Clinical UM Guideline
|Subject:||Off-Label Drug and Approved Orphan Drug Use|
|Guideline #:||CG-DRUG-01||Current Effective Date:||04/05/2016|
|Status:||Reviewed||Last Review Date:||02/04/2016|
The U.S. Food and Drug Administration (FDA) approves drugs for specific use(s) that are listed in the drug's product information label. Off-label or "unlabeled" drug use is the utilization of an FDA-approved drug for uses other than those listed in the FDA-approved labeling or in treatment regimens or populations that are not included in approved labeling. Many off-label uses are effective, well documented in the peer-reviewed literature and widely used.
An "orphan drug" is a product that treats a rare disease (e.g., affecting fewer than 200,000 Americans). Products have FDA orphan drug approval when they meet the orphan drug designation and marketing criteria established by the FDA.
Note: This Clinical UM Guideline applies to those injectables, biologics or specialty pharmacy drugs which fall under the medical benefit. It does not apply to those medications falling under the pharmacy benefit, which include, but are not limited to oral agents.
Off-Label Drug Use
Off-label drug use is considered medically necessary when all of the following conditions are met:
If the off-label drug use is determined to be medically necessary, its use shall also be determined to be "non-investigational" for the purposes of benefit determination.
Orphan Drug Use
Use of an orphan drug is considered medically necessary when it receives FDA Orphan Drug designation and approval for marketing ("Designated/Approved").
Not Medically Necessary:
Off-label drug use is considered not medically necessary when the above conditions are not met.
Use of an FDA designated orphan drug is considered not medically necessary when FDA has not approved the proposed orphan use for marketing.
The drug label approved by the FDA (2012):
Is the official description of a drug product which includes indication (what the drug is used for); who should take it; adverse events (side effects); instructions for uses in pregnancy, children, and other populations; and safety information for the patient. Labels are often found inside drug product packaging.
The terms "off-label drug" or "unlabeled drug" refer to the prescription and use of a drug for an indication that is not stated in the approved FDA labeling. While the off-label use of medications is common, there is some evidence that this practice may disproportionately contribute to preventable adverse drug events (ADEs). Eguale and colleagues (2016) evaluated the use of off-label prescription drugs and related ADEs in 46,021 individuals. The overall incidence of ADEs for all drugs was 13.2 per 10000 person-months; however, the ADE rate for on-label use was 12.5 per 10000 person-months versus the off-label use of 19.7 per 10000 person-months (44% increase in the risk for ADEs in off-label use). Notably, when off-label use was stratified to use with and without strong scientific evidence, the incidence of ADE reported 13.2 and 21.7 per 10000 person-months respectively. This study underscores the value of utilizing recognized evidentiary-based tools, such as compendia, in evaluating off-label drug use. The following compendia are used to determine the effectiveness, safety and toxicity of drugs when used in off-label indications.
American Hospital Formulary Service Drug Information (AHFS, Bethesda, MD) uses the "dagger" symbol to indicate off-label drug use. If the AHFS indicates an off-label use, but qualifies that statement with "but additional study is needed" or "further study is needed to evaluate safety and efficacy", the qualifying language does not support an off-label indication as medically necessary.
DrugDex® (Truven Health Analytics, Greenwood Village, CO) includes DrugPoints, a summary document of DrugDex. Therapeutic drug indications in the two products may vary. DrugDex is the comprehensive product which includes all FDA approved indications and all off-label indications. DrugPoints includes limited information in a summary format. For purposes of this clinical UM guideline, indications listed in DrugPoints is determined to be medically necessary when the Strength of Recommendation is Class I or IIa and Strength of Evidence is Category A or B and Efficacy is Class I or IIa. See Attachment A for Recommendation, Evidence And Efficacy Ratings from DrugDex.
The National Comprehensive Cancer Network (NCCN) Drug & Biologics Compendium is a listing of appropriate uses of agents as defined in and derived from the NCCN Clinical Guidelines in Oncology®. The compendium lists both FDA-approved uses and NCCN designated off-label indications. According to the NCCN, the identified off-label indications are based upon evaluation of evidence from scientific literature integrated with expert judgment in an evidence-based process. Indications are categorized in a systematic approach that describes the type of evidence available for and the degree of consensus underlying each recommendation. For purposes of this clinical UM guideline, any indication listed in the NCCN Drug & Biologics Compendium with a Category of Evidence and Consensus 1 or 2A is considered an off-label indication and is determined to be medically necessary. See Attachment B for NCCN Categories of Evidence and Consensus.
The Company takes into account credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community. "Peer-reviewed medical literature" does not include publications or supplements to publications that are sponsored to a significant extent by a pharmaceutical manufacturing company or health carrier.
The intent of the Orphan Drug Act (ODA) is to stimulate the research, development, and approval of products that treat rare diseases. The ODA provides special status to a product to treat a rare disease or condition upon request of a sponsor. Orphan drug designation qualifies the sponsor of the product for the tax credit and marketing incentives of the ODA. Orphan designation can be obtained prior to the submission of a marketing application. The safety and efficacy of the drug must be established through clinical studies. If the designated product meets the standard FDA regulatory requirements and process for obtaining marketing approval, it is given an FDA approved orphan drug designation status (i.e., "Designated/Approved"). The FDA (2015) notes to date, over 1700 drugs and biologics have been designated as orphan drugs and over 300 have been approved for marketing.
