Regulatory Perspectives

One of the most important aspects of regulatory decision-making is the assessment and communication of the risks and benefits of medicinal products in a transparent and structured manner. This is highlighted in the recent guidance formulated by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), as part of the revisions to its guidance document M4E: The CTD - Efficacy (ICH 2016). The updated document provides flexibility and general recommendations for formatting and structuring benefit-risk assessments, without any explicit suggestion for or against specific methodologies or approaches.

In 2005 the US FDA issued a framework for the pharmaceutical industry that consisted of guidelines for premarketing risk assessment, development, and use of risk minimization action plans, and good pharmacovigilance practices and pharmacoepidemiologic assessment (Guo et al. 2010). Subsequently, the agency developed an enhanced framework for benefitrisk assessment to provide a “structured, qualitative approach focused on identifying and clearly communicating key issues, evidence, and uncertainties in FDA’s benefit-risk assessment and how those considerations inform regulatory decisions” (FDA 2013). As depicted in Figure 2.5, the Benefit-Risk Framework (BRF) outlines the critical elements that are relevant for the benefit-risk assessment and provides specifications for describing the evidence and uncertainties as well as the conclusions and reasons for each dimension. Further, it gives an integrated summary of the assessment, with a succinct explanation and rationale for regulatory decisions.

On behalf of the European Medicines Agency (EMA), the Committee for Medicinal Products for Human Use (CHMP) has also issued similar guidelines, including an assessment of the potential value of existing benefit-risk models and methods (Guo et al. 2010). In 2010, the EMA sponsored the Benefit-Risk Methodology Project, which reviewed several qualitative and quantitative approaches, and proposed PROACT-URL

Benefit-Risk Integrated Assessment

Benefit-Risk Dimensions


Evidence and Uncertainties

Conclusions and Reasons

Analysis of Condition

Current Treatment Options


Risk and Risk Management

FIGURE 2.5 FDA Benefit-Risk Framework

Source: (Accessed on June 9,2019)

(Problem formulation, Objectives, Alternatives Consequences, Tradeoffs, Uncertainties, Risk tolerance, Linked decisions) (EMA 2010a). The agency’s emphasis on benefit-risk assessment was further reinforced in the so-called Roadmap-to-2015 framework, in which the benefit-risk balance assessment model was identified as one of the strategic areas (EMA 2011). A related unit that the EMA coordinates is the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP), which primarily focuses on the strengthening of the evaluation of the benefit-risk balance of medicines through the conduct of high-quality observational studies.

The EMA introduced the so-called Effects Table with a view to enhancing the consistency, transparency, and communication of benefit-risk assessments (EMA 2015). The table, displayed in Figure 2.6, presents effects and information for the benefit-risk balance, and allows incorporation of results based on quantitative methods.

Efforts are also under way in other countries, such as Australia, to develop a framework for effective assessment and communication of benefits vs. risks of medicines.

Recently, regulatory bodies have shown keen interest in incorporating patient preferences in making decisions. In the US, there are several FDA


Short Description




Uncertainties/ Strength of evidence




FIGURE 2.6 EMA Effects Table

Source: EMA. Guidance document on the content of the Rapporteur day 80 critical-assessment report. Overview and lists of question. 2015. EMA/90842/2015. Available from guideline/2009/10/WC500004800.pdf.

guidance documents that provide specific suggestions on integrating patient preferences into benefit-risk assessments. Further, the 21st Century Cures Act and the Prescription Drug User Fee Act, Revision VI (PDUFA VI) of the FDA Reauthorization Act highlight the importance of considering the patient experience during the drug-development process. In Europe, similar initiatives are under way, including a collaborative project known as The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT), which is concerned with the exploration of how preferences can be incorporated into the decision-making process (Hughes et al. 2016).

Benefit-Risk in Health-Technology Assessment

Some of the approaches, including the MCDA, have also been applied in health-technology assessment (HTA) decisions. HTA is a framework employed in several countries for the purpose of making reimbursement decisions for new technologies, applying agreed-upon principles and criteria. HTA bodies in several countries, such as Germany, England, Australia, and Thailand, leverage MCDA approaches in coverage decision-making (Thokala et al. 2016). Although the approaches tend to differ among the various HTA systems, there are certain elements that are common to many of them, including the incorporation of data on effectiveness, patient need, and burden of disease.

One area that seems to be a point of contention is the consideration of cost and budget impact as factors in the implementation of MCDA models in HTA. In addition, the quantitative incorporation of patient preference data in HTAs is not as well-established as it is in benefit-risk assessment (Mott 2018). This is often attributed to the limitations of the commonly used methods in HTA, such as cost-utility analysis, which only focus on eliciting health-state utilities from patients. In this respect, MCDAs may provide an attractive alternative (Angelis 2017).

Concluding Remarks

In this section, we provided a high-level overview of benefit-risk assessment methods and the associated issues. A balanced assessment of the benefits and risks of a drug presupposes a synthesis of stakeholder preference with quality evidence on effectiveness and safety and communicating the results in a transparent and succinct manner. Accordingly, there have been important achievements in recent years by regulators that include frameworks to enhance the process of benefit-risk decision-making. In addition, pharmaceutical companies routinely institute risk evaluation and mitigation strategies for their prescription drugs, and coordinate efforts with regulatory bodies to align approaches.

Notwithstanding the availability of guidelines and reporting tools, there is still a need to develop a harmonized framework to enhance the assessment and communication of benefits and risks. Although, qualitative approaches appear to be preferred by some regulatory bodies and other stakeholders, the role of quantitative approaches is expected to continue to evolve as more experience and confidence are accrued in the operating characteristics of the methods and interpretability of the associated results.

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