The Future of Benefit-Risk Assessments
Benefit-risk information can be presented in a new format and structure that enables stakeholders to make carefully balanced decisions. Having a framework for benefit-risk decision making can greatly inform and clarify the regulatory discussion, and this is recognized in the revised version of the guideline, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M4E(R2) on “Enhancing the Format and Structure of Benefit-Risk Information,” which now enters the implementation period.
Defining whether the benefit of a medicinal product outweighs its risk is a real challenge and needs to be assessed throughout the product lifecycle. This assessment is an important basis for decision making for a broad group of stakeholders, and it needs to be both transparent and consistent. Furthermore, all stakeholders are interested in seeing that the benefit-risk (BR) assessment at the time of approval predicts the BR profile of a marketed product. Historically, BR balance decision making has centered on qualitative judgments with two main challenges in performing these assessments: the lack of transparency, and consistency and the fact that the assessment at the time of approval often does not predict the BR profile in a later stage.
However, the picture is changing. Regulators are now expected to ensure consistency, transparency and predictability of the outcome of the assessment using descriptive/quantitative frameworks.
Providing greater structure for the BR assessment has long been a priority topic in drug regulation. But the associated guidance and documentation for BR assessment within the ICH Common Technical Document (CTD) — revised in 2002 — has not kept pace with this progress. Both regulators and industry have developed approaches for structured BR assessment (so-called frameworks) that are currently being implemented in their respective organizations.
While these approaches may take different forms, they include a common thread that could inform the harmonization of the format and structure of BR assessments.
During the early summer of 2016, the revised version of the regulatory guideline, ICH M4E(R2) on “Enhancing the Format and Structure of Benefit-Risk Information,” reached step 4 of the ICH process and now enters the implementation period (step 5). Based on these guidelines, the critical analysis presented in the CTD Clinical Overview should include a rationale for the product, as well as overviews of biopharmaceutics (if appropriate), clinical pharmacology, efficacy and safety, and a critical appraisal of the potential benefits and risks of using the medicinal product in clinical practice.
Table 1: Revisions to the CTD Clinical Overview (module 2.5)
While the original ICH and U.S. Food and Drug Administration (FDA) guidelines provide general recommendations on the topics that need to be covered in the BR section, regulators have over time found a high degree of variability in how the industry addresses this section. This variability has at times resulted in inefficient communication and poor facilitation of BR assessment discussions between the industry and regulators.
M4E(R2) provides significantly more guidance on how to write section 2.5.6 (benefits and risks conclusions) of the Clinical Overview, including the adoption of new subheadings that were not included in M4E(R1). M4E(R2) also provides additional guidance regarding section 2.5.1 (product development rationale). The guidance specifies inclusion of patient preference data in the CTD at the time of filing for marketing authorization.
Section 22.214.171.124, as per draft M4E(R2), will be the overall BR assessment and should include a concise description of the reasoning and clinical judgment that are used in assessing and weighing the key benefits and risks of the medicinal product. While other portions of the newly proposed section 2.5.6 can include factual descriptions of the clinical data, the BR assessment should focus on interpreting the data.
The draft guideline suggests various approaches for conducting the BR assessment, and states that a descriptive (qualitative) approach to explain the data and its interpretation may be adequate.
Beyond this, the guideline does not define a specific methodology that should be followed, although it suggests that in certain circumstances a quantitative approach may be acceptable. The guideline clarifies that section 126.96.36.199 permits summary tables and/or graphical displays to help communicate the clinical importance of the key benefits and risks, and the resulting BR assessment.
This section should consist of the following:
- How the severity of disease and expected benefit influence the acceptability of the risks of the therapy and how the medicinal product addresses a medical need
- Which key aspects of risk management are important in reaching a favorable BR assessment, such as:
- The proposed labeling
- Potential to readily identify nonresponders, allowing them to discontinue treatment
- Other risk management activities, such as registries or restricted distribution systems
Therefore, this section of the CTD requires careful alignment and integration with the risk management plan (RMP) and other sections of the CTD to maintain consistency.
Finally, whatever BR methodology is used, it needs to be presented in detail, together with the results used in the BR assessment (summarized in section 188.8.131.52) in an appendix (section 184.108.40.206).
How Huron Can Add Value
Regulatory or industry standards for the use of BR methodologies continue to elude the sector. However, their inclusion within the CTD and RMP is strongly encouraged, indeed, mandated (especially with the updated ICH M4(R2) guidance). In addition, recent draft European Medicines Agency guidelines on periodic safety update reports, the expanded template for rapporteur marketing authorization assessment and the FDA draft the Prescription Drug User Fee Act V implementation plan are positive steps in that direction, although they do not set out any preferred tools for BR assessment. New concepts and approaches for BR evaluations have emerged in recent times and these approaches will lead to more systematic, predictable and transparent BR decisions. Continuing collaboration between industry, regulators, payers and patients will be required to advance the BR frameworks for understanding benefits and risks, Pope Woodhead (PW) is ideally placed to facilitate these discussions. Different methods will be developed to suit different purposes, ranging from informing late-stage drug development to BR re-evaluation in the post-marketing space.
Ultimately drugs are developed for patients, and it is logical to place the patient at the center of any decision regarding the BR assessment of a medicine. However, this patient-focused view is far from the current practice, and a shift in the paradigm is needed. PW is prepared for this, and has much applied experience with patient interactions coming from noninterventional post-authorization safety studies it has conducted.
In addition to the BR frameworks outlined previously, the developmental risk management plan (DRMP) and RMP are valuable tools, along with post-authorization efficacy and safety studies that can include real-world effectiveness and BR data, which could (in turn) support reimbursement and provide data for additional indications.
With an in-depth knowledge of international markets and therapeutic pathways, together with understanding each stakeholder perspective and BR assessment frameworks, the PW team is ideally positioned to devise and present bespoke BR strategies. The PW development team can help with all aspects of planning, from development-stage and submission-ready documents to ongoing updates, including the design and implantation of risk mitigation and pharmacovigilance activities. PW also has extensive experience writing components of marketing applications, including clinical overviews, DRMPs and RMPs, across a wide range of therapeutic fields. Coupled with the selection and application of appropriate BR framework, PW can help to enhance the format and structure of BR information to suit all stakeholders.Download Now