Patient-reported outcome (PRO) instruments refer to multiple scales and questionnaires designed to collect patients’ personal feedback on their subjective experience in a clinical trial. These validated tools are adaptable, suitable for broad application across diverse study populations or tailored to groups with particular diseases and conditions.
Depending on the research hypothesis and objectives, patient-reported outcome measures (PROMs) may serve as primary, secondary, or exploratory endpoints. PROMs have become increasingly important to clinicians, regulators, and payors for capturing patient-centered data about disease symptoms, side effects, functional outcomes, or health-related quality of life.1
Within the context of clinical trials, “bother” is intricately linked to PROMs. It encapsulates the adverse subjective experiences—ranging from mild discomfort to significant distress—that arise as a direct consequence of side effects or trial-related procedures.2
By incorporating bother questions as part of PROMs in clinical trials, researchers can better understand how patients perceive the impact of the condition or treatment on their daily lives. This information is crucial for evaluating treatment effectiveness, making informed clinical decisions, and improving patient care and quality of life.
In fact, the FACT-G questionnaire’s item GP5, which states, “I am bothered by side effects of treatment,” serves as an aggregate indicator of the cumulative burden of treatment-related toxicity. This particular item has been linked to a significant correlation with the overall quality of life, specifically the patient’s capacity to enjoy life.3 Additionally, bother as a PROM can help regulatory agencies and healthcare providers assess the overall benefit of a treatment from the patient’s perspective.3
Why Measure “Bother”?
When used as a PROM, patients are typically asked to rate the level of bother caused by specific aspects of their condition or the study procedures using standardized questionnaires or scales. These validated assessment tools cover a range of domains, such as pain, fatigue, emotional well-being, and physical functioning.
Patients may be asked to rate bother on a numerical scale (e.g., from 0 to 10) or using descriptive categories (e.g., none, mild, moderate, severe). These instruments can provide insights into the patient’s perspective, capturing data on how bothersome they find specific side effects, which might not be apparent through clinical measures alone.
Source: FACT-G (Version 4), FACIT.org.
The wording and format of bother questions on a PROM will vary depending on the clinical trial focus and outcomes of interest3. Participants may be asked to rate the severity of specific symptoms, the frequency of certain events, or the impact of a therapeutic intervention on their daily lives. These questions can provide valuable insights into the acceptability and feasibility of the study intervention and help researchers make informed decisions about future clinical trials.
Incorporating “Bother” into Clinical Decision-Making
Patient tolerability is often assessed through measures of side effects or adverse events. However, the degree to which these side effects bother patients can vary widely. For some, mild side effects may be highly bothersome and impact their quality of life, leading to poor adherence or discontinuation of the treatment. In contrast, other patients might tolerate more severe side effects without significant bother, motivated by the drug’s benefits.2
Understanding the nuances of bother allows clinicians and researchers to make more informed decisions about treatment recommendations and drug development. It highlights the importance of a patient-centered approach in clinical trials, where patients’ subjective experiences are considered alongside traditional clinical endpoints. Understanding subjective feelings can lead to developing drugs that are effective and have tolerable side effect profiles, improving patient adherence and outcomes.
Example in a Drug Trial
In a hypothetical phase III trial of a new oncology medication, participants could be asked to complete a PROM that includes items on bother associated with side effects like nausea, fatigue, and neuropathy. By analyzing these data points, researchers can gain insights into the balance between the drug’s efficacy and the quality-of-life implications for patients. For instance, if a significant percentage of patients report high levels of bother from neuropathy, this might prompt further investigation into dose adjustments or supportive care options to mitigate this side effect.
