Approved and Accepted Off-label Medical Necessity Criteria for Products, Drugs and Biologicals (PG136) Form

The utilization management of off-label use of products is important for ensuring the safety and efficacy of drugs intended for human use. The U.S. FDA evaluates drugs and biologicals to ensure that they are safe and effective prior to marketing for all indications or uses. However, physicians may use a product for an indication not in the approved labeling, called off-label use, when the intent is the "practice of medicine". FDA-approved drugs and biologicals may be considered for use in off-label indications if determined to be reasonable and necessary by the Plan. However, off-label usage is not supported and, therefore, the drug is not covered if a use is identified as not indicated by the FDA, or if a use is specifically identified as not indicated in one or more of the compendia listed, or if the Plan determines, based on peer-reviewed medical literature, that a particular use of a drug is not safe and effective. Peer-reviewed medical literature is considered when assessing off-label use. This policy applies to products such as drugs and biologicals that need prior authorization but have no specific guidelines or coverage criteria, or for which product-specific clinical policies are still being updated due to recent changes in labeling. The Plan may review all requests made under the Medical or 1 Pharmacy benefit against specific prior authorization criteria, as applicable and at its discretion. If the Member's Provider requests an off-label use of products or if the Plan requests it, the Provider is responsible for submitting documentation that supports the non-approved use. Definitions “Biosimilar” refers to copies of biologic drugs. They are similar to an FDA-approved biologic, known as the reference product. “Brand Name Drug” means the first version of a particular medication to be developed or a medication that is sold under a pharmaceutical manufacturer’s own registered trade name or trademark. The original manufacturer is granted a patent, which allows it to be the only company to make and sell the new drug for a certain number of years. “Compendia” are summaries of drug information and medical evidence to support decision-making about the appropriate use of drugs and medical procedures. Examples include, but are not limited to:

1. American Hospital Formulary Service Drug Information
2. Elsevier Clinical Pharmacology
3. National Comprehensive Cancer Network Drugs and Biologics Compendium
4. Thomson Micromedex DrugDex
5. United States Pharmacopeia-National Formulary (USP-NF) “Documentation” refers to written information, including but not limited to:
6. Up-to-date chart notes, relevant test results, and/or relevant imaging reports to support diagnoses;
7. Prescription claims records, and/or prescription receipts to support prior trials of formulary alternatives. “Evidence-based, peer-reviewed medical journals” are publications that publish original research and scholarly articles related to the medical field. These journals use a peer-review process in which submitted articles are reviewed by independent experts in the same field to ensure their scientific accuracy, validity, and reliability before publication. The articles published in these journals are often based on research that uses rigorous scientific methods to provide evidence for medical practices, therapies, and treatments. The goal of evidence-based medicine is to provide the most effective care to patients based on the best available scientific evidence. “FDA,” or the Food and Drug Administration, is an agency of the United States federal government responsible for protecting and promoting public health through the regulation and supervision of food safety, tobacco products, dietary supplements, prescription and over-the-counter medications, vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices, 2 cosmetics, and veterinary products. The FDA's main goal is to ensure that these products are safe and effective for their intended use, and that their labeling and marketing are truthful and not misleading. “Formulary” means a list of medications available to members with or without Prior Authorization. “Generic Drugs” means prescription Drugs that have been determined by the Food and Drug Administration (FDA) to be equivalent to Brand Name Drugs, but are not made or sold under a registered trade name or trademark. Generic Drugs have the same active ingredients, meet the same FDA requirements for safety, purity, and potency and must be dispensed in the same dosage form (e.g., tablet, capsule, cream) as the Brand Name Drug. “High Strength/Quality Evidence” is defined as at least one randomized, double-blind trial without significant limitations and with intent-to-treat analysis, confidence intervals reported, and consistent results from multiple trials