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Off-label Coverage for Prescription Drugs and/or Biologics
08.00.15f

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

CRITERIA TO ESTABLISH MEDICAL NECESSITY FOR OFF-LABEL COVERAGE OF US FOOD AND DRUG ADMINISTRATION (FDA)--APPROVED DRUGS AND/OR BIOLOGICS

Off-label use of prescription drugs and/or biologics can include factors such as indications, dosages, frequencies, or routes of administration that are inconsistent with US Food and Drug Administration (FDA) labeling. For off-label use, additional clinical rationale is required to support coverage.

Off-label use of prescription drugs and/or biologics is considered medically necessary and, therefore, covered when the off-label use is supported by either the Company-recognized prescription drug and/or biologic compendia, or published research, as outlined below.

1. COMPENDIA FOR ONCOLOGIC USE (ANTI-CANCER CHEMOTHERAPY)

For coverage of an anti-cancer chemotherapy regimen, the off-label use is considered medically necessary and therefore covered when one of the following criteria is met:
  • The narrative text in American Hospital Formulary Service--Drug Information (AHFS-DI®) is supportive of the use.
  • The use is classified as Category 1 or 2A by National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium™.
  • The use is classified as Class I or Class IIa in Micromedex® DrugDex® Compendium.
An anti-cancer chemotherapy regimen is considered experimental/investigational even when above criteria have been met, and when one of the following exists:
  • The use is classified as Category 3 by NCCN® or Class III in Micromedex® DrugDex®.
  • The narrative text in AHFS-DI® is not supportive of the use.
  • Any of the compendia listed above state that the prescription drug and/or biologic is not indicated, is unsupported, is not recommended, or equivalent terms are used regarding the prescription drug and/or biologic
When a compendia is considered neither supportive nor non-supportive (ie, Category 2B in NCCN, Class IIb in Micromedex® DrugDex®, or an absence of narrative text or evidence classification from any Company-recognized compendium), please refer to the section in this policy entitled Published Clinical Research.

2. COMPENDIA FOR NON-ONCOLOGIC USE

For coverage of non-oncologic prescription drugs and/or biologics, the off-label use is considered medically necessary and therefore covered when one of the following exists:
  • The narrative text in American Hospital Formulary Service--Drug Information (AHFS-DI®) is supportive of the use.
  • The use is classified as Class I or Class IIa in Micromedex® DrugDex® Compendium.
Non-oncologic drugs and/or biologics are considered experimental/investigational and therefore not covered, even when the above criteria have been met, and when one of the following exists:
  • The use is classified as Class III in Micromedex® DrugDex®.
  • The narrative text in AHFS-DI® is not supportive of the use.
  • Either of the compendia listed above state that the prescription drug and/or biologic is not indicated, is unsupported, is not recommended, or equivalent terms are used regarding the prescription drug and/or biologic.
When a compendia is considered neither supportive nor non-supportive (i.e., Class IIb in Micromedex® DrugDex®, or an absence of narrative text or evidence classification from any Company-recognized compendium), please refer to the section in this policy entitled Published Clinical Research.

