodulatory agents (thalidomide, lenalidomide, pomalidomide) in combination with dexamethasone, and histone deacetylase inhibitors (panobinostat). Exhibit 1 lists the preferred regimens from the National Comprehensive Cancer Network (NCCN) guidelines.1 Only Category 1A regimens that have the best supporting clinical data are shown in the exhibit. Category 2A regimens that have less data are used when aggressive therapy or a quick response is desired. These regimens rely more heavily on chemotherapy. While helpful, the NCCN guidelines do not specify which agents are going to be useful in an individual. Clinicians must weigh the various factors mentioned previously. In the future, hopefully there will be personalized medicine for selecting therapy. This may be biomarkers that can be used to predict effective therapies. Exhibit 2 shows the treatment options for an indolent, slow-growing myeloma at first relapse. Switching therapy classes, such as from bortezomib to lenalidomide, makes therapeutic sense but has not been proven in clinical trials. Although lenalidomide is typically used in combination with dexamethasone, it is possible to use it without for less aggressive disease and thus steroid adverse effects are avoided. Stem cell transplant is also an option. Patients with aggressive myeloma with rapid, multiple relapses can be treated with chemotherapy, chemotherapy plus the novel agents, or transplant. Carfilzomib and pomalidomide are newer agents

and as such are typically reserved for specific indications (Exhibit 3). As more experience is gained with these agents, they will likely be used in earlier lines of therapy. Panobinostat is another new agent which causes a higher rate of adverse effects than the other classes and is currently reserved for later lines of therapy. Clinicians do not yet know which patients will get the most benefit from this agent. Additionally, the manufacturer is looking at lower-dose regimens to reduce the incidence of adverse effects. The first monoclonal antibody for treating MM was approved in November of 2015. The FDA approved daratumumab (Darzalex®) for myeloma patients who have received at least three prior lines of therapy, including both an immunomodulatory agent and a proteasome inhibitor, and for patients who are “double refractory”, meaning their disease no longer responds to treatment with at least one immunomodulatory agent and at least one proteasome inhibitor. This agent binds to the CD38 protein found on the surface of myeloma cells. Once bound to a myeloma cell, it attacks the cell while also signaling the patient’s immune system to act against the cells. It leads to antibody-dependent cellular toxicity, complement-dependent cytotoxicity, and apoptosis via targeting growth signaling pathways. The results of the study used for FDA approval showed that nearly one-third of the trial participants – who had received a median of five prior therapies – responded to single-agent daratumumab. The median time to disease progression was 3.7 months, and the estimated one-year overall survival rate was 65 percent. For patients who are refractory to all the available agents, clinical trials are options. In reality, clinical trials are an option at any point in therapy. Managing adverse effects is important in allowing patients to continue with therapy. The major adverse effects which must be considered are peripheral neuropathy, myelosuppression, and venous thromboembolic events.

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 49

Exhibit 2: Treating Indolent, Slow-Growing Myeloma in First Relapse

IMiD-Based Salvage

Transplant-Based Salvage

Pl-Based Salvage

•

Initial treatment with bortezomib

•

Initial treatment with IMiD

•

Stem cell transplant not part of initial therapy

•

May consider single agent without dexamethasone

•

Previous bortezomib therapy but good or long response

•

Long remission post transplant

•

Underlying PN

•

Renal dysfunction

IMiD = immunomodulator; PN = peripheral neuropathy; PI = proteosome inhibitor

Exhibit 3: Newer Agents

Carfilzomib-Based Salvage

Pomalidomide-Based Salvage

•

Intolerence to bortezomib

•

Lenalidomide refractory

•

Dexamethasone-sparing treatment as a part of a combination

•

Refractory to standard-dose PI

•

Intolerence to IMiDs (Steven’s Johnson reaction)

Peripheral neuropathy (PN) can be very painful and causes significant disability. Grade 3 and 4 neuropathy have been reported in 26 to 44 percent of those who receive bortezomib, 28 to 41 percent with thalidomide, and 14 percent with carfilzomib. The rate with bortezomib can be reduced by giving the agent twice weekly instead of weekly or by giving subcutaneous injections instead of intravenous injections. The rate with thalidomide increases with higher doses and prolonged therapy. Importantly, PN occurs frequently in untreated MM patients; 39 percent will have some degree of PN. Patients with hyperviscosity syndrome and hypergammaglobulinemia have higher rates. Other factors beyond MM can also increase risk of PN, including endocrine disorders (hypothyroidism, diabetes), nutritional disease (B12 deficiency), connective tissue disease, vascular disease, other medications, and herpes zoster. For PN, there are no clearly estab-

lished preventive guidelines. Duloxetine, pregabalin, gabapentin are effective for managing the pain. Glutamine and alpha lipoic acid are used by some clinicians to try to prevent PN, although there is not a lot of supportive data. Myeloma alone and immunomodulators (thalidomide, etc.) can cause venous thromboembolic events (VTE). The International Myeloma Working Group (IMWG) has developed thromboprophylaxis guidelines specifically for patients with MM receiving immunomodulation treatment. These guidelines determine prophylaxis by the number of risk factors present. VTE prophylaxis for individual risk factors (e.g., age or obesity) or myeloma-related risk factors (e.g., immobilization or hyperviscosity) is recommended. If one risk factor is present, aspirin 81 to 325 mg/day is recommended. Lowmolecular-weight heparin or full-dose warfarin is recommended for patients with two or more risk

