ver the past decade, a series of government-lead events set in motion a sea change in how patient-reported outcomes (PRO) in cancer clinical trials are assessed and reported. PRO measures have long provided an opportunity for the patient’s voice to be heard, and when rigorously implemented, PRO assessments can add quantitative symptom and functional data to help characterize risks and benefits of cancer treatments. An important example is the use of PRO to provide a direct report of symptoms and side effects from the person experiencing them.

The US National Cancer Institute (NCI) and the US Food and Drug Administration (FDA) have created publicly available tools to advance the collection, measurement, analysis, and reporting of patient-reported symptomatic adverse events in cancer trials. These initiatives have had ripple effects, expanding the definition of tolerability, developing guidelines to manage symptoms, providing new tools for industry to enhance dose finding in early-phase trials, and providing PRO data to enhance the patient-clinician interaction at the point of care.

In this article, we discuss:

• NCI’s development of the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), the FDA’s work to identify analytic and visualization methods to describe PRO-CTCAE data culminating in Project Patient Voice;
• future uses of PRO-CTCAE and other PRO data to inform early- and late-stage drug development; and
• the history of sustained scientific collaboration necessary to advance the rigorous use of PRO data to help characterize tolerability of cancer drugs.

Development and Launch of the PRO-CTCAE

In 2009, the NCI, FDA, and academic collaborators identified the need for more rigorous assessment of patient-reported adverse events in cancer clinical trials. To complement the traditional clinician-based CTCAE, the NCI issued two contracts to develop and test a PRO version of the CTCAE. To develop the instrument, a consortium of experts was established which included academics, community oncologists, software development firms, and patients. The consortium also included robust representation from across the NCI’s Division of Cancer Control and Population Sciences (DCCPS), Division of Cancer Prevention (DCP), Cancer Therapy Evaluation Program (CTEP), and Center for Biomedical Informatics and Information Technology (CBIIT), along with FDA involvement. By 2014, the PRO-CTCAE had been integrated into several multicenter clinical trials. In the first quarter of 2016, the PRO-CTCAE item library became publicly available with tools to support symptom selection and implementation in trials. Since launch, the PRO-CTCAE item library has been continually improved and now includes 124 items, representing 78 symptomatic toxicities, and has been validated in more than 30 languages.

Introducing the Cancer Moonshot

During his 2016 State of the Union Address, President Obama called for Vice President Biden to lead the national Cancer Moonshot, a government initiative to invest resources and targeted incentives to make substantial progress in the prevention, diagnosis, and treatment of cancer over a five-year period. The Cancer Moonshot initiative formed a Blue Ribbon Panel (BRP) to identify scientific priorities and areas of opportunity at NCI. One key workstream recommended by the BRP was to identify ways to minimize the debilitating side effects of cancer treatment – a task that requires understanding the patient’s perspective in the evaluation and management of symptomatic adverse events.

The Cancer Moonshot also established the FDA Oncology Center of Excellence (OCE). With a mission to achieve patient-centered regulatory decision-making through innovation and collaboration, OCE was designed to leverage expertise across the existing FDA centers and create a unified scientific environment to advance the development and regulation of anti-cancer therapies. One of OCE’s first efforts was to establish an in-house patient-focused drug development program, which has been a proactive leader and collaborator in the field of outcomes research since its inception.

Passage of the 21^st Century Cures Act

The 21^st Century Cures Act accelerated the progress from the Cancer Moonshot with critical funding for oncology initiatives and multiple key mandates related to patient-reported outcomes. The Act directed FDA to systematically incorporate patients’ experiences, needs, perspectives, and priorities into drug development and evaluation. Specifically, the legislation tasked FDA with developing guidance to industry, describing appropriate methodological approaches for collecting, measuring, and analyzing patient experience data – guidances that will be the cornerstone of how patient experience data are incorporated into drug development.