or a meta-analysis with low heterogeneity. In some cancer-related cases, a non-blinded or single-blinded trial that meets the study objectives may also be considered as High Strength/Quality Evidence, such as in National Cancer Institute (NCI)-sponsored cooperative group studies or multicenter trials. “Low Strength/Quality Evidence” is defined as evidence that includes observational studies, case reports, or case series, and in some cases, randomized clinical trials with significant limitations. It also encompasses evidence in the form of expert consensus panel reports or expert reviewer comments. “Moderate Strength/Quality Evidence” is defined as at least one non-blinded or single-blinded, randomized or non-randomized clinical trial; a meta-analysis of randomized, controlled clinical trials with heterogeneous results if reasons for heterogeneity are adequately discussed; a randomized, controlled clinical trial with important methodological limitations; or inconsistent evidence from two or more randomized controlled trials with widely varying estimates of treatment effects. In some cancer-related cases, a non-blinded, non-randomized trial such as a phase II study may be considered as Moderate Strength/Quality Evidence for rare cancers or cancers with limited treatment options. Medical Necessity Criteria for Initial Authorization If there is no product-specific Clinical Guideline or indication-specific clinical criteria, the Plan considers the requested FDA-approved or cleared product medically necessary if ALL the following criteria are met:
8. The product is being prescribed by or in consultation with a specialist or clinician with relevant specialty training IF accurate diagnosis and prescription, determination of risks and benefits of treatment, dosing, monitoring for side effects, or overall care coordination require specialist training to ensure safe and effective use of the product;AND
9. The safety and effectiveness of use for the indication is consistent with ONE of the following: 3 a. FDA approved labeling (i.e., product information) for indication, including age, dosing (dosage, frequency, duration of therapy, and site of administration), and contraindications; or b. Use is supported with an appropriate level of evidence of efficacy by at least ONE of the following compendia, and not contraindicated or otherwise not recommended in the FDA labeling: i. American Hospital Formulary Service-Drug Information (AHFS-DI) and Grades of Recommendation is EITHER “Recommended” OR “Reasonable Choice”;or ii. American Medical Association (AMA) Drug Evaluations, or its successor publication;or iii. Clinical Pharmacology and the off-label use carries a Strong Recommendation “For” use, with any level of evidence;or iv. Lexi-Drugs AND the indication is listed as "Use: Off-Label" AND rated as "Evidence Level A";or v. Micromedex DrugDex and the Strength of Recommendation for the indication is a Class I, Class IIa, or Class IIb;or vi. National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium and the level of evidence for the indication is Category 1, 2A, or 2B;or c. Evidence-based, peer-reviewed, recognized medical literature meeting ALL of the following: i. At least two articles from major peer-reviewed professional medical journals published in the United States or Great Britain have recognized, based on scientific or medical criteria, the drug's safety and effectiveness for treatment of the indication for which the drug has been prescribed;and ii. No article from a major peer-reviewed professional medical journal has concluded, based on scientific or medical criteria, that the drug is unsafe or ineffective or that the drug's safety and effectiveness cannot be determined for the treatment of the indication for which the drug has been prescribed;and iii. The use is not listed as unsupported, not indicated, not recommended (or equivalent terms) in any of the medical reference compendia;AND
10. The member must have documented evidence of ALL of the following: a. Failure of an adequate trial of at least three FDA-approved or cleared product (if available) that are considered the standard of care, unless: i. ii. iii. Clinically significant adverse effects are experienced;or All FDA-approved or cleared alternatives are contraindicated;or The request is for a product for treatment associated with cancer for a State with regulations against pre-requisite trial(s) of alternatives in certain oncology settings;and 4 b. If the requested product is a Brand drug with a generic or biosimilar available, the member is unable to use or has tried and failed the corresponding generic or biosimilar product from two or more (≥ 2) manufacturers (if available);and c. If the drug is to be used in combination with other drugs for a particular indication, the safety and efficacy of use of those drugs in combination must be supported by reliable evidence in peer-reviewed published medical literature;AND
