Medical Drug Criteria (MDC)

Policy Num:      PP.001.004
Policy Name:    Coverage Guidelines for Orphan Drugs, Off-Label and Expanded Access (Compassionate Use) Drugs
Policy ID:          [PP.001.004]  [Ac / L / M+ / P+]  [0.00.00] 

Last Review:   January 13, 2026
Next Review:   January 20, 2027

Related Policies: None

Coverage Guidelines for Orphan Drugs, Off-Label and Expanded Access (Compassionate Use) Drugs

Summary

Description

Triple S Salud has a procedure designed to ensure the evaluation of requests for coverage of covered medications recommended for orphan drugs, off- labeled and expanded access drugs indications that are prescribed for “medically accepted indications”.

Off-label or “unlabeled” drug use is the use of a drug approved by the U.S. Food and Drug Administration (FDA) for other uses that are not included in approved labeling (may be for oncology or non oncology use). The FDA approves drugs for specific indications that are included in the drug’s labeling. When a drug is used for an indication other than those specifically included in the labeling, it is referred to as an off-label use. Many off-label uses are effective, well documented in the literature, and widely used.

An “orphan drug” is a product that treats a rare disease (e.g., affecting fewer than 200,000 Americans). Products have FDA orphan drug approval when they meet the orphan drug criteria established by the FDA. The intent of the Orphan Drug Act (ODA) is to stimulate the research, development, and approval of products that treat rare diseases. Orphan designation can be obtained prior to submission of a marketing application. The safety and efficacy of the drug must be established through clinical studies. If the designated product meets the standard FDA regulatory requirements and process for obtaining marketing approval, it is given an FDA approved orphan drug designation status (i.e., “Designated/Approved”). Over 1,400 drugs and biologics have been designated as orphan drugs and over 250 have been approved for marketing.

Expanded access refers to the use of an investigational new drug (IND) outside of a clinical trial by patients with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress. This type of access may be available, in accordance with United States Food and Drug Administration (FDA) regulations, when it is clear that patients may benefit from the treatment, the therapy can be given safely outside the clinical trial setting, no other alternative therapy is available, and the drug developer agrees to provide access to the drug. The FDA refers to such a program as an expanded access program (EAP). [1] EAPs can be used in a wide range of therapeutic areas including HIV/AIDS and other infectious diseases, cancer, rare diseases, and cardiovascular diseases. There are several types of EAPs allowed in the United States. Treatment protocols and treatment INDs provide large numbers of patients access to investigational drugs. A single-patient IND is a request from a physician to the FDA that an individual patient be allowed access to an investigational drug on an emergency or compassionate use basis.

Policy Statements

A.   Off-Label Drug Use

1.     Off-label use of cancer drugs:

a.     Triple-S may consider as medically necessary all NCCN Compendia Category 1, 2A and 2B of an FDA approved prescription drug for cancer treatment, thus, making a drug as recognized for treatment of the indication in one of the standard reference compendia.  By state mandate "Ley 79 del 1 de agosto de 2020 “Ley Especial para Asegurar el Acceso al Tratamiento y Diagnóstico de los Pacientes de Cáncer en Puerto Rico” requires coverage according to nationally recognized guidelines.

OR

b.     Off-labeled use of an FDA approved prescription drug for cancer treatment is covered “if the prescription drug is recognized in substantially accepted peer reviewed medical literature. The prescribing physician shall submit to the insurer documentation supporting the proposed off-label use or uses if requested by the insurer.”

c.     Cancer treatment drugs that do not comply with an approved FDA indication or do not comply with above mentioned criteria are considered as investigational.

d.     For experimental /investigational chemotherapy drugs (not FDA approved), deny as experimental / investigational

2.     Off-label drug use for non-cancer drugs are considered medically necessary when the following conditions are met:

                         i.         The drug is approved by the U.S. Food and Drug Administration AND

                        ii.         The prescribed drug use is supported in any ONE OR MORE of the following:

a.     American Hospital Formulary Service Drug Information (AHFS) or Clinical Pharmacology or Micromedex:

                                                             i.         Strength of Recommendation Class I, IIa or IIb;

                                                            ii.         Strength of Evidence Category A or B;

                                                           iii.         Efficacy Class I, IIa or IIb;

b.     Physicians may refer evidence from published studies from major scientific or medical peer-reviewed journals that support the proposed use for the specific medical condition as safe and effective (Accepted study designs include, but are not limited to, randomized, double blind, placebo controlled clinical trials.) 

