For Cancer Uses, Medically Acceptable Uses of Antineoplastics and Biologics

A formal determination process has been developed to supplement the long-standing evidence-based process by AHFS for evaluation of off-label cancer uses of drugs and biologics. A Final Determination Report for each off-label use will be published on the AHFS website and will reflect the consensus vote of the members of the AHFS Oncology Expert Committee.

Determinations that appeared on this portion of the website prior to January 1, 2010, have been incorporated into the respective drug monographs in the AHFS DI database. Determinations subject to CMS’ revised definition of medically accepted indications, related to Section 182(b) of the Medicare Improvements for Patients and Providers Act of 2008 (MIPPA) and effective as of January 1, 2010, will be posted on this portion of the website as they are finalized.

The mission of AHFS Drug Information® (AHFS DI®) is to provide an evidence-based foundation for safe and effective drug therapy. Widely trusted for its established record in refuting unfounded efficacy claims, its rigorous science-based editorial process, and its independence from the influence of pharmaceutical manufacturers, AHFS DI has remained true to its mission for 50 years. This notable achievement of 5 decades of evidence-based medical publishing has gained AHFS DI the unique distinction of being the longest published and only remaining federally designated drug compendium issued by a scientific and professional society — the American Society of Health-System Pharmacists (ASHP). As such, AHFS DI maintains a unique role in establishing medically accepted uses of drugs, both labeled and off-label. Federal compendial recognition of this role exists under part 456 of CMS regulations governing utilization control for Medicaid and under sections 1927 and 1861 of the Social Security Act.

ASHP’s drug compendium originated at a time when various claims made by pharmaceutical manufacturers about their drugs were not even subject to federal scrutiny. Prior to passage of the Kefauver-Harris amendments to the US Food, Drug, and Cosmetic Act in 1962, pharmaceutical manufacturers were only required to establish safety, not efficacy, of drugs marketed in the US. Because of this major inadequacy in US Food and Drug Administration (FDA) oversight at the time and the principal goal of AHFS to promote rational drug therapy through objective evaluations in a standard format, much of the early commentary in the compendium dealt with refuting unfounded claims made by pharmaceutical manufacturers.

Paramount to providing such information was the critical, evidence-based evaluation of pertinent clinical data concerning drugs, with a focus on assessing thoroughly the advantages and disadvantages of various therapies, including interpretation of various claims of efficacy for pharmaceutical products.

AHFS DI is a tested and proven source of comparative, unbiased, and evidence-based drug information. Drug monographs, and final determinations specifically published for medically acceptable off-label uses, are prepared by a professional editorial and analytical staff, who critically evaluate published evidence on the drug. AHFS does not accept authorship of material published in either a monograph or an off-label final determination from external sources (e.g., practitioners, pharmaceutical manufacturers). Instead, it relies solely on its own professional staff, qualified by education, training, and experience, to research, analyze, draft, and finalize information contained in AHFS DI monographs. Through an external review process, the monographs and final determinations for off-label uses incorporate the advice of leading medical experts in the specific field of therapy under consideration, including experts from major research and clinical institutions as well as public bodies such as the National Institutes of Health (NIH) and US Centers for Disease Control and Prevention (CDC) and professional associations with therapeutic authority.

Using an independent, evidence-based, evaluative process, AHFS DI monographs and final determinations for off-label uses incorporate information from pertinent references in the literature and expert therapeutic guidelines. AHFS DI monographs and final determinations for off-label uses include information on uses, dosages, and routes and/or methods of administration that may not be included in the FDA-approved labeling for the drug (“off-label/unlabeled uses”).

ASHP holds in high regard the responsibilities attendant to the public and private trust placed in the evidence-based editorial deliberations of AHFS DI. As such, ASHP also considers it essential to protect the integrity and independence of the editorial decisions of AHFS staff by separating the Society’s business activities with pharmaceutical manufacturers (e.g., exhibits at educational meetings, journal advertising) from the editorial activities of its drug compendium. An editorial independence statement, approved by ASHP’s Board of Directors, outlines the principles that AHFS staff apply in ensuring such independence.  (See Policy on Editorial Independence of AHFS Drug Information).