11. The product being requested meets BOTH of the following: a. The requested dosage, frequency, duration of therapy, and site of administration are supported by FDA labeling (product information), compendia of current literature, practice guidelines, or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence);and b. If the requested dosage exceeds the Plan’s quantity limit AND the prescribed dosage cannot be achieved using a different dose or formulation that is within the Plan’s limit; AND
12. The member has no contraindications to the prescribed agent per FDA labeling;AND
13. Documentation (such as office chart notes, lab results or other clinical information) are provided for review to substantiate the above listed requirements. Medical Necessity Criteria for Reauthorization: Prior authorization renewals will be reviewed on a case-by-case basis to determine medical necessity. Reauthorization requests will be considered medically necessary if ALL of the following criteria are met:
14. The member meets all Medical Necessity Criteria for Initial Authorization;AND
15. The member is experiencing positive clinical response or benefit from therapy as evidenced by disease stability or disease improvement;AND
16. The member does not have evidence of unacceptable toxicity from the requested product;AND 4. If the request is for a dose increase, it must meet BOTH of the following criteria: a. The requested dosage, frequency, duration of therapy, and site of administration are supported by FDA labeling (product information), compendia of current literature, practice guidelines, or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence);and b. If the requested dosage exceeds the Plan’s quantity limit AND the prescribed dosage cannot be achieved using a different dose or formulation that is within the Plan’s limit. Table 1: Level of Evidence Definitions AHFS Grades of Recommendation Recommended (Accepted) The drug or biologic should be used, is recommended/indicated, or is useful/effective/beneficial in most cases. 5 Reasonable Choice (Accepted, with Possible Conditions) (e.g., treatment option) Not Fully Established (Unclear Risk/Benefit, Equivocal Evidence, Inadequate Data and/or Experience) Not Recommended (Unaccepted) The drug or biologic is reasonable to use under certain conditions (e.g., in certain patient groups), can be useful/effective/beneficial, or is probably recommended or indicated. Usefulness and/or effectiveness is unknown, unclear, or uncertain or is not well established relative to the standard of care. The drug or biologic is considered inappropriate, obsolete, or unproven; is not recommended, is not indicated, or is not useful/effective/beneficial; or may be harmful. Elsevier Clinical Pharmacology (quality of evidence rating and strength of recommendation) Strong Recommendation Equivocal/Weak Recommendation An off-label use that carries a Strong Recommendation “For” or “Against” use, with any level of evidence, should be considered binding and reflect that Elsevier recommends or does not recommend, respectively, the use of the drug for that indication in the situation described. All off-label uses with a strong level of recommendation will appear in the referential database and be clearly identified as recommended or not recommended; however, a strong recommendation “Against use” will not be found within the clinical decision support data. Off-label uses that have inconclusive data “For” or “Against” use carry a Weak Recommendation. A Weak recommendation, with any level of evidence, reflects a neutral or equivocal position (i.e., neither for or against use) by Elsevier. All off-label uses with a weak level of recommendation will appear in the referential database and be clearly identified as equivocal; however, a weak recommendation “Against use” will not be found within the clinical decision support data. Lexi-Drugs Level of Evidence Scale A - Consistent evidence from well-performed randomized, controlled trials or overwhelming evidence of some other form (eg, results of the introduction of penicillin treatment) to support the off-label use. Further research is unlikely to change confidence in the estimate of benefit. B - Evidence from randomized, controlled trials with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence of some other research design. Further research (if performed) is likely to have an impact on confidence in the estimate of benefit and risk and may change the estimate. C - Evidence from observational studies (eg, retrospective case series/reports providing significant impact on patient care), unsystematic clinical experience, or from potentially flawed randomized, controlled trials (eg, when limited options exist for condition). Any estimate of effect is uncertain. G - Use has been substantiated by inclusion in at least one evidence-based or consensus-based clinical practice guideline. 