The U.S. Food and Drug Administration (FDA) approves drugs for specific indications included 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 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. 

• Please check appropriate state mandates for laws that will supersede this document when applicable, such as those governing off-label use of prescription drugs.
• Any corporate medical policy or clinical UM guideline on a specific drug takes precedence over this guideline. 
• Remember to verify benefits and look for benefit exclusions. Excluded products or treatments are not covered under this document (e.g., agents for impotency or weight loss).
• This document shall not be construed to require coverage for any drug when the FDA has determined its use to be contraindicated.
• The document shall not be construed to require coverage for any drug when the benefit plan excludes drug coverage.
• The document shall not be construed to require coverage for any drug when the benefit plan includes drug benefit limitations based on a formulary and the off-label drug is not part of the formulary.

Medically Necessary:

Off-Label Drug Use

Off-label drug use is considered medically necessary when all of the following conditions are met:

1. The drug is approved by the U.S. Food and Drug Administration (FDA).
   AND
2. The drug is being prescribed to treat a medical condition not listed in the product label and for which medical treatment is medically necessary.
   AND
3. The prescribed drug use is supported in any one or more of the following:
   • American Hospital Formulary Service Drug Information^® (AHFS^®); or
   • Thomson Healthcare Inc. DrugPoints^® meeting each of the following:
     • Strength of Recommendation Class I or IIa; and
     • Strength of Evidence Category A or B; and
     • Efficacy Class I or IIa ;or
   • National Comprehensive Cancer Network (NCCN) Drug & Biologics Compendium ™ Category of Evidence and Consensus 1 or 2A; or
   • Two articles from major scientific or medical peer-reviewed journals (excluding case reports, letters, posters, and abstracts), or published studies having validated and uncontested data, which support the proposed use for the specific medical condition as safe and effective.
     • Examples of accepted journals include, but are not limited to, Journal of American Medical Association, New England Journal of Medicine, and Lancet.
     • Accepted study designs include, but are not limited to, randomized, double blind, placebo controlled clinical trials.

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 terminology "off-label drug" or "unlabeled drug" refers to the prescription and use of a drug for an indication other than those stated in the approved FDA labeling. A drug identified with "daggers" in the American Hospital Formulary Service Drug Information^® (AHFS^®) indicates off-label use. If the AHFS indicates a condition or disease as an off-label indication, 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.

Historically, a tool called the U.S. Pharmacopeia Dispensing Information^® (USP DI) was widely viewed as a reference source comparable to the AHFS. The USP DI is no longer available. In July 2007, Thomson Healthcare made DrugDex^® available to the market, which is a compendium of drug information including information to assist in determining off-label uses of drugs. Thomson also introduced DrugPoints^® to the market. DrugPoints is the summary document for the Thomson product called DrugDex. 

Indications in the two Thomson Micromedex products vary. The comprehensive product, DrugDex, includes all FDA indications and off label indications regardless of ratings. DrugPoints includes only those indications that meet the following rating criteria:

1. All FDA-approved indications regardless of rating
2. Indications with a Strength of Recommendation rating of Recommended
   (Class I)
3. Indications meeting the following criteria and containing these ratings:
   1. Efficacy rating of Effective or Evidence Favors Efficacy and Strength of Recommendation rating of Recommended in Most (Class IIa)
   2. Efficacy rating of Effective or Evidence Favor Efficacy and Strength of Recommendation rating of Recommended in Some (Class IIb) if Strength of Evidence is A or B.

See Attachment A for RECOMMENDATION, EVIDENCE AND EFFICACY RATINGS from DrugDex.

For purposes of this clinical UM guideline, any indication listed in DrugPoints as a Strength of Recommendation Class I or IIa and Strength of Evidence Category A or B and Efficacy Class I or IIa  is considered an off-label indication and is determined to be medically necessary.

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™. According to the NCCN, the uses identified 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. See Attachment B.  The Compendium lists both FDA-approved uses and appropriate off-label uses.