50 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

factors, or for those receiving immunomodulators, high-dose dexamethasone, doxorubicin, or multiagent chemotherapy. Myelosuppression is associated with both myeloma and the drugs used to treat it. Additionally, risk of infection is increased if hypergammaglobulinemia is present. Dose-modification guidelines based on degree of myelosuppression are available in the package inserts for all the medications. To prevent infections, patients should remain up-to-date on appropriate vaccinations. Varicella prophylaxis is important to prevent shingles when patients are receiving proteasome inhibitors. Use of IVIG or prophylactic antibiotics is controversial, and should only be used when warranted. Patient education emphasizing the importance of alerting treating clinicians of potential infection can reduce unnecessary antibiotic use. Management of bone disease is important in MM treatment. There is a direct effect of the disease on inflammatory cytokines, leading to inhibition of bone resorption and osteoclast stimulation. Treating the underlying cancer can help minimize bone damage. Bisphosphonates, including pamidronate and zoledronic acid, are commonly used to manage bone disease. Supplementation of calcium and vitamin D3 are recommended to maintain calcium homeostasis. Radiation to areas of active bone breakdown is not used extensively because of the long-term damage to bone marrow. It was used more extensively in the past because the available MM treatments were not very effective. Low-dose radiotherapy can be used for impending fracture, spinal cord compression, and plasmacytomas. Patients need to be referred for orthopedic consultation if they have impending or actual long-bone fractures, bony compression of the spinal cord, or vertebral column instability. Numerous novel therapies and combinations are under study to find additional alternatives for re-

lapsed/ refractory MM. Ixazomib is another oral proteasome inhibitor which was submitted to the FDA for approval in mid-2015. If approved, ixazomib, with the convenience of once-a-week oral administration compared with the currently available injectable proteasome inhibitors should provide a very meaningful advance. Another oral investigational agent is oprozomib, a structural analog of carfilzomib. Oprozomib is currently being studied in a number of trials, including several ongoing Phase I and Phase II studies in multiple myeloma, Waldenstromâ&#x20AC;&#x2122;s macroglobulinemia, and advanced liver cancer. Other histone deacetylase inhibitors (vorinostat, romidepsin) and numerous monoclonal antibodies are also under study for treating MM. Conclusion

In the relapsed/refractory setting, doublet or triplet combination therapy is standard of care. Combination treatment with either bortezomib, carfilzomib, and/or pomalidomide with dexamethasone is active and well tolerated. Novel agents in combination can achieve prolonged responses even in relapsed disease. Optimal management approaches should emphasize improving quality of life by identifying potential complications of therapy and minimizing long-term toxicity. New classes of agents and second-generation agents are under study and anxiously awaited. Rachid Baz, MD, is an Associate Professor, Departments of Oncologic Sciences and Medicine University of South Florida and Associate Member, Myeloma Section Head and Director of Clinical Research, Department of Malignant Hematology at the H. Lee Moffitt Cancer Center and Research Institute.

References 1. NCCN clinical practice guidelines in oncology: multiple myeloma: v.2.2015. www.nccn.org.

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 51

Risk Factors for Medication Nonadherence and Acute Hospital Utilization in Medicaid Recipients Prescribed Hypoglycemics, Statins, and Antihypertensives Andrea D. Gelzer, MD, MS, FACP, Wanzhen Gao, PhD, David Keleti, PhD, Thomas Donia, RPh, Timothy W. Downey, MS, Karen E. Michael, RN, MSN

Summary Medication nonadherence is reportedly associated with poorer health outcomes and increased risk of acute hospitalization in chronically ill patients. However, relatively few studies have reported the magnitude of nonadherence and examined related risk factors in the Medicaid population prescribed hypoglycemics, statins, and/or antihypertensives; still fewer have quantified the independent impact of nonadherence on acute hospitalization. Such predictive variables should be considered when designing interventions to improve medication adherence. Key Points • Medication nonadherence is associated with increased likelihood for acute hospitalization, including emergency department visits and inpatient admissions, in three demographically distinct populations of 50,456 chronically ill Medicaid beneficiaries prescribed hypoglycemics, statins, and/or antihypertensives. • Risk factors for nonadherence (reported as crude and adjusted odds ratios) were black race, non-Supplemental Security Income status, no care management, and medications prescribed from fewer than three drug classes. Protective factors for adherence were middle age, language(s) spoken other than English or Spanish, and lower concurrent DxCG risk scores. • Additional risk and protective factors associated with acute hospitalization included gender, race, age, risk scores, care management status, and drug class. • These predictive variables were later considered when designing and implementing managed care-supported interventions to improve medication adherence enterprise-wide.

POOR MEDICATION ADHERENCE SUBSTANtially contributes to increased morbidity and mortality in patients with chronic conditions.1 Approximately 20 to 30 percent of prescriptions are never filled,2 and it is estimated 50 percent of medications for chronic disease are not taken as prescribed.3 At-risk populations are particularly vulnerable.4,5 Among the Medicaid population, nonadherence is reportedly as high as 70 percent for some medication classes.6 Nonadherent patients often have poorly managed metabolic control, leading to increased

risks of hospitalization and greater financial pressure on providers, payers, and public health systems.7-9 An estimated 33 to 69 percent of all medicationrelated hospital admissions in the United States are caused by poor adherence.1 Conversely, patients who adhere to medication regimens enjoy superior health outcomes with lower use of urgent care and hospitalization services.9,10-12 Therefore, increasing medication adherence is critical to improving population health outcomes and making chronic care management more effective.

52 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 1: Demographic Characteristics by Health Plan SEPA

LCNWPA

Variables

Total

29,989

100a

10,687

100a

9,780

100a

Female

17,804

59.4

6,537

61.2

6,987

71.4

Male

12,185

40.6

4,150

38.8

2,793

28.6

18 - 39

3,545

11.8

1,626

15.2

2,204

22.5

40 - 64

24,219

80.8

8,446

79.0

7,404

75.7

65 and above 2,225

7.4

615

5.8

172

1.8

SSI

22,289

74.3

7,120

66.6

5,744

58.7

Non-SSI

7,664

25.6

2,854

26.7

4,015

41.1

Black

15,352

51.2

1,195

11.2

4,638

47.4

Caucasian

9,272

30.9

5,977

55.9

3,998

40.9

Other

5,365

17.9

3,515

32.9

1,144

11.7

English

22,590

75.3

7,104

66.5

9,751

99.7

Spanish

6,820

22.7

2,378

22.3

0.1

Other

579

1.9

1,205

11.3

0.2

Lowest

7,464

24.9

2,654

24.8

2,441

25.0

Low

7,469

24.9

2,658

24.9

2,448

25.0

High

7,475

24.9

2,655

24.9

2,443

25.0

Highest

7,471

24.9

2,659

24.9

2,446

25.0

Lowest

7,464

24.9

2,651

24.8

2,443

25.0

Low

7,471

25.0

2,662

24.9

2,446

25.0

High

7,474

24.9

2,656

24.9

2,444

25.0

Highest

7,470

24.9

2,657

24.9

2,445

25.0

28,295

94.4

10,411

97.4

9,215

94.2

Yes

1,694

5.6

276

2.6

565

5.8

Age (y)