6 Micromedex DrugDex Strength of Recommendation Class I - Recommended The given test or treatment has been proven to be useful, and should be performed or administered. Class IIa - Recommended, In Most Cases The given test, or treatment is generally considered to be useful, and is indicated in most cases. Class IIb - Recommended, In Some Cases The given test, or treatment may be useful, and is indicated in some, but not most, cases. Class III - Not Recommended The given test, or treatment is not useful, and should be avoided. Class Indeterminate Evidence Inconclusive NCCN Categories of Evidence and Consensus Category 1 Category 2A Category 2B Category 3 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. Table 2: Peer-reviewed Professional Medical Journals NOTE:Thelistofmedicaljournalsprovidedasanexampleisnotintendedtobeanall-inclusiveorcomprehensive list.Numerousothercrediblemedicaljournalsexistthatarenotincludedhere,andthislistshouldnotbeconsidered acompleterepresentationofthemedicaljournallandscape. Journal Name Academic Emergency Medicine Specialty Publisher emergency medicine Wiley-Blackwell American Journal of Respiratory and Critical Care Medicine respiratory and critical care American Thoracic Society Annals of Emergency Medicine Annals of Internal Medicine emergency medicine Elsevier internal medicine American College of Physicians Annals of Oncology oncology Elsevier 7 Annals of Surgery surgery Lippincott Williams & Wilkins Annals of Surgical Oncology oncology Springer Archives of Disease in Childhood pediatrics BMJ Group Biology of Blood and Marrow Transplantation Blood BMJ Open Bone Marrow Transplantation hematology/Onc ology Elsevier hematology American Society of Hematology general medicine BMJ Group hematology/Onc ology Springer Nature British Journal of Cancer oncology Springer Nature Cancer Circulation Clinical Cancer Research Clinical Infectious Diseases Diabetes Care Drugs Emerging Infectious Diseases oncology Wiley cardiology American Heart Association oncology infectious diseases diabetes American Association for Cancer Research Oxford University Press American Diabetes Association Pharmacology Springer infectious diseases Centers for Disease Control and Prevention European Journal of Cancer (formerly the European Journal of Cancer and Clinical Oncology oncology Elsevier Gastroenterology Gynecologic Oncology gastroenterology Elsevier gynecologic oncology Elsevier International Journal of Cancer oncology Wiley-Blackwell International Journal of Radiation Oncology, Biology, Physics radiation oncology Elsevier JAMA: The Journal of the American Medical Association general medicine American Medical Association Journal of Clinical Oncology oncology American Society of Clinical Oncology 8 Journal of Neurology, Neurosurgery, and Psychiatry neurology and psychiatry BMJ Publishing Group Journal of the National Cancer Institute oncology Oxford University Press Journal of the National Comprehensive Cancer Network Leukemia Nature Nature Communications oncology NCCN hematology/onco logy Nature multidisciplinary sciences multidisciplinary sciences Nature Publishing Group Nature Publishing Group Nature Medicine general medicine Nature Publishing Group Neurology neurology American Academy of Neurology Neuropharmacology pharmacology Elsevier New England Journal of Medicine general medicine Massachusetts Medical Society Obstetrics and Gynecology Pediatrics PLOS One obstetrics and gynecology pediatrics Wolters Kluwer American Academy of Pediatrics multidisciplinary sciences PLOS Radiation Oncology oncology BioMed Central Ltd. Stroke neurology American Heart Association The American Journal of Clinical Dermatology dermatology Springer The American Journal of Clinical Nutrition nutrition Oxford University Press The American Journal of Gastroenterology gastroenterology Wolters Kluwer The American Journal of Medicine general medicine Elsevier The American Journal of Pathology pathology Elsevier The American Journal of Physiology physiology The American Journal of Physiology - Endocrinology and Metabolism physiology American Physiological Society American Physiological Society 9 The American Journal of Psychiatry psychiatry American Psychiatric Association The American Journal of Sports Medicine sports medicine SAGE Publications The American Journal of Transplantation transplantation Wiley-Blackwell The Annals of Thoracic Surgery thoracic surgery Elsevier The BMJ (formerly the British Medical Journal) general medicine BMJ Publishing Group The British Journal of Haematology hematology Wiley-Blackwell The British Journal of Psychiatry psychiatry Royal College of Psychiatrists The British Journal of Surgery surgery Oxford University Press The Cochrane Database of Systematic Reviews evidence-based medicine Wiley-Blackwell The Journal of Adolescent Health adolescent health Elsevier The Journal of Allergy