3. PUBLISHED CLINICAL RESEARCH

In order for an off-label use to be supported by published clinical research, all of the following criteria must be met:
  • The prescription drug and/or biologic must have been studied in at least two clinical trials conducted at different centers, and the results must have been published in national or international peer-reviewed journals with an editorial committee composed of physicians. Peer-reviewed medical literature includes scientific, medical, and pharmaceutical publications. It does not include in-house publications of pharmaceutical manufacturing companies or abstracts (including meeting abstracts).
    • A use is considered supported by clinical research when it appears in at least two Phase III clinical trials that have definitively demonstrated its safety and effectiveness as an appropriate medical treatment for the condition. If no Phase III trial evidence is available, at least two Phase II clinical trials with reasonably large patient samples showing consistent results of safety and efficacy may be considered in certain instances (e.g., in rare diseases in which a Phase III study might be difficult to complete in a reasonable period of time after completion of the Phase II studies, or when overwhelmingly good evidence of safety and effectiveness is noted in the Phase II studies).
  • Reliable evidence must demonstrate that the proposed off-label use for the specified medical condition is safe and effective and that the beneficial effects of the treatment outweigh its risks.
  • In determining whether there is supportive clinical evidence for a particular use of a prescription drug and/or biologic, the quality of the evidence in published, peer-reviewed medical literature is considered. Among other things, such consideration involves the assessment of the following:
    • The prevalence and life history of the disease when evaluating the adequacy of the number of subjects and the response rate
    • The effect on the individual's well-being and other responses to therapy that indicate effectiveness (e.g., reduction in mortality, morbidity, and signs and symptoms)
    • Whether the clinical characteristics of the beneficiary and the use are adequately represented in the published evidence
    • Whether the study is appropriate to address the clinical question, such as:
      • If the study design is appropriate to address investigative questions (e.g., in some clinical studies, it may be unnecessary or not feasible to use randomization, double-blind trials, placebos, or crossover)
      • If non-randomized clinical trials with a significant number of subjects may be a basis for supportive clinical evidence for determining accepted uses of prescription drug and/or biologic
      • Generally, case reports are considered uncontrolled, are based on anecdotal information, and do not provide adequate supportive clinical evidence for determining accepted uses of prescription drugs and/or biologics
  • The off-label use is supported by published clinical research, and the results have been published in major peer-reviewed medical journals such as, but not limited to:
  • American Journal of Medicine
  • Annals of Internal Medicine
  • Annals of Oncology
  • Annals of Surgical Oncology
  • Biology of Blood and Marrow Transplantation
  • Blood
  • Bone Marrow Transplantation
  • British Journal of Cancer
  • British Journal of Hematology
  • British Medical Journal
  • Cancer
  • Clinical Cancer Research
  • Drugs
  • European Journal of Cancer
  • Gynecologic Oncology
  • International Journal of Radiation, Oncology, Biology, and Physics
  • Journal of Clinical Oncology
  • Journal of the National Cancer Institute
  • Journal of the National Comprehensive Cancer Network (NCCN)
  • Journal of Urology
  • Lancet
  • Lancet Oncology
  • Leukemia
  • Radiation Oncology
  • The Journal of the American Medical Association
  • The New England Journal of Medicine

EXPERIMENTAL/INVESTIGATIONAL

Prescription drugs and/or biologics that are considered experimental/investigational are not covered because the safety and/or effectiveness of the prescription drug and/or biologic cannot be established by a review of the available published peer-reviewed literature. Prescription drugs and/or biologics are considered experimental/investigational for any of the following:
  • The prescription drug and/or biologic has not received US Food and Drug Administration (FDA) approval for any use.
  • The off-label use of the prescription drug and/or biologic does not meet the medical necessity criteria listed in this policy or in any other specific Company Medical Policy addressing a drug and/or biologic (i.e., the off-label use is not recognized by the appropriate compendia or published clinical research). This includes products granted orphan designation by the FDA.
  • The FDA determines a prescription drug and/or biologic to be contraindicated for specific condition(s) or specific off-label use(s).
  • The off-label use is not medically accepted or not indicated by a compendium for specific conditions (i.e., the use is a Category 3 in NCCN, Class III in Micromedex® DrugDex®, or when the narrative text in AHFS-DI® is not supportive.)
    • The absence of narrative text for an off-label use is considered neither supportive nor non-supportive.
REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the prescription drug and/or biologic.

Guidelines

While the Company does not require precertification/preapproval for all prescription drugs and/or biologics, all off-label uses are subject to retrospective review and audit.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, the prescription drug and/or biologic is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

A medication or class of medications may be a product or group contract exclusion. Individual benefits must be verified.

Description

Off-label use of prescription drugs and/or biologics can include factors such as indications, dosages, frequencies, or routes of administration that are inconsistent with US Food and Drug Administration (FDA) labeling. For off-label use, additional clinical rationale is required to support coverage.

Off-label uses are generally recognized as medically accepted indications if they are supported in either 1) one or more authoritative compendia, and none list it as not indicated, unsupported, not recommended, or equivalent terms; or 2) in peer-reviewed medical literature. Reliable evidence must demonstrate that the proposed off-label use to treat the specified medical condition is safe and effective, and that the beneficial effects of the treatment outweigh its risks.

