If Patients Want A Better Quality Of Life, Why Isn't That A Focus For Pharma?

A conversation with Frédéric Fiteni, Ph.D., medical oncologist and oncology PRO specialist, University Hospital of Nîmes, and, member of Kayentis Scientific Advisory Board

“Listen to patients,” or a similar adage, is often repeated by clinical research professionals who see the value of patient input. Whether it's to help review and revise informed consent documents, ensure the suitability of the study protocol, or determine study endpoints, patient feedback can greatly impact the viability and success of a clinical trial.

That’s if patients are indeed asked.

The challenge is of particular concern to medical oncologist Frédéric Fiteni, Ph.D., who says researchers just aren’t listening to patients when it comes to the value of quality of life (QoL) endpoints — even with the backing of regulatory bodies.

In this Q&A, Fiteni reveals the widespread industry reluctance to study QoL, describes the importance of QoL to patient satisfaction, and offers best practices for its integration.

Your position is that QoL has been long-neglected by health authorities and oncologists. Can you tell us more about this, and why this is a problem?

In recent years, the value of QoL and patient-reported outcomes (PROs) has been repeatedly recognized by regulatory agencies and scientific societies. The EMA and the FDA have both provided guidance for their use, specifically in the setting of oncology clinical trials, and they are recognized as component endpoints for cancer therapy approvals. Moreover, some organizations have incorporated their data into instruments developed to define the value of a treatment, such as the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale.

Nevertheless, QoL has long been neglected as an important endpoint in clinical trials. A review of the methodology of health-related quality of life analysis in Phase 3 advanced non-small-cell lung cancer (NSCLC) clinical trials¹ showed that between January 2008 and December 2014, out of a total of 55 Phase 3 advanced NSCLC trials, QoL was declared as an endpoint in 27 studies (49 %), with only two studies with QoL as the primary endpoint. Gupta et al showed that of the 233 trials associated with 207 FDA approvals between 2015 and 2020, QoL was reported in 50% of trials, of which only 42% had the data reported by the time of FDA approval². A positive point is that Marandino et al showed in their review that the proportion of randomized Phase 3 trials that included QoL as a study endpoint has increased in recent years: QoL was included among endpoints in 67.8% of trials in 2017–2021 compared to 52.9% in 2012–2016³.

How does this affect drug development and the design of clinical trials for cancer therapies?

Endpoints refer to clinical and biological measurements that assess the efficacy of therapeutic strategies. As the American Society of Clinical Oncology stated, active treatment in cancer is generally undertaken with the goal of providing improved quantity and/or quality of patient survival. Cancer randomized clinical trials are conducted to obtain clinical evidence on the safety and efficacy of new interventions. The selection of an appropriately valid primary endpoint is an important aspect of clinical trial design to achieve this objective.

Endpoints in cancer clinical trials can be classified into two main categories: patient-centered clinical endpoints, including overall survival (OS) and QoL, and tumor-centered clinical endpoints, such as progression-free survival (PFS). The FDA considers OS benefit the foundation for the approval of new anticancer drugs in the U.S. Nevertheless, the increasing number of effective salvage treatments available in many types of cancer (i.e., subsequent lines of treatments) has resulted in the need for a larger number of patients to be included and/or the need for a more prolonged observation period to attain sufficient events that can achieve planned statistical power; this increases the cost of clinical trials and requires a longer duration to obtain results.

Consequently, tumor-centered clinical endpoints such as PFS are often used as primary endpoints because they are assessed earlier (i.e., intermediate endpoints). However, PFS is appropriate if (and only if) it is a true surrogate for either OS or QoL, and this has rarely been shown. In this context, the inclusion of QoL or PROs is particularly important when a tumor-centered endpoint such as PFS is the primary endpoint: improvement in PFS and a validated measure of QoL could show that delayed progression provides a meaningful benefit to patients.

What is the typical approach to measuring QoL within oncology clinical trials? And why is that not sufficient?

QoL reflects the patient-perceived evaluation of one’s health, including physical, emotional, and social dimensions, as well as symptoms due to disease or treatment. QoL is measured by questionnaires, which assess some of the aspects that define the QoL of cancer patients or survivors. They are administered at various points throughout the trial to track changes in patients’ quality of life over time.

