Immunotherapies Merit Unique Patient-Reported Outcomes to Inform Treatment Tolerability
Matthew Reaney
Catherine Coulouvrat
Mark Stewart
Friends of Cancer Research
Courtney Granville,
Maria Paula Bautista Acelas
Drug Information Association

mmuno-oncology (I-O) therapies provide a unique alternative for treating different cancer types. By enhancing the individual’s immune system to target and fight cancerous cells, these therapies can increase the survivorship rate for many patients. But they can also lead to a wide experience of symptoms that affect treatment tolerability.

Understanding tolerability as part of the development and delivery of I-O therapies is important. New FDA guidance advocates for collecting patient-reported outcomes (PROs) to better assess tolerability and optimize dosage in trials. However, using PROs to inform tolerability is not without its challenges.

Why Patient-Reported Tolerability?

A comprehensive understanding of patient-reported tolerability helps ensure that clinicians are able to set and manage patient expectations about how they will feel and function while receiving therapy and help patients to make well-informed therapeutic decisions. This in turn will offer the greatest opportunity for patients to truly benefit in the short and long term from I-O therapies.

However, there are significant challenges with collecting information about tolerability from patients. For example, current definitions of tolerability are incomplete, and there is little if any consensus across the ecosystem about its definition. Furthermore, tools that can adequately measure patient-reported data are needed to facilitate collection of robust, reliable, valid, interpretable tolerability data in clinical development. Finally, because I-O agents have unique side-effect profiles, measuring patient-reported tolerability for this therapeutic class warrants consideration apart from other oncology therapies.

What is Tolerability?

Tolerability is often considered synonymous with treatment-related symptoms or side effects; i.e., the greater the incidence, severity, or bother of symptoms/side effects, the less tolerable the treatment. Indeed, FDA’s draft guidance Core Patient-Reported Outcomes (PROs) in Cancer Clinical Trials proposes collecting information on both treatment-related symptoms and the overall impact of all side effects to understand the tolerability of a treatment during development.

But tolerability is likely a more multidimensional concept than treatment-related symptoms or side effects. It should be viewed as a broad set of experiences that a patient may have when receiving treatment, and how these experiences come together to inform decisions about whether to continue treatment or not. These experiences may include aspects such as perceived advantages versus disadvantages (are the side effects outweighed by the clinical therapeutic benefits?) or by other factors such as convenience, beliefs about the treatment, etc. This broad set of experiences can only be understood through direct PROs.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) defines tolerability as the degree to which overt adverse effects can be tolerated by a patient. A recent Friends of Cancer Research white paper offers an alternative definition which better encompasses the patient experience with a given treatment: the degree to which symptomatic and non-symptomatic adverse events associated with use of a product affect the ability or desire of the patient to adhere to the dose or frequency of therapy. This definition seems comprehensive, although it is hard to operationalize it in a simple way to support measurement of tolerability using PRO instruments in drug development.

Measuring Tolerability Using Existing PRO Instruments

Several PRO instruments have been developed to understand and compare individuals’ appraisal of benefits and risks.

  • The PQAT tool comprises questions focused on the treatment benefits and risks, evaluation of the balance between these benefits and risks, and reasons to continue/discontinue treatment.
  • The PGI-BR tool incorporates patients’ views on medications and perspectives on benefit-risk in clinical trials.
  • The WIWI tool adds to the existing body of evidence about the benefit-risk and additionally evaluates the cost of cancer treatments from the patient perspective.
  • The PRO-CTCAE tool evaluates symptomatic toxicity in oncology patients.

Although these PRO instruments can inform some elements of tolerability as defined by Friends of Cancer Research, none is likely to be a comprehensive measure of tolerability nor to offer a broad exploration of the factors which may influence tolerability of I-O therapies.

Tolerability of Immuno-Oncology Agents

Acquiring an accurate and deep understanding of tolerability of I-O therapy requires consideration of what would be a comprehensive definition of I-O therapy tolerability, why people may struggle to tolerate I-O therapy, plus when and how patient-reported tolerability would best be measured. This requires diverse groups—including patients, clinicians, researchers, and regulators—to share their unique perspectives.

DIA is currently establishing a working group to understand, identify, discuss, and potentially develop a patient-reported tolerability PRO instrument(s) for I-O. This working group will consist of pharmaceutical organizations, regulatory representatives, patient advocacy representatives, and healthcare providers, among other subject matter experts, to discuss:

  • Defining tolerability in consideration of I-O therapies, as well as therapy-related and non-therapy-related facilitators and barriers to “tolerable” treatment;
  • PRO measurement of patient-reported tolerability with I-O therapy;
  • Designing trials to reliably measure patient-reported tolerability and comparative differences in tolerability between therapies;
  • Defining tolerability endpoints in trials;
  • Analyzing tolerability data; and
  • Using tolerability data to inform healthcare provider/patient decision-making, benefit-risk appraisal, and product labeling.

DIA envisions that this multidisciplinary collaborative working group will provide thought leadership and ensure tangible contribution to the definition of patient-reported tolerability in I-O treatment in selected cancers. To learn more about this DIA study, or to learn how to contribute and help, please contact