Aid Category

Race

Language

Concurrent risk quartile

Prospective risk quartile

Case management

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 53

Drug class

No. of drug classes

Antihyperten- 10,012 sives

33.4

3,176

29.7

3,837

39.2

Hypoglycemics

1,742

5.8

830

7.8

811

8.3

Statins

6,052

20.2

2,231

20.9

1,551

15.9

Two

9,351

31.2

3,324

31.1

2,836

29.0

Three

2,832

9.4

1,126

10.5

745

7.6

One

17,806

59.4

6,237

58.4

6,199

63.4

Two

9351

31.2

3,324

31.1

2,836

29.0

Three

2832

9.4

1,126

10.5

745

7.6

SEPA = Southeastern Pennsylvania LCNWPA = Lehigh/Capital-New West Pennsylvania SC = South Carolina. a Percentages do not always add up to 100 due to missing data

Treatment-related variables13-15 and sociodemographic factors substantially impact patient behavior toward medication use.1,16 Understanding risk and protective factors contributing to nonadherence and subsequent hospital utilization is essential for successful adherence-improvement programs. In 2013, AmeriHealth Caritas set an enterprise goal to improve adherence by 4 percent in members prescribed drugs from four medication classes—hypoglycemics, statins, antihypertensives, and asthma controllers—across three Medicaid managed care organizations (MCOs) over a one-year period. Baseline characteristics of members prescribed these medication classes (excluding asthma controllers) were profiled, and risk and protective factors associated with nonadherence were explored. The impact of nonadherence on inpatient admissions and emergency room (ER) visits was also examined. Study results guided subsequent enterprise-wide medication adherence interventions. Statistical Analysis

A chi-square test or Fisher-exact method was performed to examine the association between predictor and outcome variables. Adherence and utilization outcomes were subjected to bivariable and multivariable logistic regression analyses. Two types of models were developed. First, medication adherence (nonadherent vs. adherent) was the dependent variable to explore the risk and protective factors associated with nonadherence. These factors

included gender, age, race, language, aid category, risk score quartile groups, case management status, and medication (number and class). Second, clinical outcomes (i.e., inpatient or ER utilization) were dependent variables and medication adherence was an independent variable in examining medication nonadherence as a risk factor for increased inpatient or ER utilization. Sociodemographic factors, aid category, risk score quartile groups, case management status, and medication (number and class) were also included as controlling factors. For both types of models, bivariable logistic regression analysis was used to explore the unadjusted effect of each predictive factor on the dependent variables (i.e., nonadherence or hospital utilization), thereby expressing the statistical significance of the factor’s effect on the cohort. Multivariable logistic regression analysis was then used to explore the independent effect of each predictive factor on the dependent variables (i.e., nonadherence or hospital utilization) after controlling for other contributing factors, thereby identifying the risk factors for medication nonadherence or hospital utilization. During multivariable logistic regression analysis, one or more variables were excluded from the model due to collinearity or lack of association. The backward selection method was used to select statistically significant effects from the candidate variables. The Nagelkerke’s R-square method was used to estimate the variability in the dependent variable explained by the model.17 Hosmer to Lemeshow’s goodness-

54 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

of-fit test was conducted to determine whether the model fit was adequate.18 Crude and adjusted odds ratios (ORs), and corresponding 95 percent confidence intervals (CI), were reported to quantify variable effects. A significance level of a ≤ .05 was deemed statistically significant for all comparisons. Adjusted ORs of greater than 1 were deemed risk factors; adjusted ORs of less than 1 were deemed protective factors. All analyses were performed using SAS version 9.2 (SAS Institute; Cary, NC, USA). Member Demographics

Substantial sociodemographic differences were found to exist among the populations of the three health plans covering the service areas of Southeastern Pennsylvania, Lehigh/Capital-New West Pennsylvania, and South Carolina (SEPA, N = 29,989; LCNWPA, N = 10,687; and SC, N = 9,780; Exhibit 1). Inclusion criteria were continuous enrollment during the baseline period ( January 1 to December 31, 2012) of members ages 18 and older prescribed antihypertensives, statins, and/or oral hypoglycemics of a specific therapeutic class code (Exhibit 2), and served by PerformRx, a Medicaid pharmacy benefit manager. Females were overrepresented in SC (71.4 percent) compared to SEPA and LCNWPA (59.4 and 61.2 percent, respectively). Blacks were overrepresented in SEPA and SC (51.2 and 47.4 percent, respectively) compared to LCNWPA (11.2 percent); Caucasians represented 30.9, 40.9, and 55.9 percent of subjects, respectively. Almost all SC subjects (99.7 percent), but progressively fewer SEPA and LCNWPA subjects (75.3 and 66.5 percent, respectively), spoke English. Finally, almost threequarters of SEPA subjects (74.3 percent), but progressively fewer LCNWPA and SC subjects (66.6 and 58.7 percent, respectively), had SSI status (paid benefits to aged, blind, and disabled population with low income and resources). Other sociodemographic characteristics were comparable among the three study groups. Members were stratified into four quartile groups based on prospective and concurrent risk scores using the Verisk Analytics DxCG® tool ( Jersey City, NJ, USA). The majority of subjects were middle age (40 to 64 years; 75.7 to 80.8 percent); substantially fewer were younger (18 to 39 years; 11.8 to 22.5 percent) or elderly (≥ 65 years; 1.8 to 7.4 percent). The majority of subjects were prescribed antihypertensives (29.7 to 39.2 percent), followed by statins (15.9 to 20.9 percent), and hypoglycemics (5.8 to 8.3 percent); a substantial proportion of subjects were prescribed medications from two drug classes (29.0 to 31.2 percent) or three drug classes (7.6 to 10.5 per-

cent). Relatively few subjects were care managed (2.6 to 5.8 percent). Medication Nonadherence and Related Predictive Factors

