Benefit-Risk Assessment Methods in Medical Product Development

Bridging Qualitative and Quantitative Assessments

Qi Jiang, Weili He, Qi Jiang, Weili He

• Publisher: Chapman and Hall/CRC
• Year: 2017
• ISBN:
  9781315355016
• Edition: 1
• Topic: Mathematics
• Subtopic: Probability & Statistics
• Index: Mathematics

Guides You on the Development and Implementation of B–R Evaluations

Benefit–Risk Assessment Methods in Medical Product Development: Bridging Qualitative and Quantitative Assessments provides general guidance and case studies to aid practitioners in selecting specific benefit–risk (B–R) frameworks and quantitative methods. Leading experts from industry, regulatory agencies, and academia present practical examples, lessons learned, and best practices that illustrate how to conduct structured B–R assessment in clinical development and regulatory submission.

The first section of the book discusses the role of B–R assessments in medicine development and regulation, the need for both a common B–R framework and patient input into B–R decisions, and future directions. The second section focuses on legislative and regulatory policy initiatives as well as decisions made at the U.S. FDA's Center for Devices and Radiological Health. The third section examines key elements of B–R evaluations in a product's life cycle, such as uncertainty evaluation and quantification, quantifying patient B–R trade-off preferences, ways to identify subgroups with the best B–R profiles, and data sources used to assist B–R assessment. The fourth section equips practitioners with tools to conduct B–R evaluations, including assessment methodologies, a quantitative joint modeling and joint evaluation framework, and several visualization tools. The final section presents a rich collection of case studies.

With top specialists sharing their in-depth knowledge, thought-provoking considerations, and practical advice, this book offers comprehensive coverage of B–R evaluation methods, tools, and case studies. It gives practitioners a much-needed toolkit to develop and conduct their own B–R evaluations.

Section IV

Benefit–Risk Assessment Methods and Visual Tools

8

Overview of Benefit–Risk Evaluation Methods: A Spectrum from Qualitative to Quantitative

George Quartey, Chunlei Ke, Christy Chuang-Stein, Weili He, Qi Jiang, Kao-Tai Tsai, Guochen Song, and John Scott

CONTENTS

8.1 Introduction

8.2 Criteria to Select BRA Methods

8.2.1 Intuitive

8.2.2 Comprehensive

8.2.3 Scientifically Sound

8.2.4 Broadly Applicable

8.3 The QSPI BRA Approach

8.3.1 Descriptive Benefit–Risk Framework

8.3.2 Methods for Patient-Level Data Analysis

8.3.2.1 Discounting Benefit by Risk within an Individual

8.3.2.2 Classifying Benefit and Risk Jointly into Categorical Responses

8.3.3 Methods for Eliciting Patient Preference

8.3.4 Methods for One Benefit and One Risk

8.3.4.1 NNT and NNH

8.3.4.2 Joint Evaluation of B–R

8.3.5 Methods for Multiple Benefits/Risks

8.3.5.1 Applications of MCDA

8.3.5.2 Advantages of MCDA

8.3.5.3 Disadvantages of MCDA

8.3.5.4 Example

8.3.6 Methods for Uncertainty Evaluation

8.4 Challenges in Applying BRA Methods

8.4.1 Decision Context Challenges

8.4.2 Data Challenges

8.4.3 Challenges in Incorporating Values

8.4.4 Challenges in Uncertainty and Communication

8.5 Discussions and Conclusions

References

ABSTRACT It has long been understood that the benefits of a medical product should be assessed in the context of the risks or harms associated with that product, and vice versa. Until recently, however, drug development and regulatory decisions were usually based on informal, qualitative weighing of benefits and risks, often leading to opaque decisions. Now, pharmaceutical companies and other clinical organizations are increasingly using structured benefit–risk assessments (BRAs), sometimes including sophisticated quantitative methods, as part of their decision-making processes. There are also vast efforts from health authorities and academia to standardize, streamline, and improve the BRA process. In the wake of these initiatives, the field of structured BRA has blossomed, with major advances in methodology and implementation. As a result, a large number of methods have been proposed to facilitate the BRA, which also further complicates the BRA picture. In this chapter, we will discuss these different BRA methodologies and recommend a set of systematic methods for general use in the pharmaceutical industry. We will also describe some criteria to select the methods as well as challenges in applying them.