The most widely used questionnaires in oncology trials are:

• The European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QLQ)-C30 questionnaire is composed of 30 items allowing the assessment of five functional scores (physical, role, cognitive, social, and emotional), a global quality-of-life score, and nine symptom scores (nausea and vomiting, pain, fatigue, dyspnoea, sleeping disturbances, appetite loss, constipation, diarrhea, and financial difficulties). These scores are measured on a 0 to 100 scale such that a high score reflects a high functional level, a high global quality of life level, and a high symptomatic level. Complementary disease-specific modules are available in the EORTC items library.
• The Functional Assessment of Cancer Therapy (FACT)-G questionnaire consists of 27 items divided into four primary domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. Each item is rated on a five-point Likert scale (0 = Not at all, 4 = Very much). Higher total scores indicate better quality of life. Complementary disease-specific modules are available through the FACIT library.

This approach of using these questionnaires has some limitations:

• These questionnaires may not capture unique patient experiences, priorities, or values, particularly in different cancer types or stages.
• Assessments are often done at set time points (e.g., every few weeks or months), missing day-to-day variations in QoL. A patient’s experience between assessments may not be adequately captured.
• Many trials focus on QoL only during treatment but fail to track patients long-term, missing important late effects of treatment, survivorship issues, or ongoing symptom burden. Questionnaires should be administered and analyzed not only during the treatment period but also during the post-progression period because most progressive diseases are diagnosed by radiological and/or biological markers in clinical trials, whereas the patients have no clinical signs of disease progression.

What do patients say about investigational drugs and clinical trials as they relate to improving their quality of life? Where is industry failing to meet patient expectations in this area?

Patients frequently state that while they want to extend their lives, they do not want to do so at the cost of severe toxicity, loss of independence, or a poor quality of life. Some feel that clinical trials overly emphasize survival metrics (PFS) and neglect QoL outcomes that matter to them. For example, in a survey conducted by Cardoso F. et al, 73% of the patients treated for first-line metastatic breast cancer declared that QoL was important for them⁴. Nevertheless, as we said before, QoL is rarely a primary endpoint in clinical trials.

What are some best practices for collecting data on quality of life in oncology clinical research?

High-quality collection of QoL data is essential to enable high-quality data analysis. Here are some best practices:

• Choose validated tools (such as the EORTC QLQ-C30 or the FACT-G questionnaires) adapted to the research goals and a limited number of tools to minimize the patient burden. The questionnaires can be selected with a co-design approach where patients provide input on what aspects of QoL matter most.
• Collect data at multiple time points, at least at baseline and during treatment. If possible, questionnaires should be administered and analyzed not only during the treatment period but also during the post-progression period to capture late treatment effects and measure the real burden of disease or treatment for the patients.
• Use digital tools, such as ePROs, to enhance data quality and reduce patient burden.
• Align with regulatory guidelines (FDA, EMA, etc.) and follow specific guidance, such as the SPIRIT-PRO guidelines for how to report the QoL section in the protocol, the SISAQoL consortium for the statistical analysis of QoL data, and the CONSORT-PRO for the reporting of the QoL results in your publications.

References:

1. Fiteni F, Anota A, Westeel V, Bonnetain F. Methodology of health-related quality of life analysis in phase III advanced non-small-cell lung cancer clinical trials: a critical review. BMC Cancer. déc 2016;16(1):122.
2. Gupta M, Akhtar OS, Bahl B, Mier-Hicks A, Attwood K, Catalfamo K, et al. Health-related quality of life outcomes reporting associated with FDA approvals in haematology and oncology. BMJ Oncol. juill 2024;3(1):e000369.
3. Marandino L, Trastu F, Ghisoni E, Lombardi P, Mariniello A, Reale ML, et al. Time trends in health-related quality of life assessment and reporting within publications of oncology randomised phase III trials: a meta-research study. BMJ Oncol. mars 2023;2(1):e000021.
4. Cardoso F, Rihani J, Harmer V, Harbeck N, Casas A, Rugo HS, et al. Quality of Life and Treatment-Related Side Effects in Patients With HR+/HER2− Advanced Breast Cancer: Findings From a Multicountry Survey. The Oncologist. 3 oct 2023;28(10):856‑65.

About The Expert:

Frédéric Fiteni, Ph.D. is a member of the Kayentis Scientific Advisory Board. He is a medical oncologist and oncology PRO specialist at the University Hospital of Nîmes – France and a lecturer at the University of Montpellier – France. Frédéric specializes in the treatment of breast and gynecological cancers. He holds a Ph.D. in methodology-biostatistics, focusing on statistical models for quality-of-life (QoL) analysis in oncology clinical trials. He continues his research on QoL models as well as supportive oncology care and clinical research in onco-senology and onco-gynecology.