Off-Label Use of Drugs and Biologic Agents

Number 5.01.549

Effective Date November 20, 2014

Revision Date(s) 11/10/14; 11/11/13

Replaces 5.01.01


Medically Necessary

Off- label use of a drug or biologic agent may be considered medically necessary if the indication for the use is supported by at least one of the following compendia:

  • American Hospital Formulary Service - Drug Information (AHFS-DI)
  • Elsevier Gold Standard Clinical Pharmacology Compendium (Clinical Pharmacology)
  • National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN)
  • Truven Micromedex [formerly known as Thompson Micromedex DrugDex® Compendium] (Micromedex)


The scientific evidence indicates the drug/biologic agent is effective for the off-label indication. The evidence must:

  • Consist of an adequate number of well-designed studies with sufficient numbers of participants (related to incidence of the disease).
  • Be published in major peer-reviewed scientific journals that publish original manuscripts only after they have been critically reviewed by independent unbiased experts for accuracy, validity and reliability.
  • Show consistent results across all studies.
  • Document a positive health outcome and demonstrate that the drug/biologic agent is as effective or is more effective than established treatment alternatives.
  • Document that the improvements are achievable outside of the research setting.

Experimental /Investigational

Prescription drugs and biologic agents are considered investigational or experimental in the following situations:

  • The drug or biologic has not received approval for any indication from the U.S. Food and Drug Administration (FDA).
  • The FDA determined a drug or biologic to be contraindicated for a specific condition or off-label use.

Drugs or biologic agents that are considered experimental/investigational are not covered because the safety and/or efficacy cannot be established after reviewing the published scientific literature.

Note: Medical policies that address individual drugs/biologic agents may override this policy. (See Related Policies)

Related Policies


Monoclonal Antibodies for the Treatment of B-Cell Malignancies


Use of Vascular Endothelial Growth Factor Receptor (VEGF) Inhibitors and Other Angiogenesis Inhibitors in Oncology Patients


Medical Necessity Criteria for Compounded Medications


Epidermal Growth Factor Receptor (EGFR) Inhibitors


Clinical Trials

Policy Guidelines

Definition of Terms

Compendium - A comprehensive listing of FDA approved drugs and biologic agents that includes:

  • The name of the drug or biologic agent
  • Summary of the pharmacologic characteristics
  • Dosing information
  • Recommended or endorsed uses in specific diseases

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).

Off-label - Use of a drug or biologic agent for indications or conditions other than those specifically approved by the U.S. Food and Drug Administration (FDA). The FDA approved use for drugs/biologic agents are stated in the package insert and available on the FDA website: Last accessed October, 2014.


Approved indications or the labeled indications for drugs/biologic agents have been proven to be safe and effective by the FDA after the review of adequate and controlled clinical trials. Unapproved or unlabeled uses of drugs include a variety of situations ranging from completely unstudied to thoroughly investigated uses of the drug/biologic agent, yet approval from the FDA has not been requested. Many off-label uses are effective, well documented in the literature, and widely used.


Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application

Health plan contracts may address off-label use of drugs/biologic agents and refer to various compendia. Over time, compendia merge, change names or cease to exist. The clinical review team uses compendia endorsed by the Secretary of HHS and CMS to support coverage decisions when the compendia referenced in individual health plans are no longer in business.

A product or group’s health plan contract may exclude coverage of a medication or a class of medications, such exclusion would override any review for a medical necessity determination or off-label use of drugs/biologic agents, addressed in a Medical Policy.


This policy adheres to the laws set forth in the Alaska state statutes AS 21.07.020 Required contract provisions for health care insurance policy. Accessed October, 2014.


This policy adheres to the laws set forth in the Oregon state revised statutes, Health insurance: Required reimbursements. Accessed October, 2014.


This policy adheres to the laws set forth in the Washington state administrative code, WAC 284-30-450, Insurance Policies and Contracts Coverage for Drugs. Accessed October, 2014.

The off-label or unapproved use of any drugs/biologic agents dispensed within an approved clinical trial may be covered if the member contract allows for coverage of clinical trials or if the criteria are met as set forth in the Clinical Trials policy. (See Related Policies.)


National Comprehensive Cancer Network Compendium

The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium is based directly on the NCCN Clinical Practice Guidelines in Oncology. The compendium lists specific panel recommendations for off-label uses of drugs, and each recommendation is supported by a level of evidence category.

The NCCN Categories of Evidence and Consensus used in the recommendations are:

  • Category 1: The recommendation is based on high level evidence (e.g. randomized controlled trials) and there is uniform NCCN consensus.
  • Category 2A: The recommendation is based on lower level evidence and there is uniform NCCN consensus.
  • Category 2B: The recommendation is based on lower level evidence and there is non-uniform NCCN consensus (but no major disagreement).
  • Category 3: The recommendation is based on any level of evidence but reflects major disagreement.

The accepted level of evidence for an off-label clinical indication is Category 1 or 2A; not 2B. (If a provider chooses to use NCCN level 2B evidence in support of a chemotherapeutic drug used for an off-label indication, The Company expects that the provider will make available for review, copies of significant peer-reviewed Phase II or Phase III studies demonstrating such support.)

Centers for Medicare and Medicaid Services (CMS) Compendia List

In 2008 CMS developed an annual review process (including criteria for transparency in the selection process) to recognize compendia. CMS may internally generate changes to the list at any time following investigation and public comment. The following are recognized as authoritative CMS compendia at this time:

  • American Hospital Formulary Service - Drug Information (AHFS-DI)
  • Elsevier Gold Standard Clinical Pharmacology Compendium (Clinical Pharmacology)
  • National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN)
  • Thompson Micromedex DrugDex Compendium (DrugDex) [Thomson Reuters has legally changed its name to Truven Health Analytics as of June 6, 2012 per a notice on the website]


  1. Issue Paper: Categories of Drugs Eligible for coverage, 1989
  2. Blue Cross Blue Shield Association (BCBSA) Medical Policy Reference Manual, Off-label Drug Use. Medical Policy Reference Manual, Policy 5.01.01, 2011. [Archived]
  3. Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Criteria 2-5.
  4. American Hospital Formulary Service - Drug Information (AHFS-DI). Editorial statement for Off-label Uses Overview. Last accessed October, 2014.
  5. Centers for Medicare & Medicaid Services (CMS). Medicare Benefit Policy Manual – Chapter 15: Covered Medical and Other Health Services Rev. 193, August 29, 2014. Section 50.4.5. Last accessed October, 2014.
  6. Elsevier Gold Standard Clinical Pharmacology Compendium (Clinical Pharmacology). Editorial statement for Off-Label Drug Data. Last accessed October, 2014.
  7. National Comprehensive Cancer Network (NCCN). The NCCN Drugs and Biologics Compendium. NCCN Compendium®. Last accessed October, 2014.
  8. Noridian Administrative Services (NAS). Medicare Part B News. Issue # 270, May 25, 2011. Available online at: Last accessed October, 2014.
  9. Truven Micromedex (Micromedex). Compendia transparency statement for Micromedex® DRUGDEX®. Last accessed October, 2014.





Type of Service

Prescription Drug


Place of Service

Physician's Office








New policy. Replaces BC policy 5.01.01. Coverage remains unchanged.


Annual Review. Policy reviewed. Definition of terms moved to Policy Guidelines section. In the Benefit Application section hyperlinks added to state statutes. No new references added reference 10 removed. Policy statements unchanged.


Update Related Policies. Remove 11.01.503 and replace with 10.01.518 (policy renumbered).

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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