8.1 Introduction

It has long been understood that the benefits of a medical product should be assessed in the context of the risks or harms associated with that product, and vice versa. Until recently, however, drug development and regulatory decisions were usually based on informal, qualitative weighing of benefits and risks, often leading to opaque decisions. For example, although two experts may agree on a set of facts regarding the benefits and risks of a drug, the experts may not agree on accepting the risks given the demonstrated benefits of the drug.

Now, pharmaceutical companies are increasingly using structured benefit–risk assessment (BRA), sometimes including sophisticated quantitative methods, as part of their internal decision-making processes. Efforts are underway within the drug development community to enhance the evaluation and communication of the benefits and risks associated with pharmaceutical products, aimed at increasing the consistency, predictability, transparency, and efficiency of pharmaceutical regulatory decision making.

There are also vast efforts from health authorities and academia to standardize, streamline, and improve the BRA process. For example, the Prescription Drug User Fee Act (PDUFA) V commits the Food and Drug Administration (FDA) to a series of meetings and workshops during 2013–2018 to develop a BRA framework. The FDA released a 2013 draft benefit–risk (B–R) implementation plan entitled “Structured Approach to Benefit–Risk Assessment in Drug Regulatory Decision-Making” (FDA 2013). The European Medicines Agency (EMA) Benefit–Risk Methodology Project was aimed at the development and testing of tools and processes for balancing multiple benefits and risks, which could be used as an aid to informed, science-based regulatory decisions about medicinal products (EMA Methodology Project 2013; EMA Reflection Paper 2008). The Institute of Medicine recommended that the FDA create a publicly available BRA management plan with periodic updates. In addition, several other proposed structured BRA initiatives developed by the PhRMA BRAT (Pharmaceutical Research and Manufacturers of America Benefit–Risk Action Team) (Coplan et al. 2011), the Universal Methodology for Benefit–Risk Assessment (UMBRA) framework by the Centre for Innovation in Regulatory Science organization (Walker et al. 2015), the PrOACT-URL framework recommended by the EMA (Phillips et al. 2013), FDA Center for Devices and Radiological Health (CDRH) Decision Analysis Initiative and CDRH/Center for Biologics Evaluation and Research Benefit–Risk Guidance, and the Periodic Benefit–Risk Evaluation Report based on the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidance (ICH E2C(R2) 2012) have placed a descriptive approach as a critical part of BRA.

In the wake of these initiatives, the field of structured BRA has blossomed with major advances in methodology and implementation. As a result, a large number of methods have been proposed to facilitate the BRA process, which also further complicates the BRA picture (Guo et al. 2010; Mt-Isa et al. 2014; Phillips et al. 2013). For example, the EMA Benefit–Risk Methodology Project Work Package 2 examined the applicability of 18 quantitative approaches for assessing the B–R balance and three qualitative frameworks (Phillips et al. 2013); the Innovative Medicines Initiative Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium WP5 recommended 13 methodologies for further examination in BRA of medicines (Mt-Isa et al. 2014); and the International Society for Pharmacoeconomics and Outcomes Research Risk-Benefit Management Working Group recommended 12 methods for use in BRA (Guo et al. 2010).

Although numerous approaches and frameworks have been proposed in recent years, there is no single approach or framework that can be applied and utilized in every setting. This is because BRA is often multifaceted and complex, and the goals of BRA in different settings (e.g., disease areas, clinical development stages) may be different. The suitability of the recommended methods still needs to be further explored in structured systematic BRAs to determine the circumstances they best fit and whether they could be us...