Optimizing therapeutic decision‐making for off‐label medicines use: A scoping review and consensus recommendations for improving practice and research +

Off‐label medicines use is a common and sometimes necessary practice in many populations, with important clinical, ethical and financial consequences, including potential unintended harm or lack of effectiveness. No internationally recognized guidelines exist to aid decision‐makers in applying research evidence to inform off‐label medicines use. We aimed to critically evaluate current evidence informing decision‐making for off‐label use and to develop consensus recommendations to improve future practice and research.

• There is currently no internationally recognized guidance for optimizing therapeutic decisionmaking when using medicines off-label.
• Currently lacking are explicit frameworks based on rigorous evidence to support therapeutic decision-making.
• To address this gap, our international, multidisciplinary expert panel developed comprehensive consensus recommendations to optimize therapeutic decision-making for off-label use and concurrently drive timely, clinically relevant medicines research.
• Our guidance has important implications for clinicians, patients, researchers, regulators, the pharmaceutical industry, health technology assessment bodies, payers, and policy makers.

Plain Language Summary
Off-label medicines use is for an indication, dose, route, or age other than what has been approved by a medicines regulator.It is sometimes needed and appropriate but is associated with important clinical, safety, ethical, and financial consequences.We critically reviewed the published literature to understand the scientific rigor of available guidance to inform therapeutic decision-making for such use.There is currently no internationally recognized guidance for optimizing therapeutic decision-making for the off-label use of medicines.Of available guidances we identified, only one-third provide explicit frameworks to support rigorous therapeutic decision-making.To address this gap, our international multidisciplinary expert panel developed comprehensive consensus recommendations to optimize therapeutic decision-making for offlabel use and to concurrently drive clinically relevant research.We recommend: (1) seeking rigorous scientific evidence; (2) using diverse expertise in evidence evaluation and synthesis; (3) using rigorous processes to formulate recommendations for appropriate use; (4) linking offlabel use with timely conduct of clinically meaningful research (including real-world evidence [RWE]) to address knowledge gaps quickly; and (5) fostering partnerships between clinical decision-makers, researchers, regulators, policy makers, and sponsors to facilitate cohesive implementation and evaluation of these recommendations.Successful implementation requires appropriate funding and infrastructure support, with significant challenges that policy makers must urgently address.

| INTRODUCTION
Off-label use of medicines is use for an indication, dose, route, or age other than what has been approved by a regulator and remains a critical issue in modern medicine. 1,2Rates of off-label prescribing vary considerably by population and setting, with up to 69%-100% of pediatric and 72%-95% of adult patients receiving offlabel prescriptions. 1,3,4Global variability in regulatory approvals, prescribing practices and methods for evaluating off-label medicines use is a significant barrier to understanding its true scope and impact.A medicine's labeling status in one country may also not always reflect the latest available evidence internationally. 5,6f-label use is sometimes needed and appropriate, but adequate research evidence to support common off-label uses is often lacking, with 73% of such prescriptions in one large US study found to have little or no scientific support. 7There are important clinical, ethical, and financial consequences of off-label medicines use, 8,9 including from potential ineffective or harmful effects. 3,10,11The COVID-19 pandemic highlighted the negative consequences of inappropriate non-evidence-based off-label use when certain treatments that were widely used off-label were later shown to be ineffective or harmful. 12,13spite efforts by national, 2,14,15 regional, 16 and global organizations like the World Health Organization, 17 there is currently no internationally accepted guidance for off-label medicine use.This contrasts with the extensive international guidances for clinical trials and medicine labeling.Specific guidance to address uncertainties in off-label prescribing would better support: (1) clinicians making prescribing decisions; (2) patients seeking more effective treatments with favorable risk: benefit characteristics; (3) guideline developers focusing on evidence-based prescribing recommendations; and (4) policy makers designing systems for safe and effective use of medicines.
To address this need, our international, multidisciplinary expert panel mapped the available literature to examine the range, nature, and characteristics of guidance for off-label prescribing, highlighting pediatrics as a use case.Our objectives were to: (1) describe the types, extent, and scientific rigor of evidence that informs therapeutic decision-making for off-label medicines use; (2) critically review available national, regional, and international guidance informing off-label prescribing practices; and (3) provide recommendations for optimal generation, evaluation, interpretation, and clinical application of research evidence regarding off-label use of medicines.

| METHODS
This work involved two components: a scoping review and a consensus development process.We undertook a scoping review using the Arksey and O'Malley methodological framework. 18The findings from the scoping review were then used to develop consensus recommendations for evaluation and clinical application of research evidence, which was accomplished using a modified Delphi process. 191 | Scoping review

| Identifying relevant papers
We identified relevant papers from multiple sources, as recommended by Arksey and O'Malley.Sources included electronic databases, reference lists, and existing networks and relevant organizations.The electronic database search strategy, developed in collaboration with a research librarian (E.F.G.), surveyed PubMed, Embase and the Cochrane library for literature published from 2003 to May 2018 (Appendix A).After de-duplication, citations were uploaded into Rayyan 20 for review.We added key publications through 2020 from peer-reviewed and gray literature sources by: (1) searching reference lists of full-text papers meeting initial selection criteria; and (2) accessing information from professional organizations and networks.