Peer-reviewed medical literature includes 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 order for a use to be supported by clinical research, it must have been studied in at least two clinical trials conducted at different centers, and the results must have been published in national or international peer-reviewed journals with an editorial committee composed of physicians. Peer-reviewed medical literature does not include in-house publications of pharmaceutical manufacturing companies or abstracts (including meeting abstracts).

According to the National Cancer Institute, clinical trials are usually conducted in a series of steps called phases. These are outlined as follows:
    Phase 0 trials are the first step in testing a new agent in people. Phase 0 trials will evaluate how the new agent is processed in the body and how it exerts its clinical effects in the body. Phase 0 trials enroll a small number of individuals (10-15 individuals) who are administered a very small amount of the new agent.

    Phase I trials evaluate what dose is safe, how a new agent should be given (by mouth, injected into a vein, or injected into the muscle), and how often. Researchers watch closely for any harmful side effects. Phase I trials usually enroll a small number of individuals (20 or more individuals) and take place at only a few locations. The dose of the new therapy or technique is increased a little at a time. The highest dose with an acceptable level of side effects is determined to be appropriate for further testing.
    Phase II trials study the safety and effectiveness of an agent or intervention, and evaluate how it affects the human body. Phase II studies usually focus on a particular aspect of a disease, and include fewer than 100 patients.
    Phase III trials compare a new agent or intervention (or new use of a standard one) with the current standard therapy. Participants are randomly assigned to the standard group or the new group, usually by computer. This method, called randomization, helps to avoid bias and ensures that human choices or other factors do not affect the study's results. In most cases, studies move into Phase III testing only after they have shown promise in Phases I and II. Phase III trials often include large numbers of individuals across the country.
    Phase IV trials are conducted to further evaluate the long-term safety and effectiveness of a treatment. They usually take place after the treatment has been approved for standard use. Several hundred to several thousand people may take part in a Phase IV study. These studies are less common than Phase I, II, or III trials.
In the field of oncology, there are many reasons to consider a medically supported off-label use of a prescription drug and/or biologic for a cancer chemotherapy agent. Prescription drugs and/or biologics may be effective for many other cancers in addition to those that were considered in the primary labeling of the prescription drug and/or biologic, and many chemotherapeutic agents are given in combinations (regimens). Any of the prescription drugs and/or biologics in the combination may not have been approved in the initial labeling of the products. In addition, the combination of effective chemotherapeutic agents changes over time. Healthcare providers are often left with few approved treatment options if initial treatment regimens have failed.

ORPHAN DRUGS
According to the US Food and Drug Administration (FDA), an orphan drug is "a product that treats a rare disease that either affects fewer than 200,000 individuals in the United States or affects more than
200,000 individuals in the United States with no reasonable expectation that the cost of drug development will be recovered from sales of the drug in the United States." If the designated product meets the standard FDA regulatory requirements and process for obtaining marketing approval, it is given an FDA orphan drug designation status.

The Orphan Drug Act (ODA) provides for granting special status, orphan drug designation, to a product to treat a rare disease or condition upon request of a sponsor. The product to treat the rare disease or condition must meet certain criteria. Orphan designation qualifies the sponsor of the product for specific benefits from the FDA.

An orphan drug designation does not imply FDA approval or medically accepted use. FDA approval of a drug means that data on the drug’s effects have been reviewed by Center for Drug Evaluation and Research (CDER), and the drug is determined to provide benefits that outweigh its known and potential risks for the intended population. Consideration for coverage requires sufficient evidence of drug safety and efficacy established through clinical studies.

References

American Hospital Formulary Service (AHFS). Drug Information 2019. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only].
Accessed January 27, 2020.

Centers for Medicare & Medicaid Services (CMS). Agency for Healthcare Research and Quality (AHRQ) Technology Assessment Program. Technology assessment: Compendia for coverage of off-label uses of drugs and biologics in an anticancer chemotherapeutic regimen. Final report. [CMS Web site]. 05/07/07. Available at: http://www.cms.gov/medicare-coverage-database/details/technology-assessments-details.aspx?TAId=46&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=Pennsylvania&KeyWord=compendia&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAABAAAAAAAA==&. Accessed January 27, 2020.

