**Abstract:**  
  
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.

**Indications:**  
  
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:

  1. A use supported by clinical research that appears in at least two Phase III clinical trials that definitively demonstrate safety and effectiveness; or,
  2. 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.
  3. 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:

  * Behcet's Disease (BD), also known as Behcet's 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