| Study selection
Identified papers were screened by five teams of two independent reviewers in two phases: (1) title/abstract and ( 2) full text review (Figure 1).Disagreements between reviewers were resolved through discussion.Data were abstracted from papers meeting the eligibility criteria (Appendix B).Papers were categorized as (A) general guidances regarding off-label medicines use or (B) therapeutic areaspecific guidances for off-label use.

| Data collection
Elements abstracted from eligible papers included author names, title, journal, publication year, PubMed identifier, authors' countries of origin, article type, organizations represented, target audience, patient population and topics covered, recommendation or guideline development process, evidence used, stakeholder involvement, guidelines for medical decision-making, and audience/expert type.REDCap (Research Electronic Data Capture) tools 21

| RESULTS
3.1 | Summary of the scoping review

| Identification of relevant papers
A total of 5109 publication records were screened, 31 of which were included in the analysis (Figure 1).[40][41][42][43][44][45][46][47] 3.1.2| Thematic concepts of general guidances for off-label medicine use The majority of general guidances were described as guidelines, guiding principles, policies, or standards (   Australia; only two had a global scope. 17,36Notably, none were primarily developed by major medicines regulators, although these agencies occasionally collaborated on guidances developed by others. 14,24,34idance development processes and expertise involved Sponsors of recommendations included national or regional professional and health care organizations as well as groups concerned with HTA or appropriate use of medicines.None received pharmaceutical industry funding.Half of general guidances explicitly described their internal guidance development processes (Table 2). 8,14,15,17,22,28,29,32,34,36,37One-third of guidances described systematic consensus development processes (e.g., Delphi, US NIH consensus development process) or invited input from external organizations. 8,14,15,32,34,36,37 Only some guidance development processes noted participants' expertise in evidence evaluation (30%), for example, clinical epidemiology, evidence-based medicine, critical appraisal; and in specialized therapeutics (15%), for example, clinical pharmacology, quality use of medicines; and health economics (40%).Other relevant areas of contributing expertise included medical ethics (60%), medical-legal issues (40%), and patient/consumers (50%) (Table 2).

Recommendations for decision-making about off-label uses
All guidances made recommendations on the need for sound decisions about the appropriateness of off-label prescribing, with 65% providing specific recommendations or key principles to guide this crucial step (Table 2).However, only one-third (35%) detailed frameworks for optimal management of proposed off-label uses, including types of evidence needed for evaluating benefits and risks, types of expertise (e.g., methodological expertise in evidence evaluation, specialized pediatric clinical expertise), and processes for evaluating evidence and reaching clinically sound judgments.]22,24,25 One-third (35%) discussed processes for improving therapeutic decision-making by linking identified evidence gaps to formal research initiatives to generate RWE. 8,14,15,17,25,28,33

Ethical considerations
Guidance recommendations diverged widely in addressing the ethics of off-label medicines use ( information for patients and caregivers and obtaining informed consent.Five guidances provided detailed ethical frameworks for evaluating the appropriateness of off-label treatment, including comprehensive informed consent processes. 8,14,22,29,301.3| Thematic concepts of off-label use guidances specific to a therapeutic area Of 10 papers addressing specific medicines or therapeutic categories (Table 3), most focused on treatment efficacy or effectiveness.With one exception, 42 safety considerations or risk-benefit evaluations were incompletely addressed.Comparative effectiveness or costeffectiveness were generally not considered except occasionally as important evidence gaps.40,42 Only four papers used systematic consensus development processes.41,[45][46][47] Multidisciplinary panels always included clinicians, usually specializing in the therapeutic area under consideration.Fewer reported participants with other relevant expertise, such as evidencebased medicine, practice guideline development, 41 or patient advocacy.45 Just two guidances concluded their evidence review processes with identification of important research priorities to address evidence gaps.The final consensus framework, with key recommendations, subthemes, and important relationships between them, are described in Recommendation 4 is to link the process of therapeutic decisionmaking for off-label medicines use routinely to the prioritization and conduct of relevant research (interventional and observational) so that knowledge gaps can be addressed in a timely manner.
Recommendation 5 is to foster enhanced partnerships among regulators, clinicians, policy makers, researchers, and sponsors to

| DISCUSSION
We identified 31 publications informing an enhanced understanding of the evidence and scientific rigor underpinning therapeutic decisionmaking for off-label medicines use.We found no globally recognized guidance for optimizing evidence-based decision-making in this context, representing a significant gap.Of 20 guidances with general recommendations, only one-third provided explicit frameworks or guidance about the types and quality of evidence needed and rigorous processes for evaluating this evidence to reach sound, ethical judgments about appropriate off-label use.Key aspects of these more rigorous frameworks informed our recommendations for optimal practice (Figure 2 and below), which focus on evidence rather than labeling status as the central driving principle.We discuss our recommendations in the context of strengths, limitations, and gaps in currently available guidances.

