Off-Label Use in Managed Care Pharmacy Presentation Developed for the Academy of Managed Care Pharmacy Updated: February 2016

Objectives Define the term off-label use Discuss the difference between off-label and off-compendium Understand the issues regarding off-label use and where it may be appropriate

Objectives Discuss the perspective of managed care pharmacy on off-label use Off-label use and non-FDA approved uses and Medicare Part D for Biologic and Chemotherapeutic Regimens

Definition of Off-Label Use The use of a drug for indications, dosage forms or regimens, or other use parameter not stated in the product labeling approved by the Food and Drug Administration (FDA)

What are the issues? Promotion of off-label use would compromise three key factors: – Definitive clinical trial data – Evidence-based medicine – Safety and efficacy standards Off-label uses may be potentially harmful and/or lead to ineffective results

Areas of High Off-Label Use of Drug Products Oncology – Medical Necessity – Compassionate Use Pediatrics – Limited availability of trial data – Many uses not listed in product labeling

Why is Off-Label Use Common? Rigorous and time-consuming FDA review process Costs associated with conducting clinical trials Lack of incentive – Some drugs already off-patent – Reimbursement already ongoing

FDA Policies Regarding Off-Label Use The Guidance for Industry on Good Reprint Practices Provides distribution of journal articles on unapproved off-label uses of approved drugs acceptable as long as the materials meet certain criteria for objectivity.

FDA Policies Regarding Off Label Use Drug manufacturers cannot pro-actively discuss or provide written materials on off- label uses. – The manufacturer can provide information if asked directly No other parties are restricted from discussing or distributing written materials on off-label uses

FDA Policies Regarding Off Label Use Off-label use of drugs by prescribers is often appropriate Prescribers and other parties may obtain, when requested, information regarding off- label uses from drug manufacturers (following the policy on solicited information)

Academy of Managed Care Pharmacy Perspective In support of off-label use of FDA-approved drugs when medically appropriate/necessary Opposed to government-mandated coverage of specific pharmaceuticals Believes each drug should be used in accordance with generally accepted medical practices Academy of Managed Care Pharmacy:

AMCP Perspective Recognizes rapidly changing nature of pharmacy and that FDA-approval of new indications may be delayed Supports the consideration of specific criteria when determining coverage of drug products for off-label uses Academy of Managed Care Pharmacy:

Criteria Considerations for Drug Coverage Whether the drug has been proven effective and accepted for the treatment of the specific medical condition for which it has been prescribed according to: – American Hospital Formulary Service-Drug Information® (AHFS-DI®) – Truven Health Analytics Micromedex DRUGDEX® – Clinical Pharmacology – NCCN Drugs & Biologics Compendium™ – Lexicomp Whether the drug is recommended for the particular condition involved, and has been proven to be safe and effective for that condition according to formal clinical studies, the results of which have been published in peer- reviewed professional medical journals. Academy of Managed Care Pharmacy:

Solutions to Consider Adequate incentives for drug manufacturers to conduct clinical trials investigating off-label uses Adoption of new strategies to get more uses on approved product labeling Practice of evidence-based medicine, including extensive literature review, to determine appropriateness of drug coverage for off-label uses

Medicare Part D FDA-approved drugs used for indications other than what is indicated on the official label may be covered under Medicare if the carrier determines the use to be medically accepted, taking into consideration the major drug compendia, authoritative medical literature and/or accepted standards Recent Developments in Medicare Coverage of Off-Label Cancer Therapies. J Oncol Pract January; 5(1): 18–20. Medicare Benefit Policy Manual. Chapter 15:

Approved CMS Compendiums and Resources American Hospital Formulary Service Drug Information (AHFS-DI) Truven Health Analytics Micromedex DrugDex Elsevier/Gold Standard Clinical Pharmacology National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium Medicare Benefit Policy Manual. Chapter 15:

Compendium Criteria In general, a use is identified by a compendium as medically accepted if the: indication is a Category 1 or 2A in NCCN, or Class I, Class IIa,or Class IIb in DrugDex; or, narrative text in AHFS-DI or Clinical Pharmacology is supportive. A use is not medically accepted by a compendium if the: indication is a Category 3 in NCCN or a ClassIII in DrugDex; or, narrative text in AHFS or Clinical Pharmacology is “not supportive.” Medicare Benefit Policy Manual Ch

Peer-Reviewed Medical Literature Peer-reviewed medical literature may appear in scientific, medical, and pharmaceutical publications in which original manuscripts are published, only after having been critically reviewed for scientific accuracy, validity, and reliability by unbiased, independent experts prior to publication. In-house publications of entities whose business relates to the manufacture, sale, or distribution of pharmaceutical products are excluded from consideration. Abstracts (including meeting abstracts) are excluded from consideration. Medicare Benefit Policy Manual Ch C

Biologics and Chemotherapeutic Regimen Summary FDA-approved drugs and biologics may also be considered for use in the determination of medically accepted indications for off-label use if determined by the Medicare contractor to be reasonable and necessary. If a use is identified as not indicated by the Centers for Medicare and Medicaid Services (CMS) or the FDA, or if a use is specifically identified as not indicated in one or more of the compendia listed, or if the contractor determines, based on peer-reviewed medical literature, that a particular use of a drug is not safe and effective, the off-label usage is not supported and, therefore, the drug is not covered. Medicare Benefit Policy Manual Ch D

Summary Off-label use refers to the use of a drug product for indications not stated in the FDA- approved labeling Off-label use is common practice and may be appropriate in many cases (Pediatrics and Oncology) Extensive review of off-label uses, including clinical trials, is necessary to determine appropriateness of drug coverage

Ustekinumab (Stelara) 2009: Ustekinumab (Stelara) is FDA-approved for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy 2013: Ustekinumab (Stelara) is FDA-approved for the treatment of adult patients with active psoriatic arthritis 2015: Ustekinumab (Stelara) is considered investigational in Crohn’s disease – Phase III data (UNITI-2) showed treatment induced clinical response and clinical remission in patients with moderate to severe Crohn’s disease who had previously failed conventional therapy Phase 3 data show Stelara induced clinical response and remission in the treatment of patients with moderate to severe Crohn’s disease [press release on the Internet]. Honolulu (HI): Janssen Oct 19 [cited Dec ]. Available from: 3-data-show-stelara-induced-clinical-response-and-remission-treatment-patients-moderate-severe.

Example: Ustekinumab (Stelara) Request A request for Stelara was received for a 50 year old female with moderate to severe Crohn’s disease. The patient had failed trials with steroids and immunosuppressive therapy and had an adverse reaction (rash) to adalimumab (Humira). – Is this request considered “off-label”? – Would you approve or deny the request?

Thank you to AMCP member Tasmina Hydery for updating this presentation for 2016.