The mission of AHFS is to provide an evidence-based foundation for safe and effective drug therapy. A key component to this mission is the ongoing evaluation of evidence concerning off-label uses of drugs. Section 1861 of the Social Security Act established AHFS DI as an official compendium for determining medically accepted indications of drugs and biologics used in anticancer chemotherapeutic regimens under Medicare Part B. AHFS DI meets the definition of a compendium as established in Section 414.930 of the Code of Federal Regulations (CFR) and has implemented enhancements to meet the desirable characteristics of compendia for use in determining medically accepted indications of drugs and biologics in anticancer therapy as recommended by the Centers for Medicare and Medicaid Services (CMS) Medicare Evidence Development and Coverage Advisory Committee (MedCAC). AHFS DI also has implemented policies and procedures to comply with the conflict of interest and transparency requirements for compendia as established by amended CFR Section 414.930(a); these requirements apply to determinations of medical acceptance in anticancer therapy made on or after January 1, 2010.
The following procedures, effective as of January 1, 2010, outline the process used by AHFS for determination of the medical acceptance of off-label uses for drugs and biologics in anticancer chemotherapeutic regimens under Medicare Part B.
The process for determination by AHFS is transparent and mitigates potential conflict of interest in order to preserve the compendium’s integrity and minimize bias. Strict firewall and conflict of interest polices are in place between AHFS staff and outside interests, to prevent any undue influence.
Selection of Off–label Oncology Uses for Consideration by the AHFS Oncology Expert Committee
Potential off-label oncology uses selected for consideration and review by the AHFS Oncology Expert Committee, for the purposes of determining medical acceptance, are identified by AHFS staff through either an internal process (i.e., ongoing literature review, advice of the Expert Committee) or an informal external request. External requests for consideration of off-label oncology uses may be submitted to AHFS via email to email@example.com; the subject line of the email should state “Off-label Use Request”. External requests also may be submitted to AHFS DI (Attention: Off-label Use Request), c/o the American Society of Health–System Pharmacists, 7272 Wisconsin Ave., Bethesda MD 20814. AHFS employs a publicly transparent process for evaluating therapies as defined by CFR Section 4141.930(a) and that includes criteria used to evaluate the use, a listing of evidentiary materials reviewed by the compendium, and a listing of all individuals who participated substantively in the development, review, or disposition of the request. (See AHFS Conflict of Interest and Disclosure Policy.)
For the purposes of establishing medical acceptance, preference is given to clinical studies that have been published in a peer-reviewed journal and present results addressing the study objectives defined a priori. Clinical information from professional meetings, in the form of abstracts, posters, or presentations, may be considered under certain circumstances, especially if the information represents fully completed studies or is in response to a data safety monitoring board (DSMB) request. In addition, information from professional meetings may be considered for use in updating descriptive information for a trial summarized in an existing off-label determination (e.g., to reflect data from longer-term follow-up of study participants). Interim results typically are addressed only when they add importantly to the understanding of an existing off-label use (e.g., new information about potential toxicity, evidence about major changes in outcomes relative to previous findings) or a major clinical breakthrough seems likely. Both the quality of evidence and the clinical importance of the use, as reflected by the following criteria, are considered by AHFS staff when selecting an off-label use for review by the AHFS Oncology Expert Committee:
- Clinical results from a well-designed and well-conducted phase 3 randomized trial comparing a novel regimen with a reasonable ‘standard of care’ (e.g., adequate sample size, full reporting of study end points)
- Clinical results from a well-designed and well–conducted phase 2 trial in rare and refractory cancers for which there is no well-established regimen
- Clinical results from a trial demonstrating a difference (improvement or worsening) in outcomes (responses, survival, quality of life, toxicity) compared with a reasonable standard of care
- Clinical results from a trial reflecting the use of a regimen in the context of advances in the understanding of the biology of a disease (e.g., newly identified biomarker or surrogate end point)
- Clinical results from a trial demonstrating a clinical difference (benefit or detriment) in a specific at-risk patient population (e.g., those with poor-risk cytogenetics, geriatric patients) or a subset of patients
- A regimen with potential for improved quality of life (e.g., oral versus parenteral regimen)
- A regimen/use described in a meta-analysis or an Agency for Healthcare Research and Quality (AHRQ)– or Cochrane-type evidence-based review
Once a potential off-label oncology use is identified, AHFS staff review and evaluate the relevant available evidence. After completion of the literature review, AHFS proposes an evidence-based rating for the specific off-label oncology use under consideration, using a composite score to rank the a) level of evidence of the supporting literature and b) the strength of the relevant end point as described in the ranking system of the National Cancer Institute–Physician’s Data Query (NCI PDQ) model.
Determination of Medical Acceptance
The relevant clinical information, based on the literature identified by AHFS staff, is incorporated into an evidence table and a narrative summary, which are provided to the AHFS Oncology Expert Committee for review.
AHFS Oncology Expert Committee members are asked to perform an independent review, complete a voting ballot, indicate their vote on the Level of Evidence rating, and provide a Grade of Recommendation and supporting comments using an evidence-based analysis of the available literature. (See AHFS Levels of Evidence Rating System and AHFS Grades of Recommendation.)
Publication of the Final Determination
A Final Determination Report for each off-label use reviewed by the AHFS Oncology Expert Committee is published on the AHFS website (www.ahfsdruginformation.com) and reflects the consensus vote of the members of the Committee. The following information is included in the Final Determination:
- Criteria used to select the off-label use for review
- Name of the drug or drug combination
- Off-label use, to include specific patient population and disease information
- Strength of Evidence, using composite score of strength of supporting literature and strength of end point
- Grade of Recommendation
- Narrative summary of the off-label use, including a description of the regimen, to facilitate consistent interpretation of the off-label recommendation
- Listing of references used as part of the off-label review
- Voting records
- Comments provided by AHFS Oncology Expert Committee members
- Listing of all individuals who substantively participated in the development, review, or disposition of the determination
- A statement summarizing the management of recognized conflicts of interest for individuals who participated substantively in the determination process
- AHFS publication date
A comprehensive review of the Final Determinations is conducted periodically, and relevant information (e.g., Level of Evidence and/or Recommendations) contained in the Final Determination is updated as needed.
Records pertaining to the publication of a Final Determination made on or after January 1, 2010 are maintained and available for not less than 5 years in accordance with CMS regulations. Such records will remain and be accessible on the AHFS website for a period of not less than 3 years, after which retention of the relevant information will be maintained for an additional 2 years by ASHP, thereby enabling public access to the material upon request.