Off-Label Use, No Coverage Criteria, Form

Off-label drug use is the utilization of an FDA-approved drug for uses other than those listed in the FDA-approved labeling or in treatment regimens or populations that are not included in approved labeling. FDA Approved Indication(s) Varies by drug product. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that all medical necessity determinations for off-label uses be considered on a case-by-case basis by a physician, pharmacist or ad hoc committee, using the guidance provided within this policy.
I. Initial Approval Criteria
A. Requests for Off-Label Use through Pharmacy Benefit (must meet all): *For medical benefit requests, see Section B below

1. There are no pharmacy and therapeutic committee approved off-label use criteria for the diagnosis;

   2. If a drug-specific clinical policy is available, the request is not for diagnoses or indications listed in Section III of the drug-specific clinical policy;
   3. Use is supported by one of the following (a, b, or c): a. The National Comprehensive Cancer Network (NCCN) Drug Information and Biologics Compendium level of evidence 1, 2A, or 2B (see Appendix D); b. Evidence from at least two high-quality, published studies in reputable peer- reviewed journals or evidence-based clinical practice guidelines that provide all of the following (i – iv): i. Adequate representation of the member’s clinical characteristics, age, and diagnosis;
      ii. Adequate representation of the prescribed drug regimen;
      iii. Clinically meaningful outcomes as a result of the drug therapy in question; iv. Appropriate experimental design and method to address research questions (see Appendix F for additional information); c. Micromedex DrugDex® with strength of recommendation Class I or IIa (see Appendix D); Page 1 of 9

   CLINICAL POLICY Off-Label Use

   4. Request is not for a benefit-excluded use (e.g., cosmetic);
2. Prescribed by or in consultation with an appropriate specialist for the diagnosis;
3. Failure of 2 alternative drugs that are FDA-approved for the requested indication and/or drugs that are considered the standard of care, tried at maximum indicated doses as described below by one of the following (a, b, c, d, or e), unless contraindicated, clinically significant adverse effects are experienced, or request is for a product for treatment associated with cancer for a State with regulations against step therapy in certain oncology settings (see Appendix E): a. The preferred biosimilar(s) of the requested brand name drug has been used, if available, unless member has contraindications to the excipients in all generics/biosimilars; b. Both agents are generics (each from a different manufacturer) within the same therapeutic class as the requested agent;
   c. If there is only 1 generic agent within the same therapeutic class as the prescribed agent, member must use at least one additional agent that is recognized as a standard of care for the treatment of the relevant diagnosis, provided that such agent exists; d. If there are no generic agents within the same therapeutic class, member must use 2 alternatives that are recognized as standards of care for the treatment of the relevant diagnosis, provided that 2 such agents exist; e. There are no generic agents within the same therapeutic class and no alternative agents recognized as standards of care for the treatment of the relevant diagnosis;

4. If request is for a non-preferred biologic product with an available biosimilar, one of the following (a or b): a. Member must use the preferred biosimilar product(s), unless contraindicated or clinically significant adverse effects are experienced; b. Request is for a product for treatment associated with cancer for a State with regulations against step therapy in certain oncology settings (see Appendix E);

   8. Member has no contraindications to the prescribed agent per the product information label;
   9. If applicable, prescriber has taken necessary measures to minimize any risk associated with a boxed warning in the product information label;
   10. Dosing regimen and duration are within dosing guidelines recommended by clinical practice guidelines and/or medical literature. Approval duration: Duration of request or 6 months (whichever is less) B. Requests for Off-label Use through Medical Benefit (must meet all):
   11. There are no pharmacy and therapeutic committee approved off-label use criteria for the diagnosis;
   12. If a drug-specific clinical policy is available, the request is not for diagnoses or indications listed in Section III of the drug-specific clinical policy;
   13. Use is supported by one of the following (a, b, or c): a. The National Comprehensive Cancer Network (NCCN) Drug Information and Biologics Compendium level of evidence 1, 2A, or 2B (see Appendix D); Page 2 of 9

   CLINICAL POLICY Off-Label Use b. Evidence from at least two high-quality, published studies in reputable peer- reviewed journals or evidence-based clinical practice guidelines that provide all of the following (i – iv): i. Adequate representation of the member’s clinical characteristics, age, and diagnosis;
   ii. Adequate representation of the prescribed drug regimen;
   iii. Clinically meaningful outcomes as a result of the drug therapy in question; iv. Appropriate experimental design and method to address research questions (see Appendix F for additional information); c. Micromedex DrugDex® with strength of recommendation Class I or IIa (see Appendix D);