Governmental Collaboration with Academic and Advocacy Organizations

In April 2017, five months after the 21^st Century Cures Act was signed, OCE and the Critical Path Institute held a public workshop to explore the use of PRO measures to inform tolerability in cancer clinical trials. The workshop highlighted how rigorous measurement of patient-reported symptomatic adverse events, using item libraries such as the PRO-CTCAE, can unlock important information that complements clinician-reported safety information. Workshop attendees, including representatives of the NCI, suggested that collection of patient-reported symptoms could add value to the assessment of tolerability in most cancer clinical trials – a developing concept at that time. The OCE Clinical Outcome Assessments in Cancer Clinical Trials workshop has become an annual event that is uniquely dedicated to the advancement of regulatory-grade oncology clinical outcomes assessments.

Two recent initiatives exemplify the growing interest in use of PRO assessments to characterize anti-cancer agents. The Lancet Haematology Commission gathered a diverse representation of drug development stakeholders to assess the current approach to safety assessment in cancer trials, and has developed a framework for re-evaluating adverse event reporting. In addition, the Friends of Cancer Research have developed a White Paper on assessing cancer treatment tolerability, which places an emphasis on inclusion of PRO data to complement existing safety assessment.

In 2017, 2018, and 2019, OCE hosted public educational workshops entitled “Partners in Progress” to provide information and to interface with patients and advocates. The three workshops provided an addition forum to discuss anti-cancer therapy tolerability, ways to incorporate PRO into cancer clinical trials, and to explore novel communication methods for this important source of data.

Launch of Project Patient Voice

In 2020, the Oncology Center of Excellence launched a novel online platform for patients and caregivers along with their healthcare providers to view patient-reported symptom data that has been prospectively collected in cancer clinical trials. The intent of this online platform, called Project Patient Voice, is to make patient-reported symptom data derived from clinical trials supporting approved cancer therapies available to patients and caregivers. This provides an important opportunity to communicate a wealth of patient-reported symptomatic adverse event data; information that is generally not included in the US Prescribing Information (drug label). The purpose of this platform is to take patient-reported symptomatic adverse event data that is appropriately collected and informative, and make it available to those that need it, when they need, at the point of care. Patient-reported symptomatic adverse events provide a complementary source of information about side effects of approved cancer therapies which can assist patients and caregivers in making treatment decisions.

Future Directions

Stirred by an aspiration to make substantial and swift progress in the treatment of cancer, passage of the 21^st Century Cures Act formalized a momentum shift in how patient-reported symptoms and side effects are collected and reported in cancer clinical trials. Although the work that led to this point started long before the Act was passed, the confluence of legislative mandates, regulatory innovation, and collaboration with highly motivated stakeholders resulted in significant advances in the field. These government efforts, in partnership with patients, academics, community providers, and industry sponsors, have allowed for substantial changes to how patient-reported symptoms and side effects are incorporated into cancer clinical trials. With thoughtful trial design, high quality PRO symptom data can be generated, and Project Patient Voice has presented at least one way that this information can be communicated back to patients and their healthcare providers. It is our hope that this example will continue to inspire a wave of new initiatives in this field.

Great strides have been made in the last decade to advance assessment, analysis, and visualization of patient-reported symptomatic adverse events. The sustained involvement and collaboration in the outcomes research community by the NCI and FDA has led to advances in use of PRO to assess symptomatic adverse events. This example can serve as a model for rigorous use of other types of patient-generated data, such as physical functioning and improvement of disease-specific symptoms.

Multi-stakeholder efforts will continue to be necessary for further advancements in the science of patient-generated evidence, and we look forward to continued progress in the field. To that end, FDA OCE is hosting two public events in 2021: (1) a meeting of the pediatric oncology subcommittee of the oncology drugs advisory committee to discuss more rigorous measurement of the pediatric patient experience in clinical trials, and (2) the 2021 Clinical Outcomes Assessments in Cancer Clinical Trials Sixth Annual Workshop to discuss novel endpoints and analytical considerations for patient reported physical function.