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The rules say that plans must pay for a medical service or item if regular Medicare would pay for it in this case. 
You can find this rule at 42 Code of Federal Regulations (CFR) Section 422.101. 
 
The rules state that An off-label/unlabeled use of a drug is defined as a use for a non-FDA approved indication, 
that is, one that is not listed on the drug's official label/prescribing information. An indication is defined as a 
diagnosis, illness, injury, syndrome, condition, or other clinical parameter for which a drug may be given. Off-
label use is further defined as giving the drug in a way that deviates significantly from the labeled prescribing 
information for a particular indication. This includes but is not necessarily limited to, dosage, route of 
administration, duration and frequency of administration, and population to whom the drug would be 
administered. Drugs used for indications other than those in the approved labeling may be covered under 
Medicare if it is determined that the use is medically accepted, taking into consideration the major drug 
compendia, authoritative medical literatures and/or accepted standards of medical practice. Determinations as 
to whether medication is reasonable and necessary for an individual patient are made on appeal on the same 
basis as all other such determinations (i.e., with support from the peer-reviewed literature, with the advice of 
medical consultants, with reference to accepted standards of medical practice, and in consideration of the 
medical circumstance of the individual case). 
 
In the case of drugs used in an anti-cancer chemotherapeutic regimen, off-label uses are covered for a 
medically accepted indication as defined in the Medicare Benefit Policy Manual (CMS publication 100-2, 
Chapter 15, Section 50.4.5). 
 
In order to meet the requirement that the use of the drug is reasonable and necessary for the treatment of 
disease, the drugs must be safe and effective. Drugs approved for marketing by the Food and Drug 
Administration (FDA) are considered safe and effective when used for indications specified on the labeling. 
Therefore, Medicare pays for the use of a FDA-approved drug, if: 
 It was injected on or after the date of the FDA's approval; 
 It is reasonable and necessary for the individual patient; and 
 All other applicable coverage requirements are met. 
A medically accepted indication, which is covered by National Government Services is one of the following: 
1. An FDA approved, labeled indication or a use supported in the American Hospital Formulary Service 
Drug Information (AHFS-DI), NCCN Drugs and Biologics Compendium, Truven Health Analytics 
Micromedex DrugDex, Elsevier/Gold Standard Clinical Pharmacology and Wolters Kluwer Lexi-
Drugs as the acceptable compendia based on CMS' Change Request 6191 (Compendia as Authoritative Sources for Use in the Determination of a "Medically Accepted Indication" of Drugs and 
Biologicals Used Off-Label in an Anti-Cancer Chemotherapeutic Regimen); or 
2. Articles or Local Coverage Determinations (LCDs) published by National Government Services. 
The compendia listed above will be accepted at the following levels; 
 American Hospital Formulary Service-Drug Information (AHFS-DI)  indication is supportive 
 NCCN Drugs and Biologics Compendium - indication is a Category 1 or 2A 
 Micromedex DrugDex  indication is Class I, Class IIa, or Class IIb or 
 Clinical Pharmacology  indication is supportive 
 Lexi-Drugs - indication is rated as Evidence Level A 
When new off-label uses for drugs are published in the above compendia at the accepted level of 
recommendation, the effective date for National Government Services coverage of those off-label uses is the 
date of publication of our revised coverage article, not the date of inclusion in the compendia. 
 
In an effort to limit the number of LCD's or articles related to off label indications for drug use, National 
Government Services will publish articles relating to drugs approved for off-label use for which there is a need 
for education or concern about utilization. These articles will include drugs with links to their FDA approved 
and compendia approved uses as listed in the American Hospital Formulary Services (AHFS), Elsevier/Gold 
Standard Clinical Pharmacology, NCCN Drugs and Biologics Compendium, Truven Health Analytics 
Micromedex DrugDex compendium and/or Wolters Kluwer Lexi-Drugs. Only off-label uses requested by 
providers according to the following criteria will be considered for inclusion. 
 
Providers may request that a drug be approved for off-label use by submitting this request in writing and 
including the data supporting its use. The data must include: 
a. A use supported by clinical research that appears in at least two Phase III clinical trials that definitively 
demonstrate safety and effectiveness; or, 
b. 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 
such as use 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. 
c. A use that is an accepted standard of medical practice. "Are there published recommendations from 
specialty societies or in other authoritative evidence-based guidelines?" (For example, a state of the art 
review article published in a recognized textbook or a reputable publication) It should be noted that 
acceptance by individual health care practitioners, or even a limited group of health care practitioners 
normally does not indicate general acceptance by the medical community. Testimonials indicating such 
limited acceptance, and limited case studies distributed by sponsors with potential financial conflict of 
interest in the outcome, are not sufficient evidence of general acceptance by the medical community. 
The broad range of available evidence must be considered and its quality must be evaluated before a 
conclusion is reached. 
The Phase III or Phase II trials must come from different centers and be published in national or international 
peer-reviewed (editorial committee is comprised of physicians) journals. Peer reviewed medical literature 
includes scientific and medical publications. It does not include in-house publications of pharmaceutical 
manufacturing companies or abstracts (including meeting abstracts). 
 In principle, rankings of research design have been based on the ability of each study design category to 
minimize bias. The following is a representative list of study designs (some of which have alternative names) 
ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias: 
 Randomized controlled trials 
 Non-randomized controlled trials 
 Prospective cohort studies 
 Retrospective case control studies 
 Cross-sectional studies 
 Surveillance studies (e.g., using registries or surveys) 
 Consecutive case series and 
 Single case reports 
The design, conduct and analysis of trials are important factors as well. For example, a well designed and 
conducted observational study with a large sample size may provide stronger evidence than a poorly designed 
and conducted randomized controlled trial with a small sample size. 
 
