Off-Label Use of Drugs and Biologic Agents

Number 5.01.01

Effective Date December 19, 2012

Revision Date(s) 12/11/12; 10/11/11; 08/11/09; 08/14/07; 02/10/04; 11/12/02; 10/05/99; 04/14/98; 01/97

Replaces N/A


Medically Necessary

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

  • American Hospital Formulary Service- Drug Information (AHFS-DI);
  • National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium;
  • Thompson Micromedex DrugDex Compendium (DrugDex); or
  • Elsevier Gold Standard’s Clinical Pharmacology Compendium (Clinical Pharmacology).


The scientific evidence indicates the drug 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 positive health outcomes and demonstrate that the drug or biologic is as effective or is more effective than established treatment alternatives.
  • Document that the improvements are achievable outside of the research setting.

Experimental /Investigational

Services that are considered experimental/investigational are not covered because the safety and/or efficacy of the drug or biologic agent cannot be established after reviewing the published scientific literature. Prescription drugs and biologic agents are considered investigational or experimental in the following situations:

  • The drug or biologic has not received FDA approval for any indication.
  • The FDA determined a drug or biologic to be contraindicated for a specific condition or off-label usage.

Note: Please see Related Policies for medical policies which separately address individual drugs and may override this policy.

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



The term off-label applies to any use of a medication or biologic agent in a manner not specifically approved by the US Food and Drug Administration (FDA) and delineated in the label given the agent during the approval process. Unapproved or unlabeled uses of drugs include a variety of situations ranging from completely unstudied to thoroughly investigated drug uses where the FDA has not been asked for approval, whereas approved uses of drugs have been proven to be safe and effective by the FDA after the review of adequate and controlled clinical trials. Many off-label uses are effective, well documented in the literature, and widely used.

A compendium is defined as a comprehensive listing of FDA approved drugs and biological that includes a summary of pharmacologic characteristics, dosing information, and recommended or endorsed uses in specific diseases, listed by drug name. In 2008 CMS developed an annual review process (including criteria for transparency in the selection process) to recognize compendia. In addition, 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);
  • National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium;
  • Thompson Micromedex DrugDex Compendium (DrugDex); and
  • Elsivier Gold Standard’s Clinical Pharmacology Compendium (Clinical Phramacology).


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.

Benefit Application

Contracts may address off-label drug usage and reference various compendia. With the passage of time, compendia have merged, changed names or ceased to exist. The Company uses compendia endorsed by the Secretary of HHS and CMS to support coverage decisions when the contractually referenced compendia are no longer in business.

A product or group contract may exclude coverage of a medication or a class of medications, which would supersede any medical necessity determinations or off-label review based on Medical Policy.

This policy adheres to the laws set forth in Washington state, WAC 284-30-150 – Insurance Policies and Contracts, Coverage for Drugs.

The use of any off-label or unapproved drugs dispensed within an approved clinical trial will be covered if the member contract allows for coverage of clinical trials or if the criteria are met as set forth in policy 11.01.503 – Clinical Trials. (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 nonuniform NCCN consensus (but no major disagreement).
  • Category 3: The recommendation is based on any level of evidence but reflects major disagreement.

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


  1. Issue Paper: Categories of Drugs Eligible for coverage, 1989
  2. Blue Cross Blue Shield Association (BCBSA). Medical Policy Reference Manual, Policy 5.01.01 Off-label Drug Use. 2003.
  3. Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Criteria 2-5.
  4. National Comprehensive Cancer Network (NCCN). The NCCN Drugs and Biologics Compendium. NCCN Compendiam. Last accessed November 5, 2012.
  5. Centers for Medicare & Medicaid Services (CMS). Medicare Benefit Policy Manual – Chapter 15: Covered Medical and Other Health Services. Issued October 24, 2008; last updated July 8, 2011. Last accessed November 5, 2012.
  6. Noridian Administrative Services (NAS). Medicare Part B News. Issue # 251, January 21, 2009. Available online at: Last accessed November 5, 2012.
  7. Washington State Legislature. WAC 284-30-450 Insurance Policies and Contracts – Coverage for Drugs. Effective September 30, 1994. Last accessed November 5, 2012.







ICD-9 Procedure


ICD-9 Diagnosis




Type of Service

Prescription Drug


Place of Service

Physician's Office








Add to Prescription Drug Section - New Policy


Replace policy - Add Appendix of Individual Drugs


Aged Policy Review - No Changes


Replace policy - Policy reviewed without literature review; new review date only. Deleted Appendix.


Replace policy - Policy reviewed without literature review; new review date only.


Update Scope and Disclaimer - No other changes.


Replace policy - Policy updated with literature review; references added. No change in policy statement. Policy status changed from AR to BC.


Cross Reference Update - No other changes.


Replace policy - Policy updated with literature search. Policy statement amended to include professional society recommendations and other compendium sources as recognized by CMS. References added.


Cross Reference Update - No other changes.


Replace policy – Policy updated with NCCN Compendium information on oncology drugs and clinical trials; Benefit Application updated to cite limitations of coverage for clinical trials and contractual limitations of off-label drug usage based upon various compendia. Title changed to include “Biological Agents”. Description, Policy and Policy Guidelines sections rewritten and reorganized. Reference to WAC added to Rationale section; references added.


Replace policy. No changes to policy. Update titles of Related Policies 2.03.502, 5.01.517, and 2.03.503 has been renumbered to 11.01.503.


Update Related Policies. Add 5.01.546.

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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