Krister Cromm, MA, MBA, MSc • Saynab Atiye, RPh
The addition of patient-reported outcomes (PROs) in clinical trials opens new and meaningful pathways for discovery. By combining clinical and patient-reported endpoints, trials featuring PROs can identify when and how a product can support improving patients’ health status inside and outside the clinic, help clinicians and patients define treatment goals together, and demonstrate an intervention’s value to multiple stakeholders in society. The Home Hemodialysis and CONVINCE consortium studies exemplify how an evolution from disease-centered to person-centered care can be integrated into clinical trial designs with digital solutions.
The development of medical devices, therapies, and pharmaceuticals relies on clinical research. Data on safety, efficacy, or performance of an intervention is collected to provide evidence to meet regulatory requirements and demonstrate potential benefit to payers and society, including information about the costs and expected use of the therapy.
Traditionally, biomedical clinical research has been conducted through quantitative research, focused on so-called “hard outcomes” and other measures that can be observed directly and are not prone to observer bias. While important, this quantitative research provides limited information about patient feelings, motivations, social or cultural values, or religious and cultural views, or the patient-physician relationship, all of which can greatly influence treatment success.
Health outcomes that are directly evaluated by the patient and included in surveys are commonly referred to as patient-reported outcomes (PROs). Data about these characteristics can be captured through qualitative research that describes life experiences in a systematic manner, giving them meaning beyond individual, subjective observations. Once qualitative research has consistently identified underlying constructs such as pain, the ability to participate in social roles, or treatment-related fatigue, individual statements arising from these surveys are developed and tested so that they can be used as qualitative factors in quantitative research designs. The technique of converting personal statements into reliable and valid quantitative measurements makes it possible to analyze how changes in clinical endpoints precede or follow changes in PROs.
Combining PROs from various domains of well-being can form an instrument designed to measure overall health-related quality of life (HRQOL). Such instruments can be generic, such as the commonly used SF-36 survey, or disease-specific, such as the Kidney Disease Quality of Life survey. Examining HRQoL in clinical trials together with clinical endpoints results in a comprehensive view of health outcomes. The outcome model ahead shows pathways that patients and clinicians can follow to achieve better health and well-being while keeping clinical endpoints in view (see Figure 1).1 In contrast to PROs, when psychological surveys measure health perceptions or views influencing patient experience, rather than the outcome of care, they are referred to as patient-reported experience measures (PREMS).
FIGURE 1 | Pathway to health-related quality of life, developed by Krister Cromm based on a conceptual model of patient outcomes by Wilson and Cleary
Ideally, patient-reported measures should be confirmed by qualitative methods in the beginning of a clinical trial, such as structured interviews with the relevant populations. In this way, such measures can be adapted or expanded to fit the patient-specific needs and circumstances. However, modern research methods follow different strategies that make it possible to choose from large sets of survey items to tailor-fit questionnaires to individual respondents. Computer-adaptive tests can be filled in via tablet computers or smartphones, such as the Patient-Reported Outcomes Measurement Information System (PROMIS®) surveys that were developed in the United States under a grant by the National Institutes of Health.2
In clinical trials, clinical and patient-reported endpoints are complementary. This is also emphasized by individuals with kidney disease, who consistently report that HRQoL is as important as established clinical outcomes, along with the fact that the alignment of these goals does not receive adequate attention. Practically, concerns with treatment priorities are more evident in clinical practice; therefore, numerous published articles over the last decade discuss improving PROs in clinical care only, rather than looking at the preceding clinical trial stage.
Very few individuals with kidney disease work in dialysis product development or are otherwise involved in decision making that leads to product purchasing decisions. HRQoL has rarely been considered as the determining factor in dialysis product research. This has resulted in systematic limitations of research findings. Nonetheless, technological, social, and economic developments have led to increasing involvement of individuals in their healthcare and have led governments to take steps toward patient involvement in clinical trials. Thus, much can and must be done to adopt patient-centered approaches in product and research design early on, to improve HRQoL for those with kidney disease.
For kidney disease, combining outcomes holistically is notably reflected in the Standardized Outcomes in Nephrology (SONG) Initiative, launched in November 2014.3 The initiative established a set of core outcomes and outcome measures across the spectrum of kidney disease for trials and other forms of research, many of which are PROs. The outcomes were developed based on the shared priorities of patients, caregivers, clinicians, researchers, policy makers, and relevant stakeholders. It is assumed that they will help to ensure research outcomes that are meaningful and relevant to patients with kidney disease, their families, and their clinicians, and to support decisions about treatment. The guidelines play an increasingly important role in peer review and article acceptance in scientific journals.
