Ensuring Patient-Centered Care in Oncology Trials
From centralized ECGs to patient-reported outcomes – a guide to optimizing assessments of drug safety and quality of life
Todd Rudo, M.D. – Chief Medical Officer at Clario
Robert Kleiman, M.D., Ph.D. – Chief Science and Regulatory Advisor, Cardiology at Clario
Kelly Dumais, Ph.D. – Director, eCOA Science and Consulting at Clario
Editor’s note: The following article is adapted from the recent webinar “Safety and Tolerability in Oncology Trials: Cardiac Imaging, Electrocardiography and the Role for Patient-Reported Outcomes” Responses have been edited for clarity. You can watch the full webinar recording here.
In oncology trials, safety and tolerability are always a core focus in every development program. Understanding the risk profile of a drug is critical to assessing whether the benefits outweigh the risks of treatment. However, there is another dimension that is as important—a consideration of the patient perspective. Assessing quality of life during clinical trials by soliciting patient feedback through patient-reported outcomes (PROs) is crucial, as this helps us understand the experiences of patients receiving novel treatments. Integrating safety data with quality of life data, as well as efficacy data, ensures that drugs reaching the market will not just have maximal therapeutic benefit, but will also favorably impact the overall well-being of patients prescribed those therapies.
Why test cardiac safety for all new drugs?
Given that all medications circulate through the heart, thorough cardiac safety assessments are a vital part of all development programs, including oncology programs. Ensuring a thorough assessment of cardiac safety protects patients from potentially serious or life-threatening adverse events, or if cardiac risks are identified, allows prescribers to monitor closely for them.
- Exposure to the Heart: All drugs, regardless of their intended target or administration route, ultimately circulate through the bloodstream and expose the heart to their effects. Therefore, any new drug creates a potential for cardiac toxicities until a clinical trial can prove otherwise.
- Prevalence of Cardiac Side Effects: Cardiac side effects caused by new oncology drugs are not uncommon, with more than half of recent approvals having some element of cardiovascular toxicity mentioned in their label.
- Risk-Benefit Analysis: While drug regulators always maintain focus on patient benefits, equal to this is the focus on the balance of potential risks. Favorable efficacy in treating a particular condition might be overshadowed if a drug causes severe or serious side effects.
- Quality of Life Considerations: Regulatory bodies including the FDA are increasingly emphasizing the role of assessing both the benefits of drugs and their impact on patients’ quality of life, systematically.
- Informative Labeling: Thoroughly assessing a medicine’s risk profile, including cardiac risks, provides sponsors and regulators with the necessary data to adequately inform healthcare professionals about safe and effective drug usage, through detailed drug labeling
Why centralize ECGs in oncology trials?
Centralizing ECGs and blood pressure in oncology trials ensures an accurate, consistent, and comprehensive set of cardiac safety assessments, allowing sponsors to have confidence in their trial results.
- Accuracy and Reliability: A study examining approximately 270,000 ECGs from 300 oncology trials revealed that relying on ECG machine-based onboard algorithms can produce a significant number of false positives. For machine-derived QTcF values greater than 500ms, there is a more than 75% chance that the centralized reading is below that threshold, with an average discrepancy of 80 milliseconds. False positives like this may prevent patients from study eligibility, or from continuing potentially life-saving treatment within a study, depending on protocol-stopping criteria. By centralizing ECGs, one can enhance the accuracy and reliability of ECG interval measurement data, ensuring that decisions made based on these readings are sound.
- False Negatives: There’s also a concerning prevalence of false negatives, which can be even more alarming since they can result in vulnerable patients continuing a medication regimen that may further exacerbate their cardiac risk with potentially disastrous consequences. Centralizing ECGs helps mitigate the frequency of false negatives from automated ECG algorithms, ensuring that patient safety is optimized, and that trial data is not compromised by the errant inclusion of individuals with a prolonged baseline QT interval.
- Holistic Cardiac Assessment: While QTc readings are important, they are not the sole indicators of cardiac health. There are many other forms of cardiac toxicities that might be present on ECGs or require other testing modalities for detection. For instance, cardiomyopathy (which can cause congestive heart failure) and dangerous arrhythmias are better detected using echocardiography and continuous ECG monitoring, respectively,
- FDA and Blood Pressure Monitoring: The FDA’s growing interest in drug-induced blood pressure fluctuations necessitates robust measurement protocols, generating data of sufficient quality to satisfy regulatory authority requirements. Centralizing blood pressure assessments not only helps streamline the operational aspects of remote data collection but also ensures higher quality data. Centralizing clinic-based readings with uniform equipment across a multi-center study can also significantly enhance data accuracy and reliability.