In order to be considered medically necessary, the orphan drug must also have orphan drug marketing approval. A product may have an orphan drug designation but fail to meet the criteria to have FDA marketing approval. Use of a product with only an orphan drug designation and without FDA marketing approval would be considered not medically necessary (FDA, 2015).
Adverse drug events: A physician initiated discontinuation of a prescription drug due to an adverse drug reaction or allergic reaction.
Biologic: A substance which is produced from a living system or a product of a living system and is comprised of large complex molecules of primarily proteins or polypeptides.
Drug: A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease; a substance (other than food) intended to affect the structure or any function of the body; biological products are included within this definition and are generally covered by the same laws and regulations, but differences exist regarding their manufacturing processes (chemical process versus biological process).
Government Agency, Medical Society, and Other Authoritative Publications:
Drugs, Unlabeled Use
Drug Use, Off-Label
Prescription Drugs, Unlabeled Use of
Unlabeled Use of Drugs
|Reviewed||02/04/2016||Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Discussion, Definitions, References Sections and Attachments.|
|Reviewed||02/05/2015||MPTAC review. Updated References.|
|Revised||02/13/2014||MPTAC review. Updated name for DrugPoints. Updated Discussion and References Sections and Attachments.|
|Reviewed||11/13/2013||Hematology/Oncology Subcommittee review. Updated References Section.|
|Revised||11/08/2012||MPTAC review. Updated name for DrugPoints. Added Definition section. Updated Discussion/General Information and References sections.|
|Revised||11/17/2011||MPTAC review. Clarified orphan drug criteria by adding "for marketing" to medically necessary and not medically necessary sections. Updated References.|
|Revised||02/25/2010||MPTAC review. Updated orphan drug language to be consistent with the FDA wording. Addition of not medically necessary statements.|
|Revised||11/19/2008||Hematology/Oncology Subcommittee review. Expansion of the NCCN Drugs & Biologics Compendia™ to Category 2A; Limited DrugPoints® to Strength of Recommendation Class I or IIa and Strength of Evidence Category A or B and Efficacy Class I or IIa.|
|Revised||07/25/2008||MPTAC review. Addition of the NCCN Drugs & Biologics Compendia™.|
|Revised||11/29/2007||MPTAC review. Replaced USP DI® with DrugPoints®.|
|Revised||05/17/2007||MPTAC review. Clarification of Off-Label criteria. Addition of Orphan Drug Approval. Updated title.|
|Revised||12/07/2006||MPTAC review. References updated. Addition of language to indicate this document pertains to those injectables, biologics or specialty pharmacy drugs which fall under the medical benefit. Reorganization of medically necessary section without change to guideline position.|
|Reviewed||03/23/2006||MPTAC review. References updated.|
|Revised||04/28/2005||MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.|
Last Review Date
|Drug Coverage Guidelines|
|Anthem MWMR UM Criteria|
|MA-035||Off-Label Prescription Drug Use|
|WellPoint Health Networks, Inc.|
|8.01.01||Off-Label Drug Use|
RECOMMENDATION, EVIDENCE AND EFFICACY RATINGS
The Truven Health Analytics Efficacy, Strength of Evidence and Strength of Recommendation definitions are outlined below:
|Table 1. Strength Of Recommendation|
|Class I||Recommended||The given test or treatment has been proven to be useful, and should be performed or administered.|
|Class IIa||Recommended, In Most Cases||The given test, or treatment is generally considered to be useful, and is indicated in most cases.|
|Class IIb||Recommended, In Some Cases||The given test, or treatment may be useful, and is indicated in some, but not most, cases.|
|Class III||Not Recommended||The given test, or treatment is not useful, and should be avoided.|
|Class Indeterminant||Evidence Inconclusive|
|Table 2. Strength Of Evidence|
|Category A||Category A evidence is based on data derived from: Meta-analyses of randomized controlled trials with homogeneity with regard to the directions and degrees of results between individual studies. Multiple, well-done randomized clinical trials involving large numbers of patients.|
|Category B||Category B evidence is based on data derived from: Meta-analyses of randomized controlled trials with conflicting conclusions with regard to the directions and degrees of results between individual studies. Randomized controlled trials that involved small numbers of patients or had significant methodological flaws (e.g., bias, drop-out rate, flawed analysis, etc.). Nonrandomized studies (e.g., cohort studies, case-control studies, observational studies).|
|Category C||Category C evidence is based on data derived from: Expert opinion or consensus, case reports or case series.|
|Table 3. Efficacy|
|Class I||Effective||Evidence and/or expert opinion suggests that a given drug treatment for a specific indication is effective|
|Class IIa||Evidence Favors Efficacy||Evidence and/or expert opinion is conflicting as to whether a given drug treatment for a specific indication is effective, but the weight of evidence and/or expert opinion favors efficacy.|
|Class IIb||Evidence is Inconclusive||Evidence and/or expert opinion is conflicting as to whether a given drug treatment for a specific indication is effective, but the weight of evidence and/or expert opinion argues against efficacy.|
|Class III||Ineffective||Evidence and/or expert opinion suggests that a given drug treatment for a specific indication is ineffective.|
© 2016 Truven Health Analytics, Inc. All rights reserved.
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
© National Comprehensive Cancer Network, Inc. 2015