Sociodemographic and clinical variables of subject cohorts were statistically analyzed to identify associative and predictive factors for nonadherence. Medication adherence/nonadherence was measured by proportion of days covered (PDC) using pharmacy claim data and calculated using the following equation: Avg. PDC = ∑ covered days of each medication class /∑ measurement period of each medication Using an 80 percent cutoff threshold,19 members were dichotomously classified as adherent (PDC ≥ 80 percent) or nonadherent (PDC < 80 percent). Overall nonadherence rates for SEPA, LCNWPA, and SC were 48.9, 47.3, and 66.8 percent, respectively. Nonadherence rates for SEPA and LCNWPA were comparable among the three medication classes (antihypertensives: 52.4 and 50.5 percent; hypoglycemics: 59.6 and 57.1 percent; statins: 50.1 and 49.3 percent, respectively), while nonadherence rates for SC were substantially higher (antihypertensives: 69.4 percent; hypoglycemics: 74.5 percent; statins: 65.0 percent). In the bivariable analysis, the majority of variables were significantly associated with nonadherence for all three plans (except gender and concurrent risk scores for LCNWPA; and language spoken and prospective risk scores for SC). Nonadherence was consistently associated with subjects who were younger, black, non-SSI, non-care managed, or taking medications from fewer than three drug classes (P < 0.01). Variables excluded from the multivariable analysis were gender and number of prescribed drug classes (all plans); concurrent risk scores (LCNWPA); prospective risk scores (LCNWPA and SC); and language spoken (SC). Risk factors associated with greater odds of nonadherence in at least two plans included black race (adjusted OR, 1.46 to 1.73), other race (adjusted OR, 1.34 and 1.36), non-SSI status (adjusted OR, 1.48 to 1.93), the absence of care management (adjusted OR, 1.26 to 1.55), and medications prescribed from fewer than three drug classes (antihypertensives: adjusted OR, 1.36 to 1.82; hypoglycemics: adjusted OR, 1.68 to 2.29; statins: adjusted OR, 1.34 to 1.86; two drug classes: adjusted OR, 1.19 to 1.50; Exhibit 3a-c). Conversely, protective factors associated with greater adherence in at least two plans were middle age (adjusted OR, 0.13 to 0.65), languages spoken other than English or Spanish (adjusted OR, 0.79 and 0.84), and lower concurrent risk quartile scores (adjusted

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 55

Exhibit 2: Drug Class Codes

STATINS

HYPOGLYCEMICSa

ANTIHYPERTENSIVES

Drug Class

Specific Therapeutic Class Code

Specific Therapeutic Class Description

Sample Medication

A4D

Antihypertensives, ACE Inhibitors

Lisinopril

A4F

Antihypertensives, Angiotensin II Receptor Blocker (ARB)

Cozaar

A4H

Angiotensin Receptor Antagonist and Calcium Channel Blocker

Exforge

A4I

Angiotensin Receptor Antagonist/Thiazide Diuretic Combination

Hyzaar

A4J

ACE Inhibitor/Thiazide and Thiazide Like Diuretic

Zestoretic

A4K

ACE Inhibitor/Calcium Channel Blocker Combination

Lotrel

A4T

Renin Inhibitors, Direct

Tekturna

A4U

Renin Inhibitors. Direct and Thiazide Diuretic Combination

Tekturna HCT

A4V

Angiotensin Receptor Antagonist/Calcium Channel Blocker/Thiazide Combination

Exforge HCT

A4X

Renin Inhibitor, Direct and Calcium Channel Blocker

Tekamlo

C4A

Antihypergylcemic DPP-4 Inhibitors and HMG CoA Reductase Inhibitors

Juvisync

C4F

Anthihyperglycemic, (DPP-4) Inhibitor and Biguanide Combination

Janumet

C4J

Anthihyperglycemic, DPP-4 Inhibitors

Januvia

C4K

Antihyperglycemic, Insulin-Release Stimulant Type

Glucotrol

C4L

Antihyperglycemic, Biguanide Type (Non-Sulfonylurea)

Metformin

C4N

Antihyperglycemic, Insulin-Response Enhancer (N-S)

Actos

C4R

Antihyperglycemic, Insulin-Response and Release Combination

Duetact

C4S

Antihyperglycemic, Insulin-Release Stimulant and Biguanide Combination

Glucovance

C4T

Antihyperglycemic, Insulin-Response Enhancer and Biguanide Combination

Actoplus Met

C4A

Antihypergylcemic DPP-4 Inhibitors and HMG CoA Reductase Inhibitors

Juvisync

M4D

Antihyperlipidemic to HMG CoA Reductase Inhibitors

Lipitor

M4I

Antihyperlipidemic to HMG CoA Reductase Inhibitors and Calcium Channel Blockers

Caduet

M4L

Antihyperlipidemic to HMG CoA Reductase Inhibitors and Niacin

Simcor

M4M

Antihyperlipidemic to HMG CoA Reductase Inhibitors and Cholesterol Absorption Inhibitors

Vytorin

Limited to oral formulations only.

56 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 3a: Forest Plot of Risk/Protective Factors in Predicting Nonadherence in SEPA Members

Variable vs Reference Group Ages 18 - 39 vs. > 65 years Ages 40 - 64 vs. > 65 years Black vs. Caucasian race Othera vs. Caucasian race Otherb vs, English language Spanish vs, English language Non-SSI vs. SSI status Non-case managed vs. case managed Lowest vs. highest concurrent risk score Low vs. highest concurrent risk score High vs. highest concurrent risk score Lowest vs. highest prospective risk score Low vs. highest prospective risk score High vs. highest prospective risk score Antihypertensives vs. three drug classes Hypoglycemics vs. three drug classes Statins vs. three drug classes Two drug classes vs. three drug classes 0.5

1.0

1.5

2.0

2.5

Odds Ratio Adjusted odds ratios (OR; blue dots) bracketed by 95 percent confidence intervals (CI; red brackets) were calculated using multivariable logistic regression analyses to quantify variable effects. Adjusted ORs greater than 1 (right side of ordinate) were deemed risk factors, while adjusted ORs less than 1 (right side of ordinate) were deemed protective factors. a Other race: race other than black or Caucasian b Other language: language other than English or Spanish SEPA = Southeastern Pennsylvania SSI = Supplemental Security Income.