Centers for Medicare & Medicaid Services (CMS). Medicare Benefit Policy Manual.Chapter 15: Covered medical and other health services. §50.4.5: Off-Label Use of Drugs and Biologicals in an Anti-Cancer Chemotherapeutic Regimen. Rev 212, Issued: 11/06/15, Effective: 08/12/15. Implementation 02/10/16. [CMS Web site]. Available at: https://www.cms.gov/media/125221 and
https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/bp102c15.pdf. Accessed January 27, 2020.

Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD). 110.17: NCD for anti-cancer chemotherapy for colorectal cancer. Coverage of colorectal anti-cancer drugs included in clinical trials. [CMS Web site]. 01/28/05. Available at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=291&ncdver=1&bc=BAABAAAAAAAA&. Accessed January 27, 2020.

Centers for Medicare & Medicaid Services (CMS). CMS Manual System. Pub. 100-04: Medicare Claims Processing. Transmittal 588. Coverage of colorectal anti-cancer drugs included in clinical trials. [CMS Web site]. 06/17/2005. Available at: https://www.cms.gov/Regulations-and-Guidance/Guidance/Transmittals/downloads/R588CP.pdf. Accessed January 27, 2020.

Centers for Medicare & Medicaid Services (CMS). NCA for anticancer chemotherapy for colorectal cancer (CAG-00179N). [CMS Web site]. 01/28/05. Available at: https://www.cms.gov/medicare-coverage-database/details/nca-details.aspx?NCAId=90&ver=23&NcaName=Anticancer+Chemotherapy+for+Colorectal+Cancer&bc=BEAAAAAAAAAA&Accessed January 27, 2020.

Company Benefit Contracts.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. [NCCN Web site]. Available at: https://www.nccn.org/professionals/physician_gls/default.aspx [via subscription only]. Accessed January 27, 2020.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium™.[NCCN Web site]. Available at: http://www.nccn.org/professionals/drug_compendium/content/contents.asp [via subscription only]. Accessed January 27, 2020.

Novitas Solutions, Inc. Local Coverage Article A53049. Approved Drugs and Biologicals; Includes Cancer Chemotherapeutic Agents. [Novitas Solutions, Inc. Medicare Services Web site]. Original 10/01/2015; Revised: 11/07/2019. Available at: https://www.cms.gov/medicare-coverage-database/details/article-details.aspx?articleId=53049&ver=77&name=331*1&UpdatePeriod=858&bc=AAAAEAAAAAAA&. Accessed January 27, 2020.

Truven Health Analytics. Micromedex® DrugDex® Compendium. [Internet database]. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed January 27, 2020.

US Food and Drug Administration (FDA). Regulatory Information. Federal Food, Drug, and Cosmetic Act. [FDA Web site]. 2018. Available at: https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/federalfooddrugandcosmeticactfdcact/default.htm. Accessed January 27, 2020.

US Food and Drug Administration (FDA). Relevant Excerpts. Orphan Drug Act [FDA Web site]. 2018. Available at: https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/orphan-drug-act-relevant-excerpts. Accessed January 27, 2020.

Coding

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Coding and Billing Requirements

Policy History

Revisions From 08.00.15e:
​03/22/2023
T​his policy has been reissued in accordance with the Company's annual review process.​​​
​02/23/2022
​This policy has been reissued in accordance with the Company's annual review process.​​
03/24/2021This policy has been reissued in accordance with the Company's annual review process.
​05/04/2020

​This version of the policy will become effective 05/04/2020. This policy was updated to include a definition of orphan drug designation, as well as requirements for consideration of coverage.
​06/03/2019
​This policy was updated to communicate a clarification of the components of off-label use of prescription drugs and/or biologics, such as indications, dosages, frequencies, or routes of administration.

Revisions From 08.00.15d:
09/12/2018This policy has been reissued in accordance with the Company's annual review process.

Effective 10/05/2017 this policy has been updated to the new policy template format.
5/4/2020
5/4/2020
3/22/2023
08.00.15
Medical Policy Bulletin
Commercial
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Independence Blue Cross is a subsidiary of Independence Health Group, Inc. — independent licensees of the Blue Cross and Blue Shield Association, serving the health insurance needs of Philadelphia and southeastern Pennsylvania.