There are various other initiatives by patient organizations, researchers, international organizations, and regulators—such as the Organization for Economic Cooperation and Development’s Patient-Reported Indicator Surveys initiative (PaRIS) or the Consensus-based Standards for the selection of health Measurement Instruments initiative (COSMIN)—to establish mechanisms to focus on patient-centered priorities or remove bias from clinical trials by advocating for patient participation starting in the design stage.4,5
Besides strengthening the consideration of PROs and PREMS that formalize the patient voice in the development of new therapies, the European Medicines Agency (EMA) generally fosters patient contributions to drug development. It also supports key initiatives like the European Patients’ Academy on Therapeutic Innovation (EUPATI) to embed patient priorities into clinical trial designs.6,7 Patients are experts in their disease area, so it is crucial that their input is reflected in decisions made by the regulator and embedded in all the work the regulators do. Therefore, the interaction should be as early as possible.
The EMA also aims to update relevant clinical guidelines to include reference to PROs addressing study objectives, design, and analysis.8 Thus, the EMA has included the reinforcement of patient relevance in evidence generation in its “Regulatory Science Strategy to 2025” as one of the five main goals. The EMA is looking to further enhance its methods to enable greater input from the wider patient community in a systematic manner. There are also opportunities arising from new digital tools and the science of patient reporting. EMA is starting to see the use of various PROs as endpoints within submissions for marketing authorization applications for pharmaceuticals. Given other trends — such as eHealth, precision medicine, and the drive for outcome-based healthcare — the use of patient data will likely continue to grow. Understanding how to generate, analyze, and use relevant patient data will be key to EMA’s regulatory science strategy.9
In the United States, the Food and Drug Administration’s Center for Devices and Radiological Health equally strives to ensure patients and their care partners are the focus of the regulatory decision-making process by encouraging the inclusion of clinical outcome assessments such as PROs in the evaluation of medical devices.10 In Australia, the Addendum to National Health Reform Agreement mandates the implementation of PROs for funding, emphasizing empowerment and health literacy as much as paying for value and outcomes.11
The EMA outlined guidance for the use of HRQoL health-related quality-of-life measures in the evaluation of medicinal products. It describes how HRQoL measures may provide more insight into interpreting the effect on the primary endpoint in terms of consequences for daily life and social functioning. Any claims about HRQoL improvements must be supported by data collected with instruments validated for use in the corresponding health condition.12
Research initiatives at Fresenius Medical Care inspire and embrace the implementation of patient-centered care and patient-reported measures.13 The company is actively reviewing where and how an evolution from the former disease-centered approach to the current patient-centered strategy can be developed toward holistic person-centered care through integration and leadership in clinical trial designs (Figure 2).
CONVINCE is a consortium that is performing an international, multi-center, prospective, randomized, controlled study — with 1,360 enrolled participants — comparing high-dose hemodiafiltration versus conventional guideline-based hemodialysis. Together with partners in industry and academia, Fresenius Medical Care has received 6.8 Mio € in funding from the EU’s Horizon 2020 grant, the top funding authority in the European Union representing more than 447 million citizens in the EU’s 27 member states. Across nine countries in Western, Southern, and Eastern Europe, the trial examines not only the effect of hemodiafiltration on hospitalizations and mortality, but also a wide range of physical, mental, and social outcomes using electronic PROMIS participant surveys. To support the comprehensive examination of PROs, the clinical trial surveys are translated into national languages. A specific dialysis recovery time module has been developed to understand how dialysis therapy increases or reduces fatigue before, during, and after treatment sessions and on the days following dialysis. The trial also examines psychosocial factors, including stress, social support, and self-efficacy. The CONVINCE study offers the opportunity to establish a valid and reliable measurement framework for PROs that allows comparing these outcomes in nephrology across treatment settings.
As we have already validated the questionnaire approach with the baseline assessment in CONVINCE, we are now building on this knowledge. In Turkey, the Home Hemodialysis (HHD) Study, a sponsor-initiated trial, plans to enroll 700 participants and examine how treatment at home affects their HRQOL until 2023. Prior to the main HHD study, a validation and pilot study of over 150 participants will be completed later in 2021. In that study, PROs will be examined in detail to establish a measurement base of what is important from the patient perspective — in particular, self-rated cognitive function and abilities, fatigue, sleep, depression, anxiety, and sexual function. This trial will also consider the economic aspects of care, which are markedly different for patients who perform treatment at home. This will render important information regarding how limited resources change healthcare outcomes and will help identify the circumstances where HHD patients experience better results, so that more patients can eventually enjoy the benefits of home therapies.
PROs in clinical trials offer new ways to expand clinical trial design. Rather than limiting the focus of clinical trial outcomes to traditional clinical or biochemical measures, trials featuring PROs can identify when a product can support a patient in improving their health status or well-being. Transforming and improving clinical care requires a more thoughtful and comprehensive approach to clinical trial design. This will allow the development of the best treatment strategy together with and for the benefit of individuals with kidney failure. Fresenius Medical Care is committed to products that meet patients’ needs, inspiring the development of new care strategies.