and Clinical Immunology allergy and immunology Elsevier The Journal of Bone and Joint Surgery orthopedics The Journal of Bone and Joint Surgery, Inc. The Journal of Cerebral Blood Flow & Metabolism neurology SAGE Publications The Journal of Clinical and Aesthetic Dermatology dermatology Matrix Medical Communications The Journal of Clinical and Experimental Neuropsychology neuropsychology Taylor & Francis The Journal of Clinical Endocrinology and Metabolism endocrinology Endocrine Society The Journal of Clinical Hypertension hypertension Wiley-Blackwell The Journal of Clinical Immunology immunology Springer The Journal of Clinical Investigation general medicine American Society for Clinical Investigation The Journal of Clinical Lipidology lipidology Elsevier The Journal of Clinical Microbiology microbiology The Journal of Clinical Oncology oncology American Society for Microbiology American Society of Clinical Oncology The Journal of Clinical Pharmacology pharmacology Wiley-Blackwell 10 The Journal of Clinical Psychiatry psychiatry Physicians Postgraduate Press The Journal of Clinical Psychology clinical psychology Wiley-Blackwell The Journal of Clinical Sleep Medicine sleep medicine American Academy of Sleep Medicine The Journal of Dental Research dentistry SAGE Publications The Journal of Emergency Medicine The Journal of Geriatric Psychiatry and Neurology emergency medicine geriatric psychiatry and neurology Elsevier SAGE Publications The Journal of Hand Surgery hand surgery Elsevier The Journal of Hospital Infection infection control Elsevier The Journal of Hospital Medicine hospital medicine Wiley-Blackwell The Journal of Infectious Diseases The Journal of Infectious Diseases and Therapy infectious diseases infectious diseases Oxford University Press Springer The Journal of Investigative Medicine general medicine BMJ Publishing Group The Journal of Medical Internet Research medical informatics JMIR Publications The Journal of Medical Microbiology microbiology Microbiology Society The Journal of Neuroscience Nursing neuroscience nursing The Journal of Neurosurgery neurosurgery The Journal of Nuclear Medicine nuclear medicine The Journal of Nuclear Medicine Technology nuclear medicine Lippincott Williams & Wilkins American Association of Neurological Surgeons Society of Nuclear Medicine and Molecular Imaging Society of Nuclear Medicine and Molecular Imaging The Journal of Pathology pathology Wiley-Blackwell The Journal of Rheumatology rheumatology The Journal of Rheumatology Publishing Company Limited The Journal of the American Academy of Dermatology dermatology Elsevier The Journal of the American Academy of Orthopaedic Surgeons orthopedics American Academy of Orthopaedic Surgeons 11 The Journal of the American Association of Nurse Practitioners nursing Wolters Kluwer The Journal of the American College of Cardiology cardiology Elsevier The Journal of the American College of Radiology radiology Elsevier The Journal of the American College of Surgeons surgery American College of Surgeons The Journal of the American Dental Association dentistry American Dental Association The Journal of the American Heart Association cardiology Wiley-Blackwell The Journal of the American Medical Directors Association geriatric medicine Elsevier The Journal of the American Medical Informatics Association medical informatics The Journal of the American Optometric Association optometry Oxford University Press American Optometric Association The Journal of the American Podiatric Medical Association podiatry American Podiatric Medical Association The Journal of the American Society of Hypertension hypertension Elsevier The Journal of the American Society of Nephrology nephrology American Society of Nephrology The Journal of the National Cancer Institute oncology Oxford University Press The Journal of Thoracic and Cardiovascular Surgery thoracic and cardiovascular surgery Elsevier The Journal of Thoracic Oncology thoracic oncology Elsevier The Journal of Urology The Journal of Vascular and Interventional Radiology urology Elsevier interventional radiology Elsevier The Journal of Vascular Surgery vascular surgery Elsevier The Lancet The Lancet Diabetes & Endocrinology The Lancet Haematology The Lancet Infectious Diseases general medicine Elsevier diabetes and endocrinology Elsevier hematology Elsevier infectious diseases Elsevier 12 The Lancet Neurology neurology Elsevier The Lancet Oncology oncology Elsevier The Lancet Public Health The Lancet Respiratory Medicine public health Elsevier respiratory medicine Elsevier Experimental or Investigational / Not Medically Necessary The use of products, drugs and biologicals are considered contraindicated, experimental, investigational, or unproven in the following cases:
17. The product, drug or biologic has not received approval or clearance for any indication from the U.S. Food and Drug Administration (FDA).