| Recommendation 1: Seek rigorous scientific evidence
To improve therapeutic decision-making for any intended off-label use, we recommend systematic evaluation of the best available research evidence (including RWE) about a medicine's clinical effectiveness and safety, rigorous assessment of overall benefits versus risks for specific patients and contexts, and assessments of comparative effectiveness and safety relative to non-intervention or other available treatments.These assessments should be informed by evidence from populations and settings where off-label use occurs.For example, safety profiles of medicines can differ between adult and pediatric populations as well as within pediatric age groups, 17 with important implications for risk: benefit assessments for these subgroups.Cost-effectiveness considerations are relevant, but such evidence is usually lacking for off-label uses.
We found few guidances that explicitly described the types of evidence needed (e.g., from randomized controlled trials, observational studies, RWE) or procedures for evaluation using recognized tools for appraising or grading evidence. 8,14,15,17,22,28,32,34Very few guidances described the specific types of evidence needed for comprehensive safety evaluations. 8,14,17Only one pediatric-focused guidance provided descriptions of specific types of evidence needed to optimally evaluate appropriateness of off-label use in this population. 17Our recommendations align with several of these key guidances which provide more details about the types of evidence to be sought and optimal approaches for evaluation to inform rigorous risk: benefit assessments.
Key national 23,24,26,27 or regional 16,25  T A B L E 3 Characteristics of medicine-specific guidances on off-label medicine use.

| Recommendation 2: Utilize expertise in evidence evaluation and synthesis
Input of relevant expertise is critical to inform judgments about the types of evidence needed, and to evaluate the validity, clinical meaningfulness, and applicability of evidence. 17 (3) diverse patient and caregiver perspectives.
Pharmacoepidemiology and pharmacovigilance expertise, methodologies, and tools are important for judicious decisions about the types of evidence needed and optimal evidence evaluations to inform rigorous risk: benefit assessments.Appropriate knowledge and skills are particularly important for critically appraising a range of data sources, methodologic approaches, and evidence produced, including RWE.Relevant clinical expertise must also inform these judgments concurrently.Similarly, patients and caregivers can provide key insights about which outcomes matter to them and how they balance risks and benefits.Appropriate processes must be in place to manage potential conflicts of interest and ensure independence of experts involved in these evaluations.
When the quality of available evidence is limited (common in pediatric and certain other populations), access to an independent, well-balanced mix of expertise and perspectives is likely to positively influence the rigor and soundness of overall evaluations, including decisions about any trade-offs between evidence and unmet clinical needs (see Recommendation 3).
Only one-fifth of general guidances provided explicit recommendations about the types of expertise to include in groups tasked with evaluating evidence and developing recommendations for off-label uses. 14,28,32,34This reflects a significant gap in most currently available guidances for therapeutic decision-making.2).We recommend adopting a similar approach.For example, one guidance 14,15   and EU, 3,[48][49][50] the prevalence of pediatric off-label prescribing remains high. 51,52Additional measures are urgently needed to provide more direct linkage between clinical use and evidentiary challenges and the prioritization of research to address them. 53Therefore, we recommend more timely conduct of relevant medicines research (interventional and observational studies) to be prioritized based on identified knowledge gaps and the likely extent and potential risks of off-label use.
To inform future decision-making with more timely evidence, we also recommend new or existing unsupported off-label uses be routinely linked to prospective evaluation of outcomes (e.g., effectiveness, safety, comparative effectiveness/safety, cost-effectiveness).Recently the U.S. FDA has released guidance statements for the use of RWE to support regulatory approval 54 and the European Medicine Regulatory Network has also outlined an ambitious vision for the use of RWE across the spectrum of medicines regulation by 2025. 55utine linkage will catalyze generation of clinically meaningful RWE to address benefits, risks, and therapeutic alternatives of

Seek Rigorous ScienƟfic EVIDENCE
• Evidence of effecƟveness in relevant populaƟon • Evidence of safety in relevant populaƟon • Benefit:risk assessments, including for different sub-populaƟons • ComparaƟve effecƟveness and safety data, if available