OR, 0.61 to 0.88). Spanish spoken was a risk factor in SEPA (adjusted OR, 1.35) and younger age was a protective factor in SC (adjusted OR, 0.15). Medication Nonadherence and ER visits

Medication adherence status and subject characteristics were compared against ER visit rates. Clinical outcomes were reported as dichotomized inpatientand ER-related claim data (Yes, â&#x2030;Ľ 1 episode; No, 0 episodes). In the bivariable analysis, the majority of variables were significantly associated with more ER visits for all three plans (except SSI status and lan-

guage spoken for SEPA and SC). Nonadherence, female gender, younger and middle age, black race, high concurrent and prospective risk scores, the prescription of antihypertensives, care management, and fewer number of prescribed drug classes were consistently associated with significantly more ER visits (P < 0.01). Variables eliminated from the multivariable analysis were number of prescribed drug classes (all plans); SSI status (LCNWPA and SC); and language spoken (SC). Compared with their adherent counterparts, nonadherent cohorts had a 23 to 47 percent greater likelihood for ER visits (OR [95 percent CI]; SEPA,

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Exhibit 3b: Forest Plot of Risk/Protective Factors in Predicting Nonadherence in LCNWPA Members

Variable vs Reference Group Ages 18 - 39 vs. > 65 years Ages 40 - 64 vs. > 65 years Black vs. Caucasian race Othera vs. Caucasian race Otherb vs, English language Spanish vs, English language Non-SSI vs. SSI status Non-case managed vs. case managed Antihypertensives vs. three drug classes Hypoglycemics vs. three drug classes Statins vs. three drug classes Two drug classes vs. three drug classes 0.5

1.0

1.5

2.0

2.5

1.28 [1.22 to 1.35]; LCNWPA, 1.23 [1.13 to 1.34]; SC, 1.47 [1.34 to 1.51]; Exhibit 4). Additional risk factors in at least two plans included female gender (adjusted OR, 1.28 to 1.44), black race (adjusted OR, 1.20 to 1.38), younger and middle age (adjusted OR, 3.71 to 4.53 and adjusted OR, 2.40 to 2.57), Spanish speaking (adjusted OR, 1.46 and 1.17), and prescription of antihypertensives (adjusted OR, 1.23 and 1.32; Exhibit 5a-c). Conversely, protective factors associated with reduced odds of ER visits in all three plans included lower concurrent risk scores (e.g., lowest risk quartile, adjusted OR, 0.22 to 0.34); lower prospective risk scores (e.g., lowest risk quartile, OR, adjusted 0.40 to 0.76); and absence of care management (adjusted OR, 0.71 to 0.76). NonSSI status (adjusted OR, 1.18) and other race and language spoken (adjusted OR, 1.45 and 1.26) were risk factors for ER visits in SEPA and LCNWPA, respectively; other race (adjusted OR, 0.76) was a protective factor against ER visits in SEPA.

Medication Nonadherence and Inpatient Admissions

Medication adherence status and subject characteristics were compared against inpatient admission rates. In the bivariable analysis, the majority of variables were significantly associated with more inpatient admissions for all three plans (except gender for all plans; race and drug class for LCNWPA; age and language spoken for SC). Nonadherence, middle age, SSI status, high concurrent and prospective risk scores, care management, and number of prescribed drug classes were consistently associated with significantly more inpatient admissions (P < 0.01). Variables eliminated from the multivariable analysis were gender, language spoken, and number of prescribed drug classes (all plans); race (SEPA and LCNWPA); age (LCNWPA); and SSI status (SC). Compared with their adherent counterparts, nonadherent cohorts had a 47 to 57 percent greater likelihood for inpatient

58 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 3c: Forest Plot of Risk/Protective Factors in Predicting Nonadherence in SC Members Variable vs Reference Group Ages 18 - 39 vs. > 65 years Ages 40 - 64 vs. > 65 years Black vs. Caucasian race Othera vs. Caucasian race Non-SSI vs. SSI status Non-case managed vs. case managed Lowest vs. highest concurrent risk score Low vs. highest concurrent risk score High vs. highest concurrent risk score Antihypertensives vs. three drug classes Hypoglycemics vs. three drug classes Statins vs. three drug classes Two drug classes vs. three drug classes 0.0

0.5

1.0

1.5

2.0

admissions (OR [95 percent CI]; SEPA, 1.57 [1.46 to 1.69]; LCNWPA, 1.51 [1.31 to 1.74], SC, 1.47 [1.28 to 1.70]; Exhibit 4). An additional risk factor in two plans was non-SSI status (adjusted OR, 1.31 and 1.28; Exhibit 6a-c). Conversely, protective factors associated with reduced odds of inpatient admission in all three plans included lower concurrent risk scores (e.g., second lowest risk quartile, adjusted OR, 0.04 to 0.06); lower prospective risk scores (e.g., second lowest risk quartile, adjusted OR, 0.40 to 0.77); and absence of care management (adjusted OR, 0.35 to 0.67). Younger age (adjusted OR, 1.38) and prescription of hypoglycemics, antihypertensives, and two drug classes (adjusted OR, 1.82, 1.25, and 1.25, respectively) were risk factors for inpatient admissions in SEPA and SC. Discussion

We identified risk and protective factors associated with medication nonadherence, and examined its impact on hospital utilization in three sociodemographically diverse Medicaid MCOs. Baseline

analysis findings helped inform global and targeted interventions to increase adherence in the three Medicaid populations. Utilization outcomes post intervention will be reported at a later date. Despite the many medication adherence studies published, relatively few examine risk factors for nonadherence in Medicaid populations with diabetes, hypertension, and congestive heart failure,5,15-24 or the interdependent roles of hospital utilization and adherence. 5,18,24-27 Our comprehensive study analyzes the risk factors for nonadherence and hospital utilization among three drug classes in three sociodemographically diverse Medicaid populations. Baseline data demonstrated nonadherence rates for antihypertensives, statins, and oral hypoglycemics in three Medicaid plans ranging from 47.3 to 66.8 percent, situated in the upper range of that typically reported in Medicaid literature (31 to 68 percent).5,15-27 These results and the impact on hospital utilization underscore the urgent need for effective programs to improve medication adherence

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 59

Exhibit 4: Emergency Room Visit and Inpatient Admission Rates of Members by Adherence Status 50

IP Admits

ER Visits

45 40 ER/IP Utilization Rate (%)