Assessing “Bother” Across Cultures
Consideration of how the term bother is interpreted in other languages is needed when using these assessments in multi-center global clinical trials. Linguistic, cultural, psychometric, and clinical factors must be evaluated.4 Aligning instruments with the cultural context of diverse patient populations improves the validity and relevance of PROM data.4
- Language: It is vital to ensure that the term bother is accurately translated to convey the intended meaning in another language. A study analyzing the back-translation of bother found that 20% of the time, PRO instruments differed from the source.5 To ensure the validity and reliability of the questions, native speakers and linguistic experts should be involved in the translation and validation process.4
- Culture: Differences in values, beliefs, and social norms may shift the concept of bother across cultures. One culture may perceive something as bothersome, whereas another culture may not. Adapting PROs to different cultures may include modifying words or context in question to fit cultural norms while maintaining the intended meaning of bother.4
- Psychometric Analysis: Cross-cultural validation studies are needed to evaluate the psychometric properties of PRO instruments across cultural settings. The instrument’s reliability, validity, and responsiveness across diverse populations should be evaluated. Psychometric analyses ensure that bother is measured consistently and accurately across cultures.
- Clinical Interpretation: Clinicians and investigators should consider the cultural context when interpreting PRO data. Recognizing nuances in the meaning of bother in different cultural contexts allows for a more accurate interpretation of PRO scores and facilitates patient-centered care.
PROMs and Payers
PROMs are often used to determine the value of an intervention. Health insurance companies and government healthcare programs use PRO data to determine the impact of treatment on a patient’s quality of life and functional status and make reimbursement decisions.
PROs are used in reimbursement decisions based on various factors: demonstrating clinical effectiveness, comparative effectiveness, determination of money for value, patient perspectives, and long-term outcomes. The increasing importance of PROs in reimbursement decisions reflects the shift toward value-based healthcare emphasizing patient-centered care. Data on the outcomes that matter most to patients are being used to allocate resources to treatments that provide the most meaning to patients.6
Conclusion
Patient-reported outcomes—such as the degree of bother—are pivotal in capturing the full spectrum of treatment impact in clinical trials. These subjective measures delve into the patient’s personal experience of discomfort or distress, which are not apparent through traditional clinical metrics such as lab results or physical assessments. By integrating these insights, we gain a deeper understanding of factors influencing patient adherence and tolerability to treatments.
Such outcomes are instrumental in shedding light on the patient’s journey—encompassing symptomatology, functional well-being, and satisfaction with the care received. Embracing a patient-centric model by incorporating bother as a metric not only aligns research with real-world experiences but also steers drug development towards therapies that resonate more closely with patient needs and lifestyle preferences.
In this endeavor, Castor’s ePRO solution stands as a robust tool for investigators. It provides access to a suite of validated ePRO questionnaires and facilitates the creation of new ones, ensuring that patient voices are heard and valued in the quest for therapeutic innovation.
References
- Mercieca-Bebber R, King MT, Calvert MJ, et al. The importance of patient-reported outcomes in clinical trials and strategies for future optimization. Patient Relat Outcome Meas. 2018 Nov 1;9:353-367. doi: 10.2147/PROM.S156279.
- Pearman TP, Beaumont JL, Mroczek D, et al. Validity and usefulness of a single‐item measure of patient‐reported bother from side effects of cancer therapy. Cancer. 2018; 124(5), 991–997. https://doi.org/10.1002/cncr.31133
- Functional Assessment of Chronic Illness Therapy – Item GP5. FACIT.org. Accessed April 16, 2024. https://www.facit.org/measures/facit-item-gp5
- FDA (Food and Drug Administration). “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.” Published December 2009. Accessed March 19, 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-reported-outcome-measures-use-medical-product-development-support-labeling-claims
- Wild D, Eremenco SMA, Mear I, et al. Multinational Trials—Recommendations on the Translations Required, Approaches to Using the Same Language in Different Countries, and the Approaches to Support Pooling the Data: The ISPOR Patient-Reported Outcomes Translation and Linguistic Validation Good Research Practices Task Force Report. Value in Health. 2009; 12(4), 430–440. https://doi.org/10.1111/j.1524-4733.2008.00471.x
- Gawlicki MC, McKown SM, Talbert MJ, et al. Application of Bother in patient reported outcomes instruments across cultures. Health and Quality of Life Outcomes. 2014; 12(1), 18–18. https://doi.org/10.1186/1477-7525-12-18
- Harnack K. PROs in the Future of Healthcare. Published March 9, 2024. CastorEDC. Accessed March 18, 2024. https://www.castoredc.com/blog/pros-in-the-future-of-healthcare/