Use rigorous PROCESSES to formulate recommendaƟons
• Establish evidence thresholds for off-label use these matters to professional judgment. 57Historically, these bodies have regulated sponsors' promotion of off-label uses 9,57 or intervened after significant safety concerns emerged. 58Regulators and sponsors also monitor off-label uses through postmarketing studies, although the suboptimal effectiveness of these measures to date needs greater attention. 59Risk minimization measures may be initiated to address problems identified and improve adherence to existing evidence-based prescribing guidelines.
We recommend regulators and sponsors consider adopting a more proactive role by collaborating with relevant stakeholders (e.g., clinicians, researchers, policy makers) to develop guidance supporting a more explicit approach to therapeutic decisionmaking for off-label uses.Such guidance would enable various decision-makers (e.g., prescribers, HTA bodies, developers of prescribing guidelines/information, funders/payers) to be more con-

| STRENGTHS AND LIMITATIONS
We used rigorous methods for our scoping review and consensus recommendations.Use of a multinational, multidisciplinary expert panel and formal consensus methods for developing recommendations strengthens their validity and generalizability.Our search strategy may not have identified all relevant publications, especially those from the gray literature, those that did not involve pediatric populations, and those published after the conduct of our literature search.
hosted at the University of Colorado Denver facilitated data abstraction.The lead investigator (M.G.) reviewed all included papers and abstracted additional details to ensure capture of relevant information and to synthesize key concepts and themes, which were then reviewed by other team members for comments and arƟcles excluded (n = 294)

38 , 42 3. 2 |
Summary of the consensus development process (modified Delphi): Recommendations to optimize therapeutic decision-making for off label medicines use Based on key thematic concepts identified by the scoping review and insights from our expert panel, we developed draft recommendations addressing five interconnected themes.The first round of voting achieved ≥80% consensus on one of the five recommendations.After several rounds of discussion, text revisions, and voting by the expert panel, ≥80% consensus was reached for all five recommendations.

Figure 2 .
Figure 2. Three of our five recommendations focus on optimizing therapeutic decision-making for off-label medicines use by: (1) Seeking rigorous scientific evidence to support proposed use; (2) Utilizing expertise in evidence evaluation and synthesis to critically evaluate available evidence, informed by relevant clinical issues and patient and caregiver perspectives; and (3) Using rigorous processes to formulate sound recommendations.
We recommend these complex tasks should be informed by expertise from multiple relevant domains: (1) methodological expertise: for example, evidence-based medicine, clinical epidemiology, pharmacoepidemiology, clinical pharmacology, pharmacoeconomics; (2) clinical and therapeutics expertise: for example, clinicians providing care to target populations (e.g., pediatricians, geriatricians, oncologists), and clinicians with broader therapeutics expertise, such as clinical pharmacology and clinical pharmacy, including specialized expertise in relevant sub-populations (e.g., pediatrics, geriatrics); and

4. 4 |
Recommendation 4: Link off-label medicines use to research Evidence thresholds to justify off-label use (see Recommendation 3) would not only help reduce inappropriate use but could facilitate addressing identified knowledge gaps by creating stronger demand for needed evidence from clinical decision-makers.This demand could help complement the current major regulatory drivers for medicines research in populations such as pediatrics.Despite strong regulatory and research measures existing for many years in the United States

3 . 3 .
(pediatric* or neonatal or newborn* or child* or infan* or adolescen* or teen* or youth* or paediatric* or baby or babies or juvenile*):ti,ab,kw. 4. #1 and #2 and #3.AP PE NDIX B: STUDY SELECTION CRITERIA FOR SCOPING REVIEW Inclusion Criteria (Study included if criterion 1 present AND at least one of criterion 2-4 also present) 1. Guidance, standards, or policy for off-label use decision-making or oversight, especially if any of the following are mentioned: Medicines regulators (e.g., FDA, EMA) Bodies involved in Health Technology Assessment and/or medicines access or funding related decision-making or advice provision Bodies involved in developing therapeutic guidelines and other medicines information resources to guide decision-making about available medicines Professional and other national bodies involved in developing policy, setting professional standards, and/or providing general guidance about medicines use 2. Explicit description of types of evidence used and the process and rigor of evidence evaluation to inform off-label use decisions Evaluate the impact of guidance on off-label use and outcomes (especially safety) 4. Address specific population where off-label use is likely to be high (e.g., pediatrics, neonates, rheumatology, oncology, etc.) and the term "off-label" is mentioned in title/abstract/key terms

Table 2
Characteristics of general guidances on off-label medicine use.
Agency for Healthcare Research and Quality; BNFc, British National Formulary for Children; CMS, Centers for Medicare and Medicaid Services; DTC, Drug and Therapeutic Committee; EMLc, Essential Medicines List for Children; FDA, Food and Drug Administration; JAMA, Journal of the American Medical Association; MEDCAC, Medicare Evidence Development and Coverage Advisory Committee; NICE, National Institute for Health and Care Excellence; NIH, National Institutes of Health PBRN, Practice-Based Research Network; WHO, World Health Organization.