The prevalence of leukemia is increasing worldwide. Chronic Myeloid Leukemia (CML) patients benefit from recently improved care but receive prolonged, sometimes even lifelong treatment. Over the last decade, managing side effects and clinical decision making have become challenging. Whilst treatment efficacy has changed the pattern of what was historically a life-threatening disease to what has become a disease with less than 20% of patients remaining at risk of dying, less than 20% achieve treatment-free remission and more than 60% require chronic, life-long treatment.
Consequently, a consideration of the treatment effects on patient quality of life (QoL) and symptom burden has become critical to improve patient care and health care quality. Such assessments can only be made via increased use of properly selected Patient Reported Outcome (PRO) measures. It is time for clinical research to not only focus on prolonging life, but also to tackle improving the quality of the life of the patients who live with this long-lasting disease.
Why you should include PRO data in your leukemia clinical research
Including PRO reports is the only way to directly obtain relevant information on symptoms from patients living with the disease and taking treatment, and on the impact of the disease or treatment on their daily lives.
- There are important discrepancies in the way symptoms are reported by clinicians and patients, and there is evidence that clinicians may miss a large proportion of symptomatic adverse events (AEs) in clinical trials.
- Specifically, in CML research, even in settings in which one would expect that side effects be collected in the most rigorous way (ie, registrative randomized controlled clinical trials), extensive variation exists in the reporting of symptoms.
- PRO measures have been associated with relevant clinical end points and are prognostic for survival outcomes in a variety of solid cancers in adults.
- It has been recognized that classic clinical endpoints do not accurately portray a full appreciation of the benefits, risks, and costs of therapy, and the fact that a correlation now exists between PROs reported data and treatment response and survival supports that more emphasis should be placed on patient’s reported information in cancer clinical research.
Health status data obtained through patient self-reporting provides clinically relevant information that cannot be captured by standard laboratory or clinical measures typically used in oncology. However, PRO data will only be valuable if a well thought out and planned eCOA strategy is in place.
Which methodology should you use for capturing the patient’s voice in leukemia clinical research?
Regulatory stakeholders have often cited methodological shortcomings in the PRO design as a reason for the lack of impact of PRO findings in regulatory decisions. Evaluating PROs in clinical trials without strong methodology is problematic, especially in leukemia clinical trials where the patients QoL is severely affected and requires careful decision-making and robust upfront planning.
1- Think with the end in mind: plan your ePRO strategy upfront
Collecting PRO data cannot be a last-minute decision. Deciding on the ePRO endpoints, collecting relevant symptoms and AEs at the appropriate timepoints with the appropriate frequency, as well as selecting the right measure for the endpoint, are decisions that need to be made early in the clinical development process.
The susceptibility to a specific type of AE (eg, muscle cramps rather than headache) may vary from patient to patient. The relevance of certain symptoms and the importance of addressing a particular symptom may not necessarily be apparent for the clinicians designing the protocol. As such, being able to identify patient-specific thresholds or preferences early may have major implications for enhancing the meaningfulness of a study and reducing nonadherence. This will help to maximize the chances of research success and possibly improving long-term treatment outcomes.
To establish a solid strategy, the definition of endpoints, the selection of the instruments to be used and their administration frequency, and the operational deployment of the PRO solution will be discussed and planned with your eCOA vendor.
2- Strengthen your ePRO data: choose the relevant PRO measures
The QoL instruments used are often cancer generic PRO measures, which might not always collect information that is relevant for leukemia patients.
- FACT-G, EORTC QLQ-C30 are the measures most often used in leukemia clinical research per ct.gov, and are strong, well-recognized, certified scales.
- However, some CML-specific questionnaires exist, which are more targeted to the symptomatology of the disease:
- The EORTC QLQ-CML24 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chronic Myeloid Leukemia 24) has shown satisfactory validity and is recognized for its applicability across multiple languages and cultures.
- The MDASI CML (MD Anderson Symptom Inventory Chronic Myeloid Leukemia Module) has been tested on 187 patients under treatment with different Tyrosine Kinase Inhibitors (TKIs) in the United States, and has been characterized as being better able to specifically assess the symptom burden than generic QoL questionnaires in CML patients.
- FACT-Leu (Functional Assessment of Cancer Therapy – Leukemia), has provided relevant information to better understand the impact of treatment on patient QoL.
There is no consensus regarding which PRO instrument is the best for leukemia clinical research; this depends on the specific research question being asked and the particular setting. The decision should be guided by a number of factors, including the protocol-defined objectives, the target patient population and countries, and the regulatory strategy. Increasing the sensitivity of PRO measurements by using a combination of questionnaires devised for the specific population and discussing the eCOA strategy with your eCOA provider are important steps for the success of the study.
3- Optimize your ePRO data: implement your ePRO strategy successfully
When the strategy is in place, you may work with your specialist eCOA partner to both incorporate disease-specific, validated measures, and to design specific eDiaries if the study requires the daily capture of data, such as specific symptoms or concomitant medication intake.
As the success of a PRO study can be jeopardized by several factors, including missing PRO data over time or logistics, clinicians should carefully consider the robustness of the methodology used by the eCOA vendor to optimize data entry and data quality.
- Opting for multiple data entry methods is a good and easy way to offer flexibility to patients and make sure they have the choice of a preferred data capture method or have a fallback plan in case of failure of the primary method of data collection.
- Accessing data in a timely manner, to monitor patient compliance, and implement targeted actions at the site or patient level to mitigate potentially risky patterns.
- Checking the audit trail any time, to allow the tracking of data credentials and data completion timestamps, and to respond to audit or inspection requests.
- Relying on the eCOA vendor logistics capabilities will ensure that the devices are made available in a timely manner at the sites so that they are ready to start up and enroll patients, and that these devices will display the relevant questionnaires in the right language together with the appropriate training material.
The value of incorporating patient self-reports in oncology clinical research is commonly accepted. A well thought out, scientifically led PRO strategy together with optimal operating processes will reinforce the chances of success of CML oncology trials. But Clinicaltrials.gov figures show that of 1491 CML registered studies, only 47 include a PRO measure as an outcome. This very low ratio (3.15%) highlights the effort that is still needed to shift the focus of leukemia clinical research towards a better understanding the impact of both the disease and the treatments on the daily life of patients.