3.     The prescriber must submit clinical justification for the requested off label use.

B.   Orphan Drug Use

1.     A product may have an orphan drug designation but fail to meet the criteria to have FDA marketing approval. Use of a product with orphan drug designation alone without FDA marketing approval is considered not medically necessary.

2.     Indication AND usage of requested product is supported by the results of TWO or more published clinical studies – prescriber must submit full text copies of each article

NOTE:

Case reports, posters, and abstracts (including published meeting abstracts) are not accepted as evidence to support for use.

Clinical studies must be supportive of use for a similar patient population (e.g., indication, diagnosis, disease severity, genetic or tumor mutations) and for the intended treatment plan, including any concomitant therapy.

C. Expanded Access (Compassionate Use)

1.     Drugs Expanded Access (Compassionate Use) Drugs (e.g. when a single patient IND (investigational new drug) request is approved by the FDA on a compassionate use basis) are considered experimental.

Policy Guidelines

A drug or biologic product meets the definition of medical necessity when ALL of the following criteria are met:

1.     Requested product has been approved by the United States Food and Drug Administration (FDA) and;

2.     One of the following is met:

a.     Requested product is listed on its formularies or coverage for a listed indication

b.     If requested indication is not included in an existing medical coverage guideline developed by Triple-S (or relevant third-party criteria document) then refer to section: Policy Statement

3.     Review criteria to determine whether chemotherapy ± supportive agent(s) are medically necessary for anticancer treatment include the following:

·       New drugs or regimens (combinations of drugs) approved by the United States Food and Drug Administration (FDA), i.e., that are used on-label.

·       Drugs and biologics may be used off-label, i.e., without FDA approval. They are considered medically accepted or necessary if supported by any of the following 5 compendia that CMS uses to determine a “medically accepted indication” for off-label drugs and biologics in anticancer chemotherapeutic treatment and are not listed as unsupported, not indicated, or not recommended within any one of the compendia below.

1.     NCCN Drugs & Biologics Compendium®

o   Category 1-2B recommendations are considered medically accepted uses

o   Category 2B recommendations will be considered if identified as medically accepted if listed in at least one of the 5 CMS-recognized compendia or supported by peer-reviewed scientific literature eligible for coverage as outlined below. Meeting abstracts and case reports are generally excluded from consideration

o   Category 3 listings are considered not medically accepted uses

o   NCCN Guidelines and the NCCN Drugs & Biologics Compendium are updated

2.     Clinical Pharmacology

o   Medically accepted uses are identified by narrative text that is supportive

o   Not medically accepted uses are identified by narrative text that is “not supportive”

3.     American Hospital Formulary Service Drug Information (AHFS DI)

o   Medically accepted uses are identified by narrative text that is supportive

o   Not medically accepted uses are identified by narrative text that is “not supportive”

4.     Thompson Micromedex DrugDex®

o   Class I, IIA, or IIb recommendations are considered medically accepted uses

o   Class III listings are considered not medically accepted uses

5.     Wolters Kluwer Lexi-Drugs®

o   Medically accepted uses are identified by an indication listed as “Use: Off-Label” and rated as “Evidence Level A”

o   Not medically accepted uses are those indications listed as “Use: Unsupported”

o   Off-label use of drugs and biologics may also be considered medically accepted if supported as safe and effective according to peer-reviewed articles eligible for coverage from  journals; this is in accordance with the medical literature used by local Medicare contractors to determine medically-accepted indications for drugs and biologics used in anticancer treatment: ie; American Journal of Medicine;  Annals of Oncology; Annals of Surgical Oncology; The Journal of the American Medical Association; Radiation Oncology, among others.