35 30 25 20 15 10 5 0

Adherent

Nonadherent

Adherent

Nonadherent

SEPA

35.2

40.8

15.1

19.3

LCNWPA

38.5

43.5

10.4

13.4

36.1

45.7

12.7

17.8

ER visits and IP admissions were included after ≥ 1 visit or admission, respectively. The adherence threshold was identified as ≥ 80 percent. The differentials between adherent and nonadherent values were statistically significant (P < 0.01) in all of the above cases. SEPA = Southeastern Pennsylvania LCNWPA = Lehigh/Capital-New West Pennsylvania SC = South Carolina ER= emergency room IP = inpatient

in Medicaid populations. In our study, risk factors for nonadherence were black race, non-SSI status, absence of case management, and medications prescribed from fewer than three drug classes. Protective factors for adherence were middle age, language(s) spoken other than English or Spanish, and lower concurrent DxCG risk scores. Black race has been reported as a significant predictor for nonadherence in the Medicaid population,6,17-22,25 an observation also reported for subjects classified as “other” race 17,20,22,24,25 in two plans. Additionally, Hispanic or “other” ethnicity has been reported as a significant predictor for nonadherence in the Medicaid population.19,21,24 While ethnicity data were not directly reported in our study, Spanish-speaking was a risk factor for nonadherence at one plan; language spoken other

than English or Spanish was a protective factor for adherence at two plans. Female gender has occasionally been reported as a significant predictor for nonadherence in the Medicaid population,6,17,19 although male gender can be a risk factor for nonadherence for individual conditions, like hypertension and congestive heart failure (CHF).18,24 Female gender was associated with nonadherence after bivariable analysis of two plans, but not supported as a risk factor after multivariable analysis. Age is often a significant predictor of nonadherence in the Medicaid population.6,16,18-21,24 Several studies reported greater medication adherence in the elderly—a result we have not observed, perhaps due to the relatively small sample size of ≥ 65 year-old cohorts. Medicaid beneficiaries who reach age 65 are usually transferred to Medicare coverage, with

60 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 5a: Forest Plot of Risk/Protective Factors in Predicting Emergency Room Visits in SEPA Members

Variable vs. Reference group Female vs. Male Ages 18 - 39 vs. > 65 years Ages 40 - 64 vs. > 65 years Black vs. Caucasian race Othera vs. Caucasian race Otherb vs. English language Spanish vs. English language Non-SSI vs. SSI status Non-case managed vs. case managed Lowest vs. highest concurrent risk score Low vs. highest concurrent risk score High vs. highest concurrent risk score Lowest vs. highest prospective risk score Low vs. highest prospective risk score High vs. highest prospective risk score Antihypertensives vs. three drug classes Hypoglycemics vs. three drug classes Statins vs. three drug classes Two drug classes vs. three drug classes Nonadherent vs. adherentc 0

Odds Ratio Adjusted odds ratios (OR; blue dots) bracketed by 95 percent confidence intervals (CI; red brackets) were calculated using multivariable logistic regression analyses to quantify variable effects. Adjusted ORs greater than 1 (right side of ordinate) were deemed risk factors, while adjusted ORs less than 1 (right side of ordinate) were deemed protective factors. a Other race: race other than black or Caucasian b Other language: language other than English or Spanish c Nonadherent (PDC<80 percent) vs. adherent (PDC ≥80 percent) SEPA = Southeastern Pennsylvania SSI = Supplemental Security Income

the exception of the aged, blind, and disabled population. However, middle age was a protective factor for adherence in our study. Medicaid-only status is reportedly associated with greater nonadherence; 20 dual-eligibility status with greater adherence.24 In our study, non-SSI status was a significant risk factor for nonadherence. SSI status is usually associated with the presence of comorbid medical and behavioral health conditions, where

multiple confounding variables (e.g., age, disability, and case management status) may have an impact.28 Relatedly, the absence of case management was also a significant risk factor for nonadherence, a variable that—to our knowledge has not been examined in prior adherence studies in the Medicaid population. Finally, medication prescribed from fewer than three drug classes was a significant risk factor for nonadherence. Several Medicaid studies6,18,19 —al-

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 61

Exhibit 5b: Forest Plot of Risk/Protective Factors in Predicting Emergency Room Visits in LCNWPA Members

Variable vs Reference Group Female vs. Male Ages 18 - 39 vs. > 65 years Ages 40 - 64 vs. > 65 years Black vs. Caucasian race Othera vs. Caucasian race Otherb vs. English language Spanish vs. English language Non-case managed vs. case managed Lowest vs. highest concurrent risk score Low vs. highest concurrent risk score High vs. highest concurrent risk score Lowest vs. highest prospective risk score Low vs. highest prospective risk score High vs. highest prospective risk score Antihypertensives vs. three drug classes Hypoglycemics vs. three drug classes Statins vs. three drug classes Two drug classes vs. three drug classes Nonadherent vs. adherentc 0

Odds Ratio Adjusted odds ratios (OR; blue dots) bracketed by 95 percent confidence intervals (CI; red brackets) were calculated using multivariable logistic regression analyses to quantify variable effects. Adjusted ORs greater than 1 (right side of ordinate) were deemed risk factors, while adjusted ORs less than 1 (right side of ordinate) were deemed protective factors. a Other race: race other than black or Caucasian b Other language: language other than English or Spanish c Nonadherent (PDC<80 percent) vs. adherent (PDC â&#x2030;Ľ80 percent)

though not all17â&#x20AC;&#x201D;report greater medication adherence with cohorts prescribed multiple drug classes. Bailey and colleagues reported that for every additional drug class prescribed to patients with hypertension, a corresponding 19 percent decrease in nonadherence was observed.18 One possible explanation is that prescribing several antihypertensive drug classes used to concurrently treat multiple comorbidities affecting a patient improved adherence, and likely indicated provider-initiated customization and/or intensification of medication regimens

critical for effective chronic disease management. Diagnosed medical comorbidity and disability have been reported as predictors of greater adherence,17,18,24 perhaps because the patients are more likely to be under regular physician care. However, rural residency (where provider-access issues may exist), obesity, and behavioral health comorbidities are risk factors for greater nonadherence.6,18 Concurrent risk models use base-period claims to predict expenditures or events incurred during the contemporaneous period. Prospective risk models

