The United States Food and Drug Administration (FDA) focuses on regulating the approval of prescription drugs rather than regulating the prescribing practices of physicians. Therefore, the use of medications for indications beyond those formally evaluated is allowable in medical clinical practice.
The full and ultimate use of a drug is rarely evident at the time of initial FDA-approval or marketing. The discovery and clinical adoption of new uses for marketed drugs or for investigational drugs often precedes FDA approval of such uses. In some cases, as in treatments for rare diseases or for underserved populations, there may be substantial literature evidence and/or clinical experience, yet little financial incentive, for a manufacturer to pursue FDA approval. A 1996 GAO report (Prescription Drugs, Implications of Drug Labeling and Off-Label Use) has shown that "off-label" drug use (e.g., the use of a drug for an indication not approved by the FDA) is substantial in situations where satisfactory treatment is not available and that there are lower rates of off-label use when there is an effective therapy.
An expected role of any drug compendia in regards to off-label drug use listings is to consolidate published scientific literature and to provide the user quick access to appropriate information that may assist in making a decision regarding the appropriate use of the drug for a specific patient. Elsevier/Gold Standard recognizes the importance of emerging therapies that promote medical advancements in the treatment of human disease and health conditions. The exclusive inclusion of only "labeled" information (e.g., uses for or information about a drug approved by the FDA and included within the FDA-approved product labeling) within our database would limit the utility and scope of our information to clinicians. Therefore, Elsevier/Gold Standard drug information databases include off-label indications and other clinical data that may be outside the scope of the FDA-approved drug product labeling.
Elsevier/Gold Standard is committed to providing unbiased, comprehensive drug information that is accurate, clinically relevant, and current. In order to represent such best practices in drug therapy, Elsevier/Gold Standard follows a specific policy regarding the incorporation off-label drug data, including indications.
Off-label drug indication data are included within the Elsevier/Gold Standard drug database when identified as a clinically relevant or as emerging treatment that are adequately supported by a systematic review of the evidence. Off-label data are primarily identified for inclusion in the database by the editorial team 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/Gold Standard 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.
The Elsevier/Gold Standard editorial team conducts a thorough search of primary literature and other accepted sources of information to identify applicable, published information, including negative or equivocal findings. Searches ensure that relevant and timely publications are considered. After the research is completed, the evidence is reviewed and independently evaluated by at least 2 members of the Elsevier/Gold Standard editorial team and/or review board. Elsevier/Gold Standard will rate all off-label indications using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.1-6 Each off-label use will be assigned a quality of evidence rating and a strength of recommendation by the Elsevier/Gold Standard editorial team. Because many studies may be used to evaluate a single off-label use, each individual study will be graded for quality of evidence; the results of the individual rankings will be combined to provide an overall quality of evidence and strength of recommendation for each off-label use.
The GRADE system provides guidelines for evaluating and rating the quality of evidence and utilizes four (4) quality of evidence levels:
High
Moderate
Low
Very Low
Initially, a well-designed randomized phase III trial receives a "High" quality of evidence level. Factors that may cause the quality of evidence to be downgraded to a lower quality level include study design flaws, inconsistent results from other studies, imprecise results (e.g., small patient numbers, wide confidence intervals), and use of study endpoints that are disease focused vs. patient focused (e.g., overall response rate vs. overall survival, LDL cholesterol concentration vs. myocardial infarction or stroke). When multiple studies are used to evaluate an off-label use and the studies differ in quality of evidence, the highest quality of evidence studies will be used to drive the strength of recommendation.
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. Utilizing GRADE as a framework, Elsevier/Gold Standard applies one of the following when assigning strength of recommendation:
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/Gold Standard 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 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 modules.
Equivocal/Weak Recommendation: Off-label uses that have inconclusive data "For" or "Against" use carry an Equivocal/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/Gold Standard. All off-label uses with an Equivocal/Weak level of recommendation will appear in the database and be clearly identified as equivocal; however, a weak recommendation "Against use" will not be found within the clinical decision support modules.
The documentation of off-label data includes all evidentiary references and will include a summary of the evidence in descriptive fashion. All off-label indications, dosage, and related data are clearly designated within the content of our data.
The Elsevier/Gold Standard Editorial Policy governs all clinical drug data production. A peer-review process is ensured via the editorial policy and our electronic drug data production systems. All editorial staff members must comply with the Elsevier/Gold Standard Editorial Conflict of Interest Policy.
Guyatt GH, Oxman AD, Vist G, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ, for the GRADE Working Group. Rating quality of evidence and strength of recommendations GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924-926
Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schünemann HJ; GRADE Working Group. Rating quality of evidence and strength of recommendations: What is "quality of evidence" and why is it important to clinicians? BMJ. 2008 May 3;336(7651):995-8
Schünemann HJ, Oxman AD, Brozek J, Glasziou P, Jaeschke R, Vist GE, Williams JW Jr, Kunz R, Craig J, Montori VM, Bossuyt P, Guyatt GH; GRADE Working Group.Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008 May 17;336(7653):1106-10
Guyatt GH, Oxman AD, Kunz R, Jaeschke R, Helfand M, Liberati A, Vist GE, Schünemann HJ; GRADE working group. Rating quality of evidence and strength of recommendations: Incorporating considerations of resources use into grading recommendations. BMJ. 2008 May 24;336(7654):1170-3
Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, Schünemann HJ; GRADE Working Group. Rating quality of evidence and strength of recommendations: Going from evidence to recommendations. BMJ. 2008 May 10;336(7652):1049-51
Jaeschke R, Guyatt GH, Dellinger P, Schünemann H, Levy MM, Kunz R, Norris S, Bion J; GRADE working group. Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive. BMJ. 2008 Jul 31;337:a744