In determining whether there is supportive clinical evidence for a particular use of a drug, the quality of the 
published evidence must be considered. Such consideration involves the assessment of the following study 
characteristics: 
 The adequacy of the number of subjects; 
 The response rate; 
 The effect on key status and survival indications. That is, the effect on the patient's well-being and other 
responses to therapy that indicate effectiveness (e.g., reduction in mortality, morbidity, signs and 
symptoms); 
 The appropriateness of the study design, that is, 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.); and 
 The prevalence and life history of the disease when evaluating the adequacy of the number of subjects 
and the response rate. 
After such evidence is received, National Government Services will, with appropriate help of specialty-specific 
consultants as indicated, make a coverage determination for the non-FDA approved indication (off-label use) of 
the drug or biological. 
 
National Government Services may determine a drug use to be reasonable and necessary for the treatment of 
illness or injury if, on the basis of available or presented evidence, if it is shown to be safe and effective and 
does not violate national or local Medicare determinations and regulations. The approval will include, but is not 
limited to, diagnosis, dose and route of administration, duration and frequency, and appropriate patient 
population. 
 
Limitations: 
 
If a use is identified as not indicated by CMS or the FDA, or if a use is specifically identified as not indicated 
in the American Hospital Formulary Services (AHFS), Elsevier/Gold Standard Clinical Pharmacology, NCCN 
Drugs and Biologics Compendium, Truven Health Analytics Micromedex DrugDex and/or Wolters Kluwer 
Lexi-Drugs compendium, the off-label use is not supported and the drug will not be covered. 
 
Regardless of the evidence supporting coverage for a particular off-label use, payment may only be made if the 
use is reasonable and necessary for the treatment of illness or injury of the specific patient receiving the drug.  
Services related to non-covered services or drugs are also not covered (e.g., administration services). 
 
Upon review, if the drug use is not on the FDA label, does not appear on the American Hospital Formulary 
Services (AHFS), Elsevier/Gold Standard Clinical Pharmacology, NCCN Drugs and Biologics Compendium, 
Truven Health Analytics Micromedex DrugDex and/or Wolters Kluwer Lexi-Drugs compendium or 
National Government Services has not published an LCD or article covering the off-label use as listed below, 
then the drug use is not approved and the use of the drug may be denied. However, determinations as to 
whether medication is reasonable and necessary for an individual patient may be made on appeal on the same 
basis as all other such determinations (i.e., with support from the peer-reviewed literature, with the advice of 
medical consultants, with reference to accepted standards of medical practice, and in consideration of the 
medical circumstance of the individual case). 
 
The route of administration must be reasonable and necessary as well as the drug. (Pub 100-02, Medicare 
Benefit Policy Manual, Chapter 15, Section 50.2 - Determining Self-Administration of Drug or Biological 
(Rev. 91; Issued: 06-20-08; Effective/Implementation Date: 07-21-08)). National Government Services will use 
evidence-based clinical guidelines to determine medical necessity of the route of administration. 
 
Specific Drugs and Biological Coverage 
 
FDA and approved Compendia Uses 
The following drugs will be covered for their FDA approved uses as well as their approved compendia uses. 
Bevacizumab and biosimilars 
Bortezomib  
Denosumab (Prolia TM, Xgeva TM) 
Hyaluronans Intra-articular Injections of 
Omalizumab  
Ranibizumab and Aflibercept  
FDA, approved Compendia and Off-label Uses  
The following drug will be covered for off label uses described below in addition to their FDA approved use 
and approved compendia uses. 
Eculizumab - NGS has approved eculizumab for biopsy proven dense deposit disease. 
Ibandronate Sodium - NGS has approved ibandronate for senile osteoporosis in male patients. 
Infliximab and biosimilars - NGS has approved infliximab for the following: 
 Behcets Disease (BD), also known as Behcets Syndrome, in patients without an adequate response to 
initial therapy, for the treatment of clinical manifestations of BD such as severe ocular involvement, 
major organ involvement, severe gastrointestinal or neurological involvement and resistant cases of 
joint or mucocutaneous involvement (i.e., painful oral and genital ulcers). 
 Pyoderma gangrenosum with coexisting inflammatory bowel disease. 
 Sarcoid refractory to treatment with steroids and other standard drug regimens. 
 Severe immune-related colitis that does not respond promptly (within 1 week) to therapy with high-
dose steroids. A single dose of infliximab is sufficient to resolve immune-related colitis in most 
patients. 
Luteinizing Hormone-Releasing Hormone (LHRH) Analogs - NGS has approved Leuprolide Acetate for the 
following: 
 Carcinoma, breast (treatment): palliative treatment of advanced breast carcinoma in premenopausal and 
perimenopausal women  Suspected endometriosis causing chronic (6 months or more) pelvic pain after an appropriate 
pretreatment evaluation (to exclude other causes) and failure of initial treatment with OCs and NSAIDs; 
not to continue beyond 3 months if there is not significant symptomatic improvement 
 Head and Neck cancers-salivary gland tumors 
Goserelin Acetate - NGS has approved Goserelin Acetate for the following: 
 Treatment of leiomyomata: 3.6 mg per month for short duration (3-6 months). 
Paclitaxel (e.g., Taxol/Abraxane TM) - NGS has approved paclitaxel for the following: 
 Hormone refractory prostate carcinoma 
 Carcinoma of the renal pelvis and ureter 
 Rhabdomyosarcoma 
 Leiomyosarcoma  
You can find this rule in the Medicare Local Coverage Determination (LCD)- L33394, Drugs and Biologicals, 
Coverage of, for Label and Off-Label Uses. 
If you want to read these Medicare rules, you can go to this website www.medicareappeal.com. 
 
The Plan contract says that the Plan covers items and services in accordance with Medicare rules.