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.

"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 (FDA, 2009). 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") (FDA, 2009). The FDA (2009) notes to date, over 2100 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 an orphan drug designation alone without FDA marketing approval would be considered not medically necessary (U.S. FDA, 2009).

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2011^®_.  Bethesda, MD: American Society of Health-System Pharmacists^®_; 2011.
2. U.S. Food and Drug Administration (FDA). Developing Orphan Products: FDA and Rare Disease Day. Last updated February 27, 2009. Available at: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm107293.htm. Accessed on September 2, 2011.
3. U.S. Food and Drug Administration (FDA). Orphan Product Designations and Approval Search. Available at: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm. Accessed on August 2, 2011.
4. DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on September 2, 2011.
5. National Comprehensive Cancer Network^®_.  NCCN Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 2, 2011.

Drugs, Unlabeled Use
Drug Use, Off-Label
Off-Label Drugs
Orphan Drug
Prescription Drugs, Unlabeled Use of
Unlabeled Use of Drugs

RESPONSE

The Thomson Efficacy, Strength of Evidence and Strength of Recommendation definitions are outlined below:

© 1974-2006 Thomson MICROMEDEX. All rights reserved.

Attachment B

NCCN Categories of Evidence and Consensus

When studying the recommendations on a pathway, the NCCN Guideline user should be given information about how the recommendation was derived. In order to provide this critical information, the NCCN Guidelines Steering Committee has devised a set of Categories of Evidence and Consensus. These annotations contain two dimensions: the strength of the evidence behind the recommendation and the degree of consensus about its inclusion.

Category 1: The recommendation is based on high-level evidence (i.e., high-powered randomized clinical trials or meta-analyses), and the NCCN Guidelines Panel has reached uniform consensus that the recommendation is indicated. In this context, uniform means near unanimous positive support with some possible neutral positions.

Category 2A: The recommendation is based on lower level evidence, but despite the absence of higher level studies, there is uniform consensus that the recommendation is appropriate. Lower level evidence is interpreted broadly, and runs the gamut from phase II to large cohort studies (Cook, 1992) to case series to individual practitioner experience. Importantly, in many instances, the retrospective studies are derived from clinical experience of treating large numbers of patients at a member institution, so NCCN Guidelines Panel Members have first-hand knowledge of the data. Inevitably, some recommendations must address clinical situations for which limited or no data exist. In these instances the congruence of experience-based judgments provides an informed if not confirmed direction for optimizing patient care. These recommendations carry the implicit recognition that they may be superseded as higher level evidence becomes available or as outcomes-based information becomes more prevalent (Baillard, 1993).

Category 2B: The recommendation is based on lower level evidence, and there is nonuniform consensus that the recommendation should be made. In these instances, because the evidence is not conclusive, institutions take different approaches to the management of a particular clinical scenario. This nonuniform consensus does not represent a major disagreement, rather it recognizes that given imperfect information, institutions may adopt different approaches. A Category 2B designation should signal to the user that more than one approach can be inferred from the existing data.

Category 3: Including the recommendation has engendered a major disagreement among the NCCN Guidelines Panel Members. The level of evidence is not pertinent in this category, because experts can disagree about the significance of high level trials (McNeill, 2001). Several circumstances can cause major disagreements. For example, if substantial data exist about two interventions but they have never been directly compared in a randomized trial, adherents to one set of data may not accept the interpretation of the other side's results. Another situation resulting in a Category 3 designation is when experts disagree about how trial data can be generalized. An example of this is the recommendation for internal mammary node radiation in postmastectomy radiation therapy. One side believed that because the randomized studies included this modality (Woolf, 1997), it must be included in the recommendation. The other side believed, based on the documented additional morbidity and the role of internal mammary radiation therapy in other studies, that this was not necessary. A Category 3 designation alerts users to a major interpretation issue in the data and directs them to the manuscript for an explanation of the controversy.

© National Comprehensive Cancer Network, Inc. 2010