   4. Request is not for a benefit-excluded use (e.g., cosmetic);
5. Prescribed by or in consultation with an appropriate specialist for the diagnosis;
6. Failure of 2 alternative drugs that are FDA-approved for the requested indication and/or drugs that are considered the standard of care, tried at maximum indicated doses as described below by one of the following (a, b, c, d, or e), unless contraindicated, clinically significant adverse effects are experienced, or request is for a product for treatment associated with cancer for a State with regulations against step therapy in certain oncology settings (see Appendix E): a. The preferred biosimilar(s) of the requested brand name drug has been used, if available, unless member has contraindications to the excipients in all generics/biosimilars; b. Both agents are generics (each from a different manufacturer) within the same therapeutic class as the requested agent;
   c. If there is only 1 generic agent within the same therapeutic class as the prescribed agent, member must use at least one additional agent that is recognized as a standard of care for the treatment of the relevant diagnosis, provided that such agent exists; d. If there are no generic agents within the same therapeutic class, member must use 2 alternatives that are recognized as standards of care for the treatment of the relevant diagnosis, provided that 2 such agents exist; e. There are no generic agents within the same therapeutic class and no alternative agents recognized as standards of care for the treatment of the relevant diagnosis;

7. If request is for a non-preferred biologic product with an available biosimilar, one of the following (a or b): a. Member must use the preferred biosimilar product(s), unless contraindicated or clinically significant adverse effects are experienced; b. Request is for a product for treatment associated with cancer for a State with regulations against step therapy in certain oncology settings (see Appendix E);

   8. Member has no contraindications to the prescribed agent per the product information label;
   9. If applicable, prescriber has taken necessary measures to minimize any risk associated with a boxed warning in the product information label;
   10. Dosing regimen and duration are within dosing guidelines recommended by clinical practice guidelines and/or medical literature. Approval duration: Duration of request or 6 months (whichever is less) Page 3 of 9

   CLINICAL POLICY Off-Label Use II. Continued Therapy A. Requests for Off-Label Use through Pharmacy or Medical Benefit (must meet all):

   1. Member meets one of the following (a, b, or c): a. Currently receiving medication via Centene benefit; b. Member has previously met initial approval criteria; c. State or health plan continuity of care programs apply to the requested drug and indication (e.g., seizures, heart failure, human immunodeficiency virus infection, and psychotic disorders [e.g., schizophrenia, bipolar disorder], oncology) with documentation that supports that member has received this medication for at least 30 days (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B) AND use is supported by one of the following (i, ii, or iii): i. The NCCN Drug Information and Biologics Compendium level of evidence 1, 2A, or 2B (see Appendix D); ii. Evidence from at least two, high-quality, published studies in peer-reviewed journals or evidence-based clinical practice guidelines that provide all of the following (1 – 4): 1) Adequate representation of the member’s clinical characteristics, age, and diagnosis;
      2) Adequate representation of the prescribed drug regimen;
      3) Clinically meaningful outcomes as a result of the drug therapy in question; 4) Appropriate experimental design and method to address research questions (see Appendix F for additional information); iii. Micromedex DrugDex with strength of recommendation Class I or IIa (see Appendix D);
   2. Member is responding positively to therapy;

8. If request is for a non-preferred biologic product with an available biosimilar, one of the following (a or b): a. Member must use the preferred biosimilar product(s), unless contraindicated or clinically significant adverse effects are experienced; b. Request is for a product for treatment associated with cancer for a State with regulations against step therapy in certain oncology settings (see Appendix E);

   4. If request is for a dose increase (quantity or frequency), member has been titrated up from the lower dose with documentation of partial improvement, and the new dose does not exceed dosing guidelines recommended by the product information label or clinical practice guidelines and/or medical literature. Approval duration: Duration of request or 12 months (whichever is less) III. Diagnoses/Indications for which coverage is NOT authorized:
      A. Indications or diagnoses in which the drug has been shown to be unsafe or ineffective. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration NCCN: National Comprehensive Cancer Network Page 4 of 9

