Balancing benefit and risk of medicines: a systematic review and classification of available methodologies

Mt‐Isa, Shahrul; Hallgreen, Christine Erikstrup; Wang, Nan; Callréus, Torbjörn; Genov, Georgy; Hirsch, Ian; Hobbiger, Stephen F.; Hockley, Kimberley; Luciani, Davide; Phillips, Lawrence D.; Quartey, George; Sarac, Sinan B.; Stoeckert, Isabelle; Tzoulaki, Ioanna; Micaleff, Alain; Ashby, Deborah

doi:10.1002/pds.3636

Cited by 105 publications

(171 citation statements)

References 99 publications

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“…These data, in combination, can then inform a more comprehensive risk-benefit assessment of medications by using 1 of numerous proposed methods. 8 …”

Section: Effectiveness Research Throughmentioning

confidence: 99%

Beyond the Label: Steering the Focus Toward Safe and Effective Prescribing

et al. 2017

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Each year, hundreds of millions of prescription medications are dispensed to pediatric patients. 1 A significant proportion of prescriptions are used in an off-label manner, outside the specifications approved by the US Food and Drug Administration (FDA), rendering off-label prescribing a "public health issue for infants, children and adolescents, " as described by the Committee on Drugs for the American Academy of Pediatrics. 2 The committee also explicitly states that off-label use "does not imply an improper, illegal, contraindicated or investigational use. " Yet, when used in research, clinical practice, or even the lay media, the term off-label commonly carries a negative connotation. This interpretation probably reflects the sense of uncertainty in understanding the risk-benefit balance of a medication without FDA review and approval. However, prescribing according to the package insert does not necessarily translate to the safe and effective use of a medication. 3 The clinical trial data required for FDA approval often represent highly select populations in controlled settings with limited follow-up. These data may not translate well to real-world use, hence the need for postmarketing surveillance and research. Conversely, lack of pediatric labeling for a medication does not necessarily indicate a lack of evidence. It may simply mean the pharmaceutical company has not submitted an application for FDA approval to add a new indication or population.This apparent paradox gives us the opportunity to consider how we, the pediatric community of clinicians, researchers, and policymakers, think about the issue of off-label prescribing and how best to direct future efforts in medication research and policy. The Best Pharmaceuticals for Children Act prioritization process focuses on gathering expert opinion to inform research priorities related to therapeutic needs, with a primary goal of identifying drugs for pediatric clinical trials. 4 We argue that such approaches should be complemented by a structured consideration of risks and benefits informed by increasingly available data from practice. Pediatric research on off-label prescribing often focuses on the dichotomy of on-label versus off-label prescribing rates, defined mainly by age limits and occasionally indication. Understanding the extent of off-label practice is important, but it represents only a single dimension of a complex issue. This information does not necessarily determine whether the way a

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“…These data, in combination, can then inform a more comprehensive risk-benefit assessment of medications by using 1 of numerous proposed methods. 8 …”

Section: Effectiveness Research Throughmentioning

confidence: 99%

Beyond the Label: Steering the Focus Toward Safe and Effective Prescribing

et al. 2017

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“…12 Other methodologies may also be suitable depending on the situations and must not blindly be dismissed. 12,14,26 The choice of methodologies may depend on different therapeutic area (e.g. depending on use of time-toevent statistics), time of appraisal and regulatory requests.…”

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confidence: 99%

“…26,57 It was suggested by IMI-PROTECT WP5 to test 13 methodologies in future benefit-risk assessment: PrOACT-URL, BRAT, MCDA, SMAA, NNT/NNH, Impact numbers, QALY, Q-TWiST, INHB, BRR, probabilistic simulations, MTC, and DCE (see Table 6 and Table 7 for abbreviations), and further classifications of methodologies can be found in the PROTECT WP5 report. 12 Other methodologies may also be suitable depending on the situations and must not blindly be dismissed. 12,14,26 The choice of methodologies may depend on different therapeutic area (e.g.…”