               Meeting abstracts and case reports are generally excluded from consideration

o   Coverage determination may also be directed by CMS National Coverage Determinations (NCDs) or state-specific Local Coverage Determinations (LCDs), state-specific Medicaid drug utilization requirements and/or health plan-specific drug coverage policies, where applicable.

o   Unique cases that do not fit NCCN Categories 1-3:

§  Non-standard protocols may be approved based on unique clinical circumstances, especially for rare diseases that may lack guideline-based treatment recommendations

§  Non-standard protocols are entered into the database, as needed

Coding

FDA-approved drugs may be reported using the appropriate alphanumeric HCPCS Level II code.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for off labeled use.  Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverage may have all or some of the services discussed in this medical policy excluded from their coverage.

State and Federal mandates and health plan member contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. To verify a member's benefits, contact Triple-S Blue Cross and Blue Shield of Puerto Rico Customer Service. Triple S Medical Policies contained herein are for informational purposes and apply only to members who have health insurance through Triple S or who are covered by a self-insured group plan administered by Triple S. Medical Policy for FEP members is subject to FEP medical policy which may differ from Triple S Medical Policy.  The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents of Triple S Blue Cross and Blue Shield of PR and are solely responsible for diagnosis, treatment and medical advice. If your patient is covered under a different Blue Cross and Blue Shield plan, please refer to the Medical Policies of that plan.

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION IN POLICY GUIDELINES.

Background

The sale and use of drugs are regulated in almost all countries by governmental agencies. In the United States, the Food and Drug Administration (FDA) oversees the drug evaluation process and grants approval for marketing of new drug products. Drug companies seeking FDA approval to sell a drug in the United States must evaluate the drug in various ways. This will include laboratory and animal tests, and finally, tests in humans to determine if the drug is safe and effective when used to treat or diagnose a disease.

After testing the drug, the company then sends the FDA an application called a New Drug Application (NDA), or for new biologic drugs, a Biologics License Application (BLA). Whether an NDA or a BLA, the application includes

·       Drug's test results

·       Manufacturing information to demonstrate the company can properly manufacture the drug

·       Proposed label for the drug

The label provides necessary information about the drug, including uses for which it has been shown to be effective, possible risks, and how to use it. If a review by FDA physicians and scientists shows the drug's benefits outweigh its known risks and the drug can be manufactured in a way that ensures a quality product, the drug is approved and can be marketed in the United States.

When a drug is used for an indication other than those specified in the labeling, it is referred to as an off-label (or “unlabeled”) use. Many off-label uses are effective, well documented in the literature, and widely used.

Unapproved or unlabeled uses of drugs include a variety of situations ranging from completely unstudied to thoroughly investigated drug uses where the FDA has not been asked for approval.

Orphan drug designation is a special status granted under the provisions of the Orphan Drug Act of the U.S. Food and Drug Administration (FDA) based on specific criteria. The Orphan Drug Designation program provides orphan status to drugs and biologicals that are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the United States, or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug. Orphan drug designations can be found at http://www.fda.gov/orphan/designat/list.htm.

REGULATORY STATUS

       1. United States Food and Drug Administration (FDA) regulations.

        2. Ley 79 del 1 de agosto de 2020 “Ley Especial para Asegurar el Acceso al Tratamiento y Diagnóstico de los Pacientes de Cáncer en Puerto Rico”, also known as “Ley Gabriela Nicole Correa Santiago".

        3. (P. del S. 1399); 2024, ley 165 Para enmendar los Artículos 3, 4, 5, 6 y 7 de la Ley Núm. 275 de 2012, Carta de Derechos de los Pacientes y Sobrevivientes de Cáncer.

        4. The Orphan Drug Act (ODA) is a US law that encourages pharmaceutical companies to develop drugs for rare diseases. The ODA was passed in 1983 by the US Congress. 