62 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 5c: Forest Plot of Risk/Protective Factors in Predicting Emergency Room Visits in SC Members

Variable vs Reference Group Female vs. Male Ages 18 - 39 vs. > 65 years Ages 40 - 64 vs. > 65 years Black vs. Caucasian race Othera vs. Caucasian race Non-case managed vs. case managed Lowest vs. highest concurrent risk score Low vs. highest concurrent risk score High vs. highest concurrent risk score Lowest vs. highest prospective risk score Low vs. highest prospective risk score High vs. highest prospective risk score Antihypertensives vs. three drug classes Hypoglycemics vs. three drug classes Statins vs. three drug classes Two drug classes vs. three drug classes Nonadherent vs. adherentb 0

Odds Ratio Adjusted odds ratios (OR; blue dots) bracketed by 95 percent confidence intervals (CI; red brackets) were calculated using multivariable logistic regression analyses to quantify variable effects. Adjusted ORs greater than 1 (right side of ordinate) were deemed risk factors, while adjusted ORs less than 1 (right side of ordinate) were deemed protective factors. a Other race: race other than black or Caucasian b Nonadherent (PDC<80 percent) vs. adherent (PDC ≥80 percent)

use base-period claims to predict future expenditures or events. Prospective risk scores give more weight to persistent (i.e., chronic) conditions, while downplaying the contribution of more transitory (i.e., accidental or acute) conditions, thereby better reflecting chronic illness burden.29 However, concurrent risk scores yield more accurate predictions, because they rely on diagnosis and drug codes captured during the same year the risk is measured. In our study, lower concurrent risk scores, but not prospective risk scores, were observed to be protective factors for nonadherence in two plans. The association between medication adherence and hospital utilization or cost in chronically ill patients is well established.30 Several studies also report on the mutually detrimental effects of prior hospital

service utilization and adherence in the Medicaid population.5,18,24-26 A multistate analysis of medical and pharmacy claim data from Medicaid beneficiaries with CHF reported adherent subjects had 13 percent fewer hospitalizations, 25 percent fewer inpatient days, and 10 percent fewer ER visits.26 Nonadherent cohorts in our study were at significantly high risk for ER visits and inpatient admissions. Additional risk and protective factors—including female gender, black race, younger age, Spanish speaking, higher risk scores, and adverse effects of antihypertensive use31,32—have been reported previously,25,33-35 and are consistent with our findings. To our knowledge, non-SSI status—a risk factor for inpatient admissions—has not been reported previously as a risk factor for nonadherence. Unexpect-

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 63

Exhibit 6a: Forest Plot of Risk/Protective Factors in Predicting Inpatient Admissions in SEPA Members

Variable vs Reference Group Ages 18 - 39 vs. > 65 years Ages 40 - 64 vs. > 65 years Non-SSI vs. SSI status Non-case managed vs. case managed Lowest vs. highest concurrent risk score Low vs. highest concurrent risk score High vs. highest concurrent risk score Lowest vs. highest prospective risk score Low vs. highest prospective risk score High vs. highest prospective risk score Antihypertensives vs. three drug classes Hypoglycemics vs. three drug classes Statins vs. three drug classes Two drug classes vs. three drug classes Nonadherent vs. adherenta 0.0

0.5

1.0

1.5

Odds Ratio Adjusted odds ratios (OR; blue dots) bracketed by 95 percent confidence intervals (CI; red brackets) were calculated using multivariable logistic regression analyses to quantify variable effects. Adjusted ORs greater than 1 (right side of ordinate) were deemed risk factors, while adjusted ORs less than 1 (right side of ordinate) were deemed protective factors. a Nonadherent (PDC<80 percent) vs. adherent (PDC ≥80 percent) SEPA = Southeastern Pennsylvania SSI = Supplemental Security Income.

edly, the absence of case management was identified as a protective factor for ER visits and inpatient admissions, despite the observation it was a risk factor for medication nonadherence. Possible explanations include selection bias (i.e., subjects under case management had more complex disease conditions and comorbidities, leading to poorer ER and inpatient outcomes) and a lack of statistical power (i.e., the case-managed cohort was substantially smaller than the non-case-managed cohort). Although most sociodemographic factors are nonmodifiable, once identified they can help care management teams use limited resources more efficiently to target high-need Medicaid subgroups. For example, race/ethnicity and language concordance between patients and physicians has facilitated improvement in adherence in African-American and Spanish-speaking patients.36 Variations in risk and

protective factors among different plans are attributable to multiple reasons—especially sociodemographic—which deserve future consideration when customizing plan-specific intervention programs. Study limitations should be recognized when interpreting these results. First, adherence status and health outcome variables were measured concurrently, so no causal or temporal relationships could be defined. Second, the dichotomization of adherence using 80 percent of PDC as cutoff value for adherence was likely suboptimal, although commonly used in pharmacy refill records. The association between nonadherence and clinical outcomes is reportedly consistent for a wide range of PDC cutoffs.29 Future studies should explore multiple cutoff points or categorize PDC levels into ordinal groups (e.g., deciles) to examine dose-effect relationships. Third, limitations of pharmacy refill data to calcu-

64 Journal of Managed Care Medicine | Vol. 19, No. 1 | www.namcp.org

Exhibit 6b: Forest Plot of Risk/Protective Factors in Predicting Inpatient Admissions in LCNWPA Members

Variable vs Reference Group Non-SSI vs. SSI status Non-case managed vs. case managed Lowest vs. highest concurrent risk score Low vs. highest concurrent risk score High vs. highest concurrent risk score Lowest vs. highest prospective risk score Low vs. highest prospective risk score High vs. highest prospective risk score Nonadherent vs. adherenta 0.0

0.5

1.0

1.5

Odds Ratio Adjusted odds ratios (OR; blue dots) bracketed by 95 percent confidence intervals (CI; red brackets) were calculated using multivariable logistic regression analyses to quantify variable effects. Adjusted ORs greater than 1 (right side of ordinate) were deemed risk factors, while adjusted ORs less than 1 (right side of ordinate) were deemed protective factors. a Nonadherent (PDC<80 percent) vs. adherent (PDC â&#x2030;Ľ80 percent)

late adherence are well established (e.g., not all subjects may consume medications once prescriptions are filled),37 but refill records are reportedly well correlated with electronic adherence monitoring.38 Finally, several covariates displayed characteristics of the Simpsonâ&#x20AC;&#x2122;s paradox, whereby risk factors were converted into predictive factors after their OR values were adjusted by multivariable logistic regression analysis. These covariates were not identified as either risk or protective factors, but may be subject to further examination. In conclusion, medication nonadherence is prevalent among Medicaid beneficiaries prescribed hypoglycemics, statins, and/or antihypertensives in three demographically diverse health plans, and positively associated with adverse clinical outcomes. Multifaceted, culturally appropriate interventions to reduce access barriers and empower disease self-management are urgently needed to improve adherence so patients can realize the full benefit of prescribed therapies.

