At the Partnerships in Clinical Trials Conference in Barcelona in November 2018, Strategic Consultant Ursula Garczarek participated in a thought leadership stream tackling various developments in Real World Evidence, Pediatrics, Trial Design & Big Data. As well as participating in a panel discussion on innovations in clinical trial design, she was impressed by the contributions and innovations offered from other stakeholders across the healthcare landscape. One of these exceptional contributions came from from Galina Velikova, Professor of Psycho-social and Medical Oncology at the University of Leeds, and in this blog, we are thrilled to share an interview with Professor Velikova, in which she expands her discussion of the role of Patient Reported Outcomes (PROs) and Quality of Life Measures in trials and clinical practice.
In the interview, Professor Velikova discusses the evolution of patient reported outcomes, the regulatory environment, and how using PROs in patient care be seen as an intervention that results in real improvement in outcomes.
She gives insights into her experiences at the University of Leeds of conducting online monitoring of toxicity during cancer chemotherapy using patient self-reported side-effects integrated with the electronic patient records (electronic patient self-Reporting of Adverse-events: Patient Information and aDvice- eRAPID research program funded by the National Institute for Health Research).
Could you give us an overview of your role and your background? I'm an academic medical oncologist. I treat breast cancer patients half of my time, working in the Leeds Cancer Centre and I have an academic role, as a professor of patient-centered research at the University of Leeds. The primary interest of my research work is in using patient-reported outcomes in clinical practice. I also have a clinical investigator role in a couple of clinical trials that use quality of life outcomes as secondary measures. So, breast cancer treatment and patient-reported outcomes are my main areas of focus, and I combine academic and clinical work.
What sparked your research interest in patient-reported outcomes? Many years ago, when I started doing oncology for the first time, I wanted to understand whether the toxic chemotherapy that we used to give at that time helps people, and find out how you can measure that benefit for the individual patient. That was the time when we were providing chemotherapy without 5-HT3 antagonists, so vomiting was a big problem. We had to admit patients for chemotherapy to control the vomiting the best we could. I wanted to find ways of measuring if patients feel better from their treatment in metastatic disease setting, despite all the side effects.
What is meant by patient-reported outcomes, and how has their use and appreciation evolved? Patient-reported outcomes as a term evolved from the United States via the FDA. The definition, as you probably know, is any reports that come from the patients, without being modified by somebody else. Before that, there were several decades of measuring psychological morbidity such as general distress, anxiety, depression, using questionnaires from patients. The other contributing area was the health status measures, like the Sickness Impact Profile. Quality of life measures came developed as questions derived straight from patients with a different, more positive perspective. The initial use of the health status and quality of life measures was descriptive to find out what problems people have, and whether we can address these on a broad epidemiological-type scale. The individual patient use, at that time, was screening for psychological morbidity and diagnosing depression. The next level was when the quality of life measures, which are now called PROs, were implemented in clinical trials to compare between different groups usually as secondary outcomes. Over time, we have moved gradually towards asking whether we can use patients' self-reports in clinical practice to inform patient care. Can we ask patients to report their pain or nausea, sore mouth, and give that information to the clinician? The most recent development has been the more formal use of patient-reported outcomes to measure toxicity during treatment both in individual patient care and clinical trials. This latter development follows a publication by Ethan Basch using online reporting of side effects during treatment. Subsequently, the NCI funded a programme to develop a version of the common toxicity criteria that are essentially patient-derived- the NCI PRO-CTCAE. These are the key developments as I've seen them through my work in that area over the last 25 years.
What is the regulatory perspective on patient-reported outcomes? It varies. The EMA has a broader perspective and guidelines on how quality of life measures and PROs can be used in clinical trials, as well as how to then interpret that information. Because of the marketing options that are available in the United States, the FDA has produced a set of strict guidelines on when a product can claim quality of life benefits. These are also guidelines on the instruments, which the sponsors can use and how to validate them for the specific setting.
Can using PROs in patient care be seen as an intervention that results in real improvement in care?Can you describe what evidence you've seen to support the existence of these benefits? The way we have used PROs and the way Ethan Basch has done his trial in Memorial Sloan Kettering (1) is that patients report side effects online and then they get advice when to contact the hospital. This process has benefits. While I haven’t yet analyzed my most recent data, in the past I did one study using an EORTC questionnaire mainly around symptom monitoring during chemotherapy (2). We were able to show better symptom control, and better quality of life of patients when they completed the questionnaire in the clinic before seeing the doctor. Ethan's trial showed similar effects and demonstrated improvement in quality of life using EQ-5D. It also showed a survival advantage.