   CLINICAL POLICY Off-Label Use Appendix B: Therapeutic Alternatives
   Varies by drug product Appendix C: Contraindications/Boxed Warnings Varies by drug product Appendix D: General Information
   • These criteria are to be used only when specific prior authorization criteria do not exist. • The U.S. FDA approves drugs for specific indications included in the drug’s product information label. The approval by the FDA means that the company can include the information in their package insert. Omission of uses for a specific age group or a specific disorder from the approved label means that the evidence required by law to allow their inclusion in the label has not been submitted to the FDA. Off-label, or “unlabeled,” drug use is the utilization of an FDA-approved drug for indications, treatment regimens, or populations other than those listed in the FDA-approved labeling. Many off-label uses are effective and well-documented in the peer-reviewed literature, and they are widely used even though the manufacturer has not pursued the additional indications. Refer to the drug’s FDA-approved indication(s) and labeling (varies among drug products). • NCCN Categories of Evidence and Consensus: o Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. o Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. o Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. o Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. • Micromedex DrugDex Strength of Evidence, Strength of Recommendation, and Efficacy Definitions (Tables 1, 2, and 3): Table 1. Strength of Recommendation Class I Recommended Class IIa Class IIb Class III Recommended, In Most Cases Recommended, In Some Cases Not Recommended The given test or treatment has been proven to be useful, and should be performed or administered. The given test, or treatment is generally considered to be useful, and is indicated in most cases The given test, or treatment may be useful, and is indicated in some, but not most, cases. The given test, or treatment is not useful, and should be avoided. Class Indeterminate Evidence Inconclusive Not applicable Page 5 of 9

   CLINICAL POLICY Off-Label Use Table 2. Strength of Evidence Category A Category A evidence is based on data derived from: Meta-analyses of randomized controlled trials with homogeneity with regard to the directions and degrees of results between individual studies. Multiple, well-done randomized clinical trials involving large numbers of patients Category B evidence is based on data derived from: Meta-analyses of randomized controlled trials with conflicting conclusions with regard to the directions and degrees of results between individual studies. Randomized controlled trials that involved small numbers of patients or had significant methodological flaws (e.g., bias, drop-out rate, flawed analysis, etc.). Nonrandomized studies (e.g., cohort studies, case-control studies, observational studies) Category C evidence is based on data derived from: Expert opinion or consensus, case reports or case series Category B Category C No Evidence Not applicable Table 3. Efficacy Class I Effective Class IIa Evidence Favors Efficacy Class IIb Evidence is Inconclusive Class III Ineffective Evidence and/or expert opinion suggests that a given drug treatment for a specific indication is effective Evidence and/or expert opinion is conflicting as to whether a given drug treatment for a specific indication is effective, but the weight of evidence and/or expert opinion favors efficacy. Evidence and/or expert opinion is conflicting as to whether a given drug treatment for a specific indication is effective, but the weight of evidence and/or expert opinion argues against efficacy. Evidence and/or expert opinion suggests that a given drug treatment for a specific indication is ineffective. Appendix E: States with Regulations against Redirections in Cancer State Step Therapy Prohibited? Yes Yes FL GA IA LA NV PA Yes Yes Yes Yes Notes For stage 4 metastatic cancer and associated conditions. For stage 4 metastatic cancer. Redirection does not refer to review of medical necessity or clinical appropriateness. For standard of care stage 4 cancer drug use, supported by peer- reviewed, evidence-based literature, and approved by FDA. For stage 4 advanced, metastatic cancer or associated conditions. Exception if “clinically equivalent therapy, contains identical active ingredient(s), and proven to have same efficacy. Stage 3 and stage 4 cancer patients for a prescription drug to treat
   the cancer or any symptom thereof of the covered person For stage 4 advanced, metastatic cancer Page 6 of 9

   CLINICAL POLICY Off-Label Use State Step Therapy Prohibited? Yes Yes TN TX Notes For advanced metastatic cancer and associated conditions For stage 4 advanced, metastatic cancer and associated conditions Appendix F: Appropriate Experimental Design Methods • Randomized, controlled trials are generally considered the gold standard; however:
   o In some clinical studies, it may be unnecessary or not feasible to use randomization, double-blind trials, placebos, or crossover. o Non-randomized clinical trials with a significant number of subjects may be a basis for supportive clinical evidence for determining accepted uses of drugs. • Case reports are generally considered uncontrolled and anecdotal information and do not provide adequate supportive clinical evidence for determining accepted uses of drugs.
   V. Dosage and Administration
   Varies by drug product VI. Product Availability
   Varies by drug product VII.