Evidence-based Information Analysis for Off-label Uses

AHFS employs sound evidence-based editorial policies; high-quality, content development involving a professional editorial and analytical staff; a well-established expert-review process; independence from pharmaceutical manufacturers and others who may seek to use the source to promote their own interests; an ongoing updating process; a mechanism for correction notification; and broad-based authoritative guideline and best practices incorporation. Use of external volunteers is limited to expert review, not content development

Analysis of information is an intramural process performed by a professional staff of drug information analysts and editors with strong scientific and therapeutic backgrounds. Conducting the process with a professional staff provides a high level of quality control and consistency in content development. The process involves assessment of the scientific merits of available data, typically drawn from numerous references. Comparisons with other therapies are performed when possible. Emphasis is placed on well-designed, controlled studies; published meta-analyses and other systematic reviews (e.g., Cochrane reviews) are addressed, if available, and published cost-effectiveness/benefit and quality-of-life studies also are addressed. If applicable, therapeutic guidelines (e.g., from NIH, AAP, CDC, AHA and other professional organizations) are addressed and incorporated to provide authoritative therapeutic perspective.

When AHFS staff perform a review for an unapproved use, the following elements are considered when evaluating a potential, medically accepted off-label use:

  • availability of published reports of well-designed clinical studies
  • support in peer-reviewed literature
  • assessment of the level of evidence reflected in published reports and systematic reviews
  • absence of potential clinically important concerns about the drug such as increased toxicity with no substantial therapeutic gain
  • positive therapeutic perspective as reflected by clinical evidence, expert opinion, best practices, and/or authoritative guidelines

The importance and severity of the disease, availability of alternative therapies and their relative toxicities, the number of patients affected by the disease, other patient population considerations (e.g., age, gender, pharmacogenomics), and other factors (e.g., cost and economic considerations) also are important considerations. Adding to the weight of evidence are the strength of efficacy data, availability of independent confirmatory studies, support in other peer-reviewed literature (e.g., meta-analyses and other systematic reviews, editorials, disease and drug therapy reviews), recommendations of authoritative groups (e.g., CDC, NIH), evidence of improved risk-to-benefit ratios (including compliance) relative to existing therapeutic alternatives, evidence of a new mechanism or site of action relative to existing alternatives, and evidence of improved pharmacokinetics or pharmacodynamics.

Positive commentary depends on the level of such evidence and expert assessment of the clinical role and importance of the drug as part of reasonable/good medical practice and care. Because of the descriptive nature of the type of drug information published by AHFS, the strengths and limitations of available evidence, as well as any lack of consensus, about the specific role of the drug can be described if necessary.

In addition to this descriptive method of presenting the evidence and recommendations concerning the use of drugs, AHFS DI recently initiated a codified process for objectively summarizing the level of evidence and strength of recommendation for drugs and biologics used in anti-cancer chemotherapeutic regimens.

Codified Levels of Evidence

AHFS initiated a process for developing a codified method for summarizing its evidence-based analyses. (See AHFS Levels of Evidence Rating System). While the principles of the AHFS DI editorial development process had not changed, moving to a structured, codified format that would summarize ongoing staff assessments of new and changing evidence was initiated to aid analysis and evaluation of various drug uses by both staff and expert reviewers. The development of the AHFS evidence rating system applied the principles of Fletcher and Sackett, as reflected most notably in the work of the American College of Chest Physicians (ACCP). FDA guidance documents for assessing clinical trials, levels of evidence applied by the Agency for Healthcare Research and Quality (AHRQ; formerly Agency for Health Care Policy and Research, AHCPR) and ASHP’s Council on Therapeutics, as well as several dozen other documents and resources on evidence-based medicine were addressed as part of this process.

Codified Levels of Evidence-Cancer Specific

Assessment of the recent loss of the United States Pharmacopeia’s (USP’s) evidence-based development process for antineoplastic agents as well as discussions with leading oncology experts prompted development of a separate codified method for summarizing AHFS’ evidence-based analyses of cancer uses for drugs. The decision to create a separate method resulted from the unique characteristics of evidence-based decisions that are applied to serious and life-threatening conditions such as cancer. The principal difference in assessing cancer use information is the inclusion of an indicator of the strength of study end points (e.g., survival, quality of life) in the evidence ratings. In addition, the types and quantity of clinical data that can support a given use will vary depending on the cancer use being evaluated, the availability and acceptability of other therapies, and the specific observations reported in the studies. For example, in refractory cancers where therapies with meaningful benefit are unavailable or there is evidence of improvement over other available therapies, evidence that is reasonably likely to predict clinical benefit (surrogate evidence) can be acceptable. Under such circumstances, even evidence from unblinded, single-arm studies with drugs exhibiting a relatively high degree of toxicity may be acceptable. This approach by AHFS is consistent with distinctions applied to evidence-based assessments of cancer treatments by both the National Cancer Institute (NCI) and FDA.

For additional information, see AHFS Review Process for Off-label Oncology Uses.