Off-label Use and Reimbursement 5/4/21

When the Food and Drug Administration (FDA) approves a drug for sale in the United States, the approval includes a section entitled “Indications for Use.” This section lists the one or more diseases, conditions, or symptoms for which the drug’s sponsor (usually the manufacturer) has provided, to FDA’s satisfaction, evidence in support of the drug’s safety and effectiveness. Prescribing for these parameters is considered “on-label” or “labelled” uses.

The FDA traditionally has not regulated the practice of medicine and therefore physicians may prescribe an FDA-approved drug for indications not listed in the official FDA-approved labels. This is considered as “off-label” or “unlabeled” use. Credible researchers have estimated that off-label use makes up as little as 12% or as much as 38% of office prescriptions, and up to 50% for anti-cancer drugs.

When and how are off-label uses reimbursed by Medicare for Parts A and B?

If Medicare has issued a National Coverage Determination (NCD), Local Coverage Determination (LCD), or other Medicare instruction, providers must follow the guidance to determine coverage. For example, NCD 110.24- National Coverage Determination (NCD) for Chimeric Antigen Receptor (CAR) T-cell Therapy indicates that coverage is for “FDA-approved indication, or for other uses when the product has been FDA-approved and the use is supported in one or more CMS-approved compendia.”

What are the CMS-approved compendia for cancer drugs?

CMS has established five drug compendia as authoritative sources on drug benefit category for cancer drugs. The approved compendia are as follows in no particular order.

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

• National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium

• Micromedex DrugDex

• Clinical Pharmacology

• Lexi-Drugs

What about coverage for non-cancer drugs?

CMS has addressed anti-cancer drugs in their internet-only manuals, but the MACs have provided direction for all drugs. This excerpt is from Noridian: Determination of approved and accepted off-label  drug indications:

For all drugs, including anti-cancer drugs, and in the absence of any statutory, CMS, or MAC exclusion of any drug or specific drug indication, Medicare recognizes an indication to be medically accepted if the indication is both:

• FDA-approved for the drug at the FDA published dose and frequency; or

• Listed in one or more of the approved compendia with an appropriate level of evidence of efficacy (see below); or

• Recognized, following Medicare’s review of the peer reviewed literature, as an appropriate treatment: (The requestor is expected to provide significant peer reviewed full articles to the Contractor for review)

AND

• The use is not listed as unsupported, not indicated, not recommended (or equivalent terms) in any of the compendia. Any such listing precludes reimbursement for the drug.

“Medically accepted” definitions by compendium:

1. NCCN: The level of evidence for the indication is Category 1 or 2A. (If a provider chooses to use NCCN level 2B in support of a chemotherapeutic drug used for an off-label indication, the MAC expects that the provider will make available to the MAC significant peer reviewed phase II or phase III studies demonstrating such support.)

2. DrugDex: The level of evidence for the indication is a Class I, Class IIa, or Class IIb.

3. AHFS-DI or Clinical Pharmacology: The narrative text is supportive.

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

Not “medically accepted” by a compendium:

1. NCCN: The level of evidence for the indication is Category 3 in NCCN.

2. DrugDex: The level of evidence for the indication is Class III in DrugDex.

3. AHFS-DI or Clinical Pharmacology: The narrative text is “not supportive” (or equivalent term).

4. Lexi-Drugs: Indication is listed as “Use: Unsupported.”

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

Why is my claim for a drug denied as “non-covered”?

As clinical practice is constantly evolving, MACs use a variety of sources to keep their internal lists updated of off-label drug coverage criteria including FDA updates to drug labeling, updated compendia, critically reviewed medical literature and input from local medical societies, consensus expert medical opinion and consultation with internal medical staff. However, a claim may be submitted for an indication that has not yet been considered by the MAC. This claim can be appealed with the appropriate documentation.

When to Appeal?

Claims denied for non-coverage for off-label use should be appealed

• when the indication is listed in the FDA labeling and the documentation supports medical necessity in this patient, or

• when the indication is listed as covered in an NCD or LCD, or

• when the indication is listed in the CMS-recognized compendia and evidence level supports that the use is medically accepted, or

• when the indication is supported by a significant number of peer-reviewed full articles.

In all appeals, related portions of the medical record should be provided that document medical necessity of the drug for the patient as well as the evidence supporting the off-label use as indicated above. If submitting journal articles, the full article should be submitted (not just the summary or conclusions).

SHOUT-OUTS!

1. Claims denied as non-covered for an off-label use should be reviewed for potential appeal when the indication is listed in the FDA labeling, NCD, LCD, or CMS-recognized compendia as medically acceptable.

2. If necessary, Pharmacy or Physicians should provide a significant number of peer-reviewed full articles to support the off-label use.

3. When appropriate, an LCD reconsideration request should be submitted to the MAC to request an off-label use review so that the related diagnosis codes can be included in future LCD updates and edits.