        5. Other state mandates may apply.

RATIONALE

Coverage for an off-label use of the prescribed drug or biologic product does not meet the definition of medical necessity when any of the following apply:

1. The FDA determines the drug or biological to be contraindicated for the specific requested condition(s).

2. The drug has not received FDA approval for any indication.

3. The compendia list the drug as "not indicated” or “not recommended” or categorized as lower than 2B.

4. The requested off-label use is not supported by adequate clinical research as determined by Triple S Blue Cross Blue Shield of Puerto Rico,

5. The drug is not recognized as described above in at least one of the identified compendium.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

PRACTICE GUIDELINES AND POSITION STATEMENTS

AHFS (American Hospital Formulary Service)

The American Hospital Formulary Service® Drug Information (AHFS DI) from the American Society of Health-System Pharmacists® (ASHP - www.ashp.org) provides an evidence-based foundation for safe and effective drug therapy. These full-text monographs have been officially designated as a federal standard on drug therapy, based on accepted medical practice, and are used by pharmacists, physicians, nurses, and other clinical Evidence Levels

Level 1: High Strength/Quality

·       Evidence consists of at least one randomized, double-blind trial without important limitations (i.e., large treatment effect); intent-to-treat analysis used, confidence intervals reported. If more than one trial is available, these trials have consistent results. or

·       Evidence consists of a meta-analysis of such trials with consistent results (i.e., low heterogeneity).

·       Evidence consisting of a non-blinded or single-blinded trial that meets study objective end points may be considered as Level 1 evidence in some cancer-related cases (e.g., NCI-sponsored cooperative group study or a multicenter trial).

Level 2: Moderate Strength/Quality

·       Evidence consists of at least one non-blinded or single-blinded, randomized clinical trial. or

·       Evidence consists of at least one non-blinded or single-blinded, non-randomized clinical trial. or

·       Evidence consists of a meta-analysis of randomized, controlled clinical trials with heterogenous results if reasons for heterogeneity in individual trials are adequately discussed. or

·       Evidence consists of at least one randomized, controlled clinical trial, but with important methodological limitations (e.g., large number of patients lost to follow-up and/or no intent-to-treat analysis and/or important data not recorded). or

·       Evidence is inconsistent (i.e., two or more randomized controlled trials with unexplained, widely varying estimates of treatment effects, even if results of individual trials would constitute strong Level 1 evidence when considered alone).

·       Evidence consisting of a non-blinded, non-randomized trial (i.e., a phase II study) may be considered as Level 2 evidence in some cancer-related cases (i.e., rare cancers or cancers with limited available treatment options).

Level 3: Low Strength/Quality

·       Evidence consists of observational studies, case reports, or case series; may also include randomized clinical trials with multiple serious deficiencies or study limitations.

Level 4: Opinion/Experience

·       Evidence consists of expert consensus panel reports or expert reviewers’ comments.

AHFS Grades of Recommendation

1. Recommended (Accepted) The drug or biologic should be used, is recommended/indicated, or is useful/effective/beneficial in most cases.
2. Reasonable Choice (Accepted, with Possible Conditions) (e.g., treatment option) 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.
3. Not Fully Established (Unclear Risk/Benefit, Equivocal Evidence, Inadequate Data and/or Experience) Usefulness and/or effectiveness is unknown, unclear, or uncertain or is not well established relative to the standard of care.
4. Not Recommended (Unaccepted) 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. 

Clinical Pharmacology®

Compendium to fulfill the drug reference requirements for licensed pharmacies and is officially recognized by Center of Medicare and Medicaid Services (CMS) as a drug compendium for determining the appropriate use of drugs and biologics for cancer patients. Off-label drug indication data are included in our drug information database when identified as a clinically relevant or emerging treatment by the drug information editorial team. Off-label data are primarily identified by the drug information editorial team for inclusion in the database through regular and comprehensive review of:

·       Primary published literature

·       New or updated national practice guidelines

·       Surveillance of other accepted sources of medical information (e.g., FDA, CDC, NIH communications)

·       Dialogue with customers or other external reviewers of our content

The Elsevier drug information editorial team will review external requests to add off-label indication information. External requests are handled in the same manner as those indications identified through the internal review processes.