18. The FDA determined a product, drug or biologic to be contraindicated for a specific condition or off-label use.
19. The Pharmacy and Therapeutics (P&T) Committee classifies it as experimental, investigational, or unproven because the safety and/or efficacy cannot be established after reviewing the published scientific literature. 4. Indications or diagnoses in which the drug has been shown to be unsafe or ineffective.
20. Continued therapy for members who have developed an absolute contraindication or intolerance to the product, or who have failed to respond or who have lost response to the product.
21. Not "medically accepted" by a Compendium: a. AHFS-DI or Clinical Pharmacology: The narrative text is "not supportive" (or equivalent term). b. DrugDex: The level of evidence for the indication is Class III in DrugDex. c. Lexi-Drugs: Indication is listed as "Use: Unsupported." d. NCCN: The level of evidence for the indication is Category 3 in NCCN.
22. The quality of evidence provided or reviewed is poor (i.e., Low Strength/Quality Evidence), as it primarily consists of: a. Observational studies: These are studies where the researchers observe a group of people without any intervention, and then analyze the data collected. These studies are prone to bias and confounding variables. b. Case reports and case series: These are studies that describe the medical history and treatment of one or more individual patients. These studies do not have a control group and are therefore not able to show cause-and-effect relationships. c. Non-randomized studies: These are studies where the participants are not randomly assigned to different groups. This can introduce bias into the study and make it difficult to draw reliable conclusions. 13 d. Studies with serious deficiencies or limitations: These are studies that have flaws in their design, execution, or analysis that make it difficult to trust their findings. e. Expert consensus panel reports or expert reviewers' comments: These are opinions or experiences of experts in the field and are not based on empirical evidence. Clinical Guideline Revision / History Information Original Date: 3/23/2023 Reviewed/Revised: References
23. American Hospital Formulary Service - Drug Information (AHFS-DI). Available at: http://www.ahfsdruginformation.com
24. Elsevier Gold Standard Clinical Pharmacology Compendium (Clinical Pharmacology). EdElsevier Editorial Policy for Off-Label Data within Drug Information Products and Databases. Available at: https://www.elsevier.com/clinical-solutions/drug-information/editorial-policy/off-label-data 3. IBM® Micromedex® DRUGDEX®. IBM Watson Health. IBM Micromedex Policy on Compendia Drug Content. Available at: https://www.ibm.com/downloads/cas/GXNB3ZG4
25. National Comprehensive Cancer Network (NCCN). The NCCN Drugs and Biologics Compendium. NCCN Compendium®. Available at: https://www.nccn.org/compendia-templates/compendia/nccn-compendia
26. U.S. Department of Health and Human Service Food and Drug Administration (FDA). Center for Drug Evaluation and Research | CDER. Available at: https://www.fda.gov/about-fda/fda-organization/center-drug-evaluation-and-research-cder.
27. U.S. Department of Health and Human Service Food and Drug Administration (FDA). Understanding Unapproved Use of Approved Drugs "Off Label". Available at: https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/unders tanding-unapproved-use-approved-drugs-label.
28. U.S. Food and Drug Administration (FDA). Off-label and investigational use of marketed drugs, biologics, and medical devices. Available at: https://www.fda.gov/regulatoryinformation/guidances/ucm126486.htm
29. U.S. Food and Drug Administration. Drugs@FDA. U.S. Department of Health & Human Services. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda.
30. Wolters Kluwer Lexi-Drugs®. Clinical Drug Information. Available at: http://www.wolterskluwercdi.com/lexicomp-online/ 14