As a result, a universal framework, together with an appropriate documentation system for recording benefit-risk decisions, has been developed and applied.
This is a valuable addition to the benefit risk toolbox. The opportunity to examine the implementation of this approach by several regulatory authorities places this framework in a unique position and has the potential to positively contribute to the ongoing debate in this area.
The field of benefit-risk assessment continues to evolve rapidly, due to political and societal pressure, also reflected in the recent FDA PUDFA agreement, as well as in the EMA 2015 Roadmap. Therefore, this is not an attempt to provide a comprehensive and complete account of the current benefit-risk assessment environment.
However, the strength of it is that it provides an evaluation of some current approaches to the benefit-risk assessment of medicines, and outlines the development of a new universal framework.
It also demonstrates how a number of mature agencies have implemented this universal framework together with the methodology for documenting their benefit-risk decisions, and reviews current publicly-available documents, together with their strengths and weaknesses in communicating benefit-risk decisions to stakeholders.
Compared with the Benefit-Risk Universal Framework Template (the BRT), existing regulatory report formats are inadequate regarding the listing of benefits and risks, the assigning of relative importance and values, visualisation and the utilisation of a detailed, systematic, standardised structure.
A universal template
The BRT is based on the principles of benefit-risk assessment common to major regulatory agencies. Given that there are minimal differences among the existing regulatory report formats, it is timely to consider the feasibility of a universal template.
Most patients’ primary concern would be the efficacy and safety of a product, while physicians would want to know the details to make a better-informed decision when choosing an optimal treatment for their patients. Therefore, clarity in the presentation of such information is of paramount importance.
For pharmaceutical companies, a documented transparent decision-making process would enable them to understand the basis of the regulatory decision, the rationale for the inclusion or exclusion of benefits and risks, and the final benefit-risk balance. This would therefore provide a suitable platform to discuss any discrepancies in interpretation or differences in opinions.
In evaluating the product for pricing and reimbursement, health technology assessment (HTA) agencies would also want to understand the rationale for the approval of a product. A failure to achieve this understanding might affect a products accessibility for patients and influence the healthcare delivery in terms of cost and clinical management.
Assessment reports of major regulatory agencies are often accessed by smaller agencies in emerging markets to support their local decisions, and thus these regulatory agencies should also be considered as key stakeholders for the publicly-available assessment reports.
Certain jurisdictions may require publication of the assessment reports as a move to increase the transparency of the decision-making processes, while others may require varying amounts of information to be made public.
As previously discussed, it is also not known if the current practices of providing the publicly-available assessment reports actually achieve the transparency required or desired by the stakeholders, as there are no studies describing this type of feedback from pharmaceutical companies, physicians, patients or regulatory agencies.
In fact, the vast amount of unstructured information provided may possibly hamper understanding and thus communication. The use of summaries like the executive summary of the European public assessment reports (EPAR), the benefit-risk assessment of the FDA and overall conclusion of the Australian Public Assessment Report (AusPAR) for prescription medicines aims to further improve communication.
A more structured and guided discussion, such as that provided by the BR Summary Template of the Universal Framework, may further help improve both transparency and communication and prevent the omission of information assessed by the reviewer and deemed important to stakeholders.
The comparison of the summaries shows that there are elements missing which could facilitate effective communication. As such, the elements from the BR Summary Template found missing in the summaries of the mature agencies may serve as a starting platform to enhance the effectiveness in communicating benefit-risk decisions.
Provision of a list of identified benefits and risks and visualisations would aim to facilitate communication by reducing the amount of text needed to convey the messages. Therefore, future attempts to improve the quality of communication should include:
• A listing of benefits and risks, with justification for their roles in assessing the benefit-risk balance and the reasons for their inclusion or exclusion;
• Valuation of the identified benefits and risks;
• Weighting (relative importance) of the identified benefits and risks;
• Visualisations of the outcomes;
• Guided discussions and structured questions such as deliberations on uncertainties, consistency of outcomes across studies and additional risks compared with a standard of care to illustrate key discussion points leading to benefit-risk decisions. Such an approach to decision-making replaces the currently disjointed decision-making process around commissioning a new drug.
Given that there are minimal differences among the existing formats of the mature agencies, it is timely to consider the feasibility of a universal template. The BR Template and BR Summary Template were based on the EMA reflection paper, published in 2008, for the assessment of benefits and risks and to allow documentation of these considerations in support of the decision.
Familiarity with a standard template and its presentation format will enhance the stakeholders experience in seeking to understand the key messages. A universal framework for the assessment of benefits and risks will be required to bring focus to the agencies, which would then facilitate the implementation of a standard, universal documentation tool.
The eight-step universal benefit-risk framework incorporates the existing frameworks of major regulatory agencies and those used by pharmaceutical. Given that the BR Template and BR Summary Template was developed using the principles from this universal framework, there is now the opportunity to explore their universal use.
However, as the basis for publicly-available assessment reports, it would be prudent to seek more confirmative opinions from stakeholders on the feasibility and utility of such an initiative through further studies.
In the course of the development of the Universal Framework, some areas for improvement were identified for the BR Template and BR Summary Template. These included expanding the discussion on pharmacovigilance and EU risk management plans and US risk evaluation and mitigation strategies, which would then align to the recent requirements for periodic benefit-risk evaluation report (PBRER) and the emphasis on post-market activities.
As stakeholders are increasingly seeking the acknowledgment of their opinions, there should also be dedicated and defined areas for inputs from the various stakeholders, particularly patients, which would in turn further reduce the global gap in patients’ access to new medicines. These improvements may enable the BR Template to accommodate requirements in the post-marketing setting as well as functioning as a tool for product life cycle management.
If used as a universal template, it could trace and document the evolution of the benefit-risk balance of a product and provide meaningful comparisons using valid baselines. Ultimately, this may translate to an increase in consistency, transparency and the quality decision-making.
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