GRADE utilizes two grades or strengths of recommendation: Strong and Weak.  The strength of recommendation is primarily derived by evaluating the risks vs. benefits of the recommendation to the alternatives, the quality of the evidence, the variability in the importance of the risks and benefits to the patients and clinicians (i.e., an outcome that is important to most patients such as preventing a stroke vs. the inconvenience of warfarin in atrial fibrillation is more likely to receive a strong recommendation), and resources or costs of the intervention.

·       Strong 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.

·       Equivocal/Weak Recommendation: 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.

MEDICARE NATIONAL COVERAGE

For Medicare Part B and Medicare Advantage members, the reviewer shall refer to National and Local Coverage Determinations. National and Local Coverage Determinations can be found at: http://www.cms.gov/medicare-coverage-database/overview-and-quick-search.aspx.

REFERENCES

1.         CMS:  https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdId=33394&ver=47

2. Drugs@FDA [Internet]. Silver Spring (MD): US Food and Drug Administration; 2018. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name/. Accessed 9/4/18.
3. NCCN Content © National Comprehensive Cancer Network, Inc 2011-2026       
4. DailyMed [Internet]. Bethesda (MD): National Library of Medicine; 2018. Available from: http://dailymed.nlm.nih.gov/dailymed/index.cfm/. Accessed 9/4/18   
5. NCCN Content © National Comprehensive Cancer Network, Inc 2011-2026, All Rights Reserved. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, NCCN TEMPLATES®, and NCCN COMPENDIUM® are trademarks owned by the National Comprehensive Cancer Network, Inc.
6. Database: MICROMEDEX® 2.0 [online] Available: http://www.thomsonhc.com/home/dispatch [Accessed October,2011]
7. FDA Website:  http://www.fda.gov/orphan/designat/list.htm.
8. American Hospital Formulary Service (AHFS) (electronic version). Available at: http://www.ahfsdruginformation.com/
9. Local Coverage Determination (LCD) For Label and Off-label Coverage of Outpatient Drugs and Biologics (L33915)
10.  Ley de Puerto Rico Núm. 194; Artículo 4.050
11.  Reglamento de Puerto Rico 7617, Reglamento para implantar las disposiciones de     la ley número 194; Artículo 8, Sección 5, inciso A 10
12.  Contract between Administración de Seguros de Salud de Puerto Rico (ASES) and Triple-S Salud, for Provision of Physical & Behavioral Health Services under the Government Health Plan Program (Contract No: 2019-000052)
13. Normative Letter 21-0817: Política para asegurar el acceso a medicamentos, tratamiento y pruebas para el diagnóstico de Cáncer.
14. ASES-OC-2023/P003: Puerto Rico Health Insurance Administration Policy for Medication Exception Requests.
15. Contract between Administración de Seguros de Salud de Puerto Rico (ASES) and Triple-S Salud, for Provision of Physical & Behavioral Health Services under the Government Health Plan Program (Contract No: 2023-000046) Amendment effective until September 30,2025
16. AHFS Website: https://ahfsdruginformation.com/levels-of-evidence-rating-system/
17. https://www.ncbi.nlm.nih.gov/books/NBK572052/#:~:text=In%201983%2C%20the%20United%20States,specifically%20at%20treating%20rare%20diseases.
18. https://www.rarecoalition.com/wp-content/uploads/ODA-Overview.pdf
19. https://www.fda.gov/news-events/expanded-access/expanded-access-information-physicians
20. https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/designating-orphan-product-drugs-and-biological-products
21. https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label
22. https://www.ncbi.nlm.nih.gov/books/NBK56187/
23. Pharmacy Policy GHP-MAPD 048.1
24. PUBLIC LAW 97-414-JAN. 4, 1983 Orphan Drug Act.
25. Ley Núm. 165 de 15 de agosto de 2024 para enmendar los Artículos 3, 4, 5, 6 y 7 de la Ley Núm. 275 de 2012, Carta de Derechos de los Pacientes y Sobrevivientes de Cáncer.

Codes

FDA-approved drugs may be reported using the appropriate alphanumeric HCPCS Level II code.

policy History