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INTRODUCTION

“I will go out on a limb and predict that this is the most important meeting you will attend this year, at the National Academy of Medicine or elsewhere.” So said Joseph Selby, Executive Director of the Patient-Centered Outcomes Research Institute (PCORI), in his opening remarks at the National Academy of Medicine (NAM) workshop titled Evidence and the Individual Patient: Understanding Heterogeneous Treatment Effects for Patient-Centered Care. While Selby’s opening comments were intentionally provocative, they indeed captured the clear sense of many attendees that the workshop topic was both timely and extremely important.

Heterogeneous treatment effects (HTE) refer to the way effects of a treatment can differ, sometimes dramatically, from one patient to the next. While such variation, or heterogeneity, can be quite challenging to clinicians, who would find their jobs easier if every patient responded to a treatment uniformly and predictably, heterogeneity also offers great opportunities. The challenge, then, is to learn how to transform those opportunities into concrete benefits for patients.

In his introduction, Selby discussed the relationship between HTE and the field of evidence-based medicine (EBM), which seeks to firmly ground medical practice in the strongest possible evidence, such as data from randomized controlled trials. One problem with EBM, Selby said, is that doctors are often expected to apply evidence-based recommendations to all patients. If, for example, randomized controlled trials show that the average patient with high blood pressure will benefit by lowering blood pressure to below 120/80 mm Hg, then doctors are expected to work to get the blood pressure of all their patients under that level.

Further acknowledging this problem, he said,

The study of HTE, however, offers the potential for doctors to once again personalize treatments for their patients.

OVERVIEW OF THE WORKSHOP

The workshop, held on May 31, 2018, at the National Academy of Sciences building in Washington, DC, convened physicians, medical researchers, representatives from funding agencies, health insurance companies, pharmaceutical companies, federal agencies, professional associations, and medical journals; as well as patients and patient advocates, to discuss approaches to leveraging health data to examine HTE in order to personalize and improve patient care (see Appendix C for the complete workshop agenda). By understanding the reasons for the heterogeneity and developing ways to predict how individual patients will respond to a treatment, medical researchers and physicians should be able to personalize medicine to a far greater degree than is possible today. Such an ability would open the door to treatments that are more effective with fewer side effects and would also allow patients to make more informed decisions about the types of medical treatments they choose to receive.

That is the potential of understanding HTE, as many workshop participants commented. But to reach that potential will require advances on both the research side and the clinical side. To explore those requirements, the NAM, in conjunction with the Predictive Analytics and Comparative Effectiveness (PACE) Center at the Tufts Medical Center, convened this workshop, with funding from two awards from PCORI.

Participants were asked to consider four motivating topics over the course of the meeting (see Appendix B for list of workshop participants, web participants, and staff):

• Potential: How can clinical trial data be analyzed to yield reliable patient-centered treatment effect estimates? What are the state-of-the-science methods for assessing treatment heterogeneity?
• Risks: How can we be sure personalizing evidence will improve decision making, as compared with the default of relying on overall average treatment effects? What are the evidentiary standards for implementing changes to clinical practice to personalize care based on evidence of HTE?

• Lessons learned: What can be learned from the challenges of genomics-based personalized medicine? What can be learned from the efforts of previous clinical trialists to understand more personalized treatment effect estimates?
• Strategies: How should clinical research and clinical practice be redesigned to support the generation and the dissemination of patient-centered evidence?

In addition to these questions, there was an explicit recognition that there are additional questions of central importance to patients. Not only will patient cooperation be critical in the design and performance of clinical trials that aim to understand HTE, the patients themselves will also inevitably be partners with clinicians in making treatment decisions about their care whenever HTE are present. As several workshop participants noted, it will be important for patients to have a clear understanding of HTE in order to make informed choices about their care. With this in mind, the workshop participants were asked to think about HTE from the point of view of the patient and to consider the following questions that patients might ask:

• Given my personal characteristics, conditions, and preferences, what should I expect will happen to me?
• How can I use knowledge about HTE to improve the outcomes that are most important to me?
• How can clinicians, as well as the care delivery systems they work in, help me make the best decisions about my health and health care?

The day-long workshop was divided into five sessions, each with individual presenters and responders, as well as a discussion session that followed the presentations. This NAM Special Publication provides a summary and synthesis of the presentations and the discussions that took place during the workshop. Its structure mirrors that of the workshop, with each of the five chapters reflecting one session.

Chapter 2 provides an overview of HTE, introducing concepts, examples of types of analyses that have been done, and illustrations of how their application has led to more individualized clinical decisions. Chapter 3 summarizes a discussion with patients, patient representatives, and other stakeholders regarding the importance of understanding HTE. Chapter 4 examines methods that can be used to produce models that will predict treatment effects, with a discussion of the strengths and the weaknesses of the various approaches. Chapter 5 delves into the issues involved with implementing clinical programs that take HTE into

account. The final chapter, Chapter 6, offers a look to the future, addressing what will be required to account for HTE in medical practice.

The opinions expressed by workshop attendees and reproduced within this publication are those of the individual speakers and are not the position of the National Academies of Sciences, Engineering, and Medicine or the NAM. Workshop presenters and participants were not asked to come to any consensus opinions, and any recommendations made were those of individuals, not the group as a whole. However, there were various areas in which there was apparent widespread agreement among those at the workshop, and those areas are noted, as appropriate.