- Catering to Vulnerable Populations: Many participants in oncology trials are older, have already received multiple prior treatments, and may already have underlying cardiac conditions. Centralization ensures that ECGs of these patients are monitored more accurately, helping detect cardiac toxicities and potentially preventing further damage.
Why use PROs to evaluate tolerability?
There is a growing interest in Patient-Reported Outcomes (PROs). By incorporating the use of PROs in oncology trials, researchers and clinicians can provide more patient-centered care. This enriches the field of oncology research with nuanced and comprehensive data while developing treatments that are closely aligned with patients’ needs and preferences.
While paper PRO collection is still an option, there has been a shift towards electronic data collection (ePRO). Data captured using ePRO is more accurate and makes regular reporting easier and more convenient for patients because they are not required to come to a site. Furthermore, in a recent study, oncology patients reported that ePRO was less difficult and stressful than paper PRO 1. ePRO also allows for continual measurement, which may provide a more rounded view of a patient’s quality of life and their trial experience2. Whether you choose paper or digital, incorporating PROs early in drug development is pivotal for several key reasons:
- Enhanced Patient-Centric Approach: PROs ensure that the patient’s experience, including side effects and impact on daily life, is systematically documented and considered during oncology trials. For example, one of the prominent tools used to assess symptomatic side effects is the PRO-CTCAE, which is a complementary tool to the clinician-reported NCI-CTCAE. While the clinician-reported NCI-CTCAE is essential to report symptomatic and laboratory clinical adverse events, the PRO-CTCAE provides an additional, more holistic view of symptoms and their impact on daily functioning as the recorded experience comes directly from the patient.
- Richer Data for Regulatory Bodies: Using PROs aligns with guidelines from regulatory authorities like the FDA and EMA. These organizations value the comprehensive data that PROs offer, especially regarding symptomatic adverse events and their functional impact on patients. Inclusion of PROs early in drug development programs can be pivotal during the regulatory review and approval processes and denotes submission-readiness, given that many drug approvals are based on early phase trials.
- Informative for Future Trials: The early inclusion of PROs in clinical trials optimizes and potentially streamlines subsequent trial phases. It provides relevant and impactful data that can inform the design and focus of future PRO strategy (e.g., assessments, frequency of administration).
- Enhancement of Risk-Benefit Evaluations: Given the increased survival rates in various cancers, understanding and optimizing quality of life during and post-treatment is pivotal. PROs provide invaluable data that enrich the evaluation of the risk-benefit profile of new oncology treatments. They inform clinicians and patients in decision-making processes so that treatment strategies are tolerable, effective, and aligned with patients’ experiences and expectations.
The rapidly evolving regulatory environment for oncology drug development requires adaptation in the ways we assess patient safety and quality of life in these programs. The importance of incorporating high-quality cardiac safety assessments into trials is critical as all drugs have potential to induce cardiac side effects. The cardiovascular toxicities associated with many recently approved oncology drugs further underscores this necessity. A centralized ECG approach in trials enhances the accuracy of cardiac evaluations, reducing both false positives and negatives, resulting in enhanced patient safety, and reduced risk for inappropriately withholding therapy.
Simultaneously, the rise of PROs in oncology trials reinforces a patient-centered movement in drug development. As a result, it has become clear that for a comprehensive safety and tolerability evaluation, PROs have become an important piece of the puzzle. Integrating efficacy and safety data with patient experience data will pave the way for development of better therapies for cancer patients worldwide, addressing the massive unmet medical need, but doing so in a way that considers the patient’s perspective as a priority.
Todd Rudo, M.D.
Chief Medical Officer at Clario
Robert Kleiman, M.D., Ph.D.
Chief Science and Regulatory Advisor, Cardiology at Clario
Kelly Dumais, Ph.D.
Director, eCOA Science and Consulting at Clario
1Graf, et al., J Med Internet Res. 2022;24(2):e16128
2Shiroiwa et al., Med Decis Making. 2022 Jan;42(1):60-67