Services and the South Carolina Department of Health and Human Services for their continuing support. Financial support for this study was provided by the AmeriHealth Caritas Family of Companies. The authors of this study have no conflicts of interest to declare. Andrea D. Gelzer, MD, MS, FACP, is Senior Vice President and Corporate Chief Medical Officer for the AmeriHealth Caritas Family of Companies, Philadelphia, PA. Wanzhen Gao, PhD, is Manager of Medical Economics, Advanced Analytics for the AmeriHealth Caritas Family of Companies, Philadelphia, PA. David Keleti, PhD, is Manager of Clinical Outcomes for the AmeriHealth Caritas Family of Companies, Philadelphia, PA. Thomas Donia, RPh, is Vice President of Corporate Medical Economics for the AmeriHealth Caritas Family of Companies, Philadelphia, PA. Timothy W. Downey, MS, is Director of Medical Economics, Advanced Analytics for the AmeriHealth Caritas Family of Companies, Philadelphia, PA. Karen E. Michael, RN, MSN, is Vice President of Corporate Medical Management for the AmeriHealth Caritas Family of Companies, Philadelphia, PA.

Acknowledgements

References

The authors wish to thank Lauren Brophy, PharmD, Anna Kovacs, Evan

1. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353(5):

Johnstone, Joe Bradley, Jr., and Maggie DeWitt for their analytical,

487-97.

editorial, and graphic design-related contributions to the develop-

2. Fischer MA, Stedman MR, Li J, et al. Primary medication non-adherence:

ment of this manuscript, and the Pennsylvania Department of Human

analysis of 195,930 electronic prescriptions. J Gen Intern Med 2010;25(4):284-90.

www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 65

Exhibit 6c. Forest Plot of Risk/Protective Factors in Predicting Inpatient Admissions in SC Members

Variable vs Reference Group Black vs. Caucasian race Othera vs. Caucasian race Non-case managed vs. case managed Lowest vs. highest concurrent risk score Low vs. highest concurrent risk score High vs. highest concurrent risk score Lowest vs. highest prospective risk score Low vs. highest prospective risk score High vs. highest prospective risk score Antihypertensives vs. three drug classes Hypoglycemics vs. three drug classes Statins vs. three drug classes Two drug classes vs. three drug classes Nonadherent vs. adherentb 0.0

0.5

1.0

1.5

2.0

2.5

Odds Ratio Adjusted odds ratios (OR; blue dots) bracketed by 95 percent confidence intervals (CI; red brackets) were calculated using multivariable logistic regression analyses to quantify variable effects. Adjusted ORs greater than 1 (right side of ordinate) were deemed risk factors, while adjusted ORs less than 1 (right side of ordinate) were deemed protective factors. a Other race: race other than black or Caucasian b Nonadherent (PDC<80 percent) vs. adherent (PDC â&#x2030;Ľ80 percent)

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www.namcp.org | Vol. 19, No. 1 | Journal of Managed Care Medicine 67

C A N Y OU DIST ING UISH B E T W E E N M OT HER AND CHIL D ?

Neither can the other non-invasive prenatal screening tests (NIPTs) . . .

Only Panorama ® distinguishes between maternal & fetal DNA

Feature

Clinical Significance

Panorama ®

All Other NIPTs

Triploidy

Miscarriage or severe birth defects in fetus; risk of severe complications for the mother

√

Maternal contribution 1, 2

May lead to false positive or false negative results when not detected

√

Vanishing twin

Common cause of false positive results when not detected 3,4

√

N AT E R A’S OT HE R PR OPR I ETARY P ROD U C TS HorizonTM is one of the only carrier screening tests that can identify Spinal Muscular Atrophy (SMA) silent carriers (2+0) in individuals of Ashkenazi Jewish and Asian ancestry and further refine the residual carrier risk for all other ethnic groups.5 Anora® is the only Products of Conception (POC) microarray singlenucleotide polymorphism (SNP) test which automatically rules out Maternal Cell Contamination (MCC) without needing to order a separate test, at no additional charge. Anora is also the only test to detect complete uniparental disomy (UPD) with the ability to determine parent of origin. Spectrum® is the only Preimplantation Genetic Diagnosis & Screening (PGD/PGS) test that detects uniparental disomy (UPD), haploidy, and polyploidy. Spectrum can determine parental origin of aneuploidy with simultaneous 24-chromosome aneuploidy screening. References: 1 Pergament et al. Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort. Obstetrics & Gynecology, Aug 2014; 124(2 Pt 1): 210-8. 2 Nicolaides et al. Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy on chromosomes 21, 18, 13, X and Y. Prenatal Diagnosis. 2013;33:1-5. 3 Porecco et al. Noninvasive prenatal screening for fetal trisomies 21, 18, 13 and the common sex chromosome aneuploidies from maternal blood using massively parallel genomic sequencing of DNA. AJOG, 2014; 1.e1. 4 Futch et al. Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples. Prenat Diag 2013; 33(6):569-74. 5 Luo M et al. An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy. Genet Med 2014 Feb;16(2):149-56.

201 Industrial Road, Suite 410 | San Carlos, CA 94070 | www.natera.com | 1-650-249-9090 | Fax 1-650-730-2272 The test described has been developed and its performance characteristics determined by the CLIA-certified laboratory performing the test. This test has not been cleared or approved by the U.S. Food and Drug Administration (FDA). Although FDA does not currently clear or approve laboratory-developed tests in the U.S., certification of the laboratory is required under CLIA to ensure the quality and validity of the tests. | © Natera 2016 All Rights Reserved