The most striking example is a study in France by Fabrice Denis(3) in lung cancer where patients received online monitoring and were given advice when to call their nurse during chemotherapy and during targeted or immunotherapies. The study was powered for survival difference, and it shows a survival difference of about seven months median survival difference in lung cancer, which is quite impressive. My view is that the benefit is partly due to educating people about their symptoms and which of those symptoms are significant, so they can self-manage and know when to call the hospital. This education also perhaps allows earlier treatment in the metastatic disease and earlier detection of important side effects like infections in the earlier disease.
Can you tell us about the eRAPID programme? The eRAPID research programme is about online monitoring of side effects, adverse events, and then linking that to advice to patients about self-management of mild side effects, contacting the hospital immediately and sending an alert to the hospital team when they have serious adverse events. In between these extremes is an advice on moderate symptoms, namely, if that problem continues, contact your medical team when convenient. I want to roll this out in routine clinical practice. We're still analyzing the data from the programme, so I don't have the results available yet. However, I'm looking at tailoring the intervention towards some of the oral targeted treatments where patients don't come to the hospital frequently.
What are the challenges and opportunities of online monitoring for patient care? Challenges are training staff and adapting the IT systems which are very different in different hospitals. To use online monitoring for routine patient care, ideally, the results that patients are reporting should be displayed within their electronic records. The online system is easy to set up, but then it needs to be linked to electronic records. It's not technically challenging, but it's just not the top priority for the big hospitals, and so it takes a long time to implement. I think the future is likely in the use of patient portals where patients are given access to their electronic records through a secure gateway, and then putting the patient-reported outcomes as part of that portal. So patients can then do the questionnaires, the patient-reported outcomes, by just logging into the portal, completing it there, and it's already there in the electronic records. Whereas our current system is, they do the questionnaires online in a secure and anonymous system, and then we use other software to pull that information into their electronic records.
Comment: Potential for the future and implications for statisticians by Ursula Garczarek One important implication for statisticians when planning clinical trials and when doing meta-analysis, is to be aware that PROs can have a treatment effect, especially when they are taken online. There is quite some interest in PROs as outcomes in Virtual Clinical Trials, and in that case, when comparing the effect sizes in the treatment arms with other trials without such an endpoint, one needs to pay attention. For all statisticians, programmers, and data managers, the message that a well-designed ePRO tool that connects patients with health care providers can be a truly effective medical device is very exciting. Finally, we can directly contribute to the well-being and the treatment of patients!
Thank you to Professor Velikova for her generosity in participating in this blog and sharing her knowledge.
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About Professor Velikova
Professor Galina Velikova is an academic Medical Oncologist at the University of Leeds and Leeds Teaching Hospitals, UK with over 20 years’ track record of successful patient-centred research using electronic Patient-Reported-Outcome Measures in daily practice and clinical trials. She currently leads a National Institute for Health Research (NIHR) 5-year Programme Grant for applied research on patient self-reported symptoms and toxicity, using an online reporting system (QTool), uniquely integrated in electronic records, along re-designed care pathways for remote monitoring during cancer treatment to improve patient safety. Further research projects evaluate the use of the electronic system for remote monitoring and follow-up of cancer patients after treatment.
Professor Velikova has experience in leading collaborative research, both nationally and internationally, such as Quality of Life sub-studies of international breast cancer trials (TACT2, SUPREMO). She is the past Chair of the British Psychosocial Oncology Society, past Chair of the EORTC Quality of Life Group; and past President of the International Society for Quality of Life Research (ISOQOL). Prof Velikova is currently the Chair of the National Cancer Research Institute (NCRI) Psychosocial Oncology and Survivorship Clinical Studies Group and is also a member of the board of the EORTC.
Professor Velikova is a practising oncologist (Consultant in Medical Oncology) with clinical work focused on systemic treatment of breast cancer patients with early and advanced disease. References 1) Basch, E., Deal, A., Kris, M., Scher, H., Hudis, C., Sabbatini, P., Rogak, L., Bennett, A., Dueck, A., Atkinson, T., Chou, J., Dulko, D., Sit, L., Barz, A., Novotny, P., Fruscione, M., Sloan, J. and Schrag, D. (2016). Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial. Journal of Clinical Oncology, 34(6), pp.557-565. 2) Velikova, G., Booth, L., Smith, A., Brown, P., Lynch, P., Brown, J. and Selby, P. (2004). Measuring Quality of Life in Routine Oncology Practice Improves Communication and Patient Well-Being: A Randomized Controlled Trial. Journal of Clinical Oncology, 22(4), pp.714-724.
3) Denis, F., Basch, E., Lethrosne, C., Pourel, N., Molinier, O., Pointreau, Y., Domont, J., Bourgeois, H., Senellart, H., Bennouna, J., Urban, T., Septans, A., Balavoine, M., Solal-Celigny, P., Dueck, A. and Letellier, C. (2018). Randomized trial comparing a web-mediated follow-up via patient-reported outcomes (PRO) vs. routine surveillance in lung cancer patients: Final results. Journal of Clinical Oncology, 36(15_suppl), pp.6500-6500.