CMS Pub. 100-02, ch. 15, § 50.4.5

Regimen

(Rev. 212, Issued: 11-06-15, Effective: 08-12-15, Implementation: 02-10-16)

A. Overview

Effective January 1, 1994, off-label, medically accepted indications of Food and Drug Administration-(FDA)

approved drugs and biologicals used in an anti-cancer chemotherapeutic regimen are identified under the

conditions described below. A regimen is a combination of anti-cancer agents clinically recognized for the

treatment of a specific type of cancer. Off-label, medically accepted indications are supported in either one or

more of the compendia or in peer-reviewed medical literature. The contractor may maintain its own

subscriptions to the listed compendia or peer-reviewed publications to determine the medically accepted

indication of drugs or biologicals used off-label in an anti-cancer chemotherapeutic regimen. Compendia

documentation or peer-reviewed literature supporting off-label use by the treating physician may also be

requested of the physician by the contractor.

B. Recent Revisions to the Compendia List

Do not deny coverage based solely on the absence of FDA-approved labeling for the use, if the use is supported

by any of the following compendia and the use is not listed as unsupported, not indicated, not recommended, or

equivalent terms, in any of the following compendia:

Existing - American Hospital Formulary Service-Drug Information (AHFS-DI)

Effective June 5, 2008 - National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium

Effective June 10, 2008 - Micromedex DrugDex

Effective July 2, 2008 - Clinical Pharmacology

Effective August 12, 2015 – Lexi-Drugs

The listed compendia employ various rating and recommendation systems that may not be readily cross-walked

from compendium to compendium. In general, a use is identified by a compendium as medically accepted if

the:

1. indication is a Category 1 or 2A in NCCN, or Class I, Class IIa, or Class IIb in DrugDex; or,

2. narrative text in AHFS-DI or Clinical Pharmacology is supportive, or

3. indication is listed in Lexi-Drugs as “Use: Off-Label” and rated as “Evidence Level A”

A use is not medically accepted by a compendium if the:

1. indication is a Category 3 in NCCN or a Class III in DrugDex; or,

2. narrative text in AHFS or Clinical Pharmacology is “not supportive,” or

3. indication is listed in Lexi-Drugs as “Use: Unsupported”

The complete absence of narrative text on a use is considered neither supportive nor non-supportive.

C. Use Supported by Clinical Research That Appears in Peer-Reviewed Medical Literature

Contractors may also identify off-label uses that are supported by clinical research under the conditions identified

in this section. Peer-reviewed medical literature may appear in 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-house publications of

entities whose business relates to the manufacture, sale, or distribution of pharmaceutical products are excluded

from consideration. Abstracts (including meeting abstracts) are excluded from consideration.

In determining whether an off-label use is supported, the contractors will evaluate the evidence in published,

peer-reviewed medical literature listed below. When evaluating this literature, they will consider (among other

things) the following:

• Whether the clinical characteristics of the beneficiary and the cancer are adequately represented in the

published evidence.

• Whether the administered chemotherapy regimen is adequately represented in the published evidence.

• Whether the reported study outcomes represent clinically meaningful outcomes experienced by patients.

• Whether the study is appropriate to address the clinical question. The contractor will consider:

1. whether the experimental design, in light of the drugs and conditions under investigation, is

appropriate to address the investigative question. (For example, in some clinical studies, it may be

unnecessary or not feasible to use randomization, double blind trials, placebos, or crossover.);

2. that non-randomized clinical trials with a significant number of subjects may be a basis for supportive

clinical evidence for determining accepted uses of drugs; and,

3. that case reports are generally considered uncontrolled and anecdotal information and do not provide

adequate supportive clinical evidence for determining accepted uses of drugs.

The contractor will use peer-reviewed medical literature appearing in the regular editions of the following

publications, not to include supplement editions privately funded by parties with a vested interest in the

recommendations of the authors:

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 (formerly the European Journal of Cancer and Clinical Oncology);

Gynecologic Oncology;

International Journal of Radiation, Oncology, Biology, and Physics;

The Journal of the American Medical Association;

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;

The New England Journal of Medicine; or

Radiation Oncology

D. Generally

FDA-approved drugs and biologicals may also be considered for use in the determination of medically accepted

indications for off-label use if determined by the contractor to be reasonable and necessary.

If a use is identified as not indicated by the Centers for Medicare and Medicaid Services (CMS) or the FDA, or if

a use is specifically identified as not indicated in one or more of the compendia listed, or if the contractor

determines, based on peer-reviewed medical literature, that a particular use of a drug is not safe and effective, the

off-label usage is not supported and, therefore, the drug is not covered.