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confidence: 99%

“…The IMI-PROTECT Work Package 5 (WP5) on Benefit-Risk Integration and Representation performed a review on 47 benefit-risk assessment methodologies and classified them into benefit-risk frameworks, metric indices for BR assessment, estimation techniques and utility 12,26 Several case studies used publically available data to test the recommended methods in order to assess their practicalities when applied to real-life decision problems of pharmaceutical products with delicate benefit-risk balance. [27][28][29][30][31][32][33][34][35] The key summary and lessons learned from testing the methods in case studies were distilled into a final set of recommendations in a roadmap of benefit-risk assessment stages.…”

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confidence: 99%

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Structured Benefit–risk assessment: a review of key publications and initiatives on frameworks and methodologies

Mt‐Isa

Ouwens

Robert

et al. 2015

Pharmaceutical Statistics

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Abstract:Introduction The conduct of structured benefit-risk assessment (BRA) of pharmaceutical products is a key area of interest for regulatory agencies and the pharmaceutical industry. However, the acceptance of a standardized approach and implementation are slow. Statisticians play major roles in these organizations, and have a great opportunity to be involved and drive the shaping of future BRA. MethodWe performed a literature search of recent reviews and initiatives assessing BRA methodologies, and grouped them to assist those new to BRA in learning, understanding, and choosing methodologies. We summarized the key points and discussed the impact of this emerging field on various stakeholders, particularly statisticians in the pharmaceutical industry. ResultsWe provide introductory, essential, special interest, and further information and initiatives materials that direct readers to the most relevant materials, which were published between 2000 and 2013. Based on recommendations in these materials we supply a toolkit of advocated BRA methodologies. Discussion Despite initiatives promoting these methodologies, there are still barriers, one of which being the lack of a consensus on the most appropriate methodologies. Further work is needed to convince various stakeholders.

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“…Better communication will also facilitate the cost-effectiveness exercise. Frameworks for better structuring and communicating the assessment are being assessed by EMA, FDA and the pharmaceutical industry (Phillips et al, 2011;Food and Drug Administration, 2013;Mt-Isa et al, 2014;Levitan et al, 2011). Implementation of personalized medicine will challenge the current oncology practice, regulatory standards for drug access and approval, and reimbursement policies (Tsimberidou et al, 2013).…”

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confidence: 99%

Assessment of benefits and risks in development of targeted therapies for cancer — The view of regulatory authorities

Pignatti¹,

Jönsson

Blumenthal

et al. 2014

Molecular Oncology

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A B S T R A C TDrug licensing and approval decisions involve the balancing of benefits against the risks (harms) in the presence of uncertainty. Typically, the benefits are estimated from primary efficacy endpoints from confirmatory (phase III) clinical trials although exceptions where promising early data from single-arm studies have led to accelerated approvals are not uncommon, particularly for cancer drugs.The challenge for regulators is to balance early evidence of efficacy that might support approval versus the need to establish clinical benefit based on conclusive evidence. Targeted agents offer the promise that knowledge about the mechanism of the disease will help identify patients with tumors likely to respond, resulting in higher efficacy and less toxicity, and earlier regulatory decisions based on convincing evidence of clinical benefit.In this paper, we describe methods and examples of benefit-risk assessment of targeted drugs, recent initiatives from EMA and FDA on improving communication about benefits and risks, and discuss future steps.Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.

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Balancing benefit and risk of medicines: a systematic review and classification of available methodologies

Cited by 105 publications

References 99 publications

Beyond the Label: Steering the Focus Toward Safe and Effective Prescribing

Beyond the Label: Steering the Focus Toward Safe and Effective Prescribing

Structured Benefit–risk assessment: a review of key publications and initiatives on frameworks and methodologies

Assessment of benefits and risks in development of targeted therapies for cancer — The view of regulatory authorities

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