|By Tré LaRosa
PROs and clinical trials
While patient-reported outcomes are becoming increasingly standard in clinical trials, their impact still needs to be fully understood. Clinical trials, like peer-reviewed journals, face scrutiny and require rigorous analysis before results can be considered confirmatory. This degree of proof is the strength of science: Stringent guidelines governing evidence encourage researchers to be careful and more particular with the way they design clinical trials. As discussed in our blog about how medications reach patients, I discussed the incremental way therapeutics progress their way from agents of interest in the lab to standards of care in the clinic. Few compounds become FDA-approved, “failing” at different phases in the clinical research pipeline, in some cases before they even reach humans. This is not a bug but a feature of the system: Through high burdens of proof, compounds must demonstrate safety and promise in the lab, in animal models, and then at very low doses in small populations of healthy people before they ever reach patients, at which point there is a high degree of likelihood that the compounds are safe, though there is still no guarantee they are efficacious. In the same vein, patient-reported outcome measures must be considered highly valid, reliable, and acceptable to patients before they are endpoints for clinical trials.
To illuminate how PROs were useful as part of clinical trials, researchers performed a systematic review of publications about the impact of PROs on clinical trials. Their specific aims included understanding how clinical trials reported PROs, the types of impact PROs had on trials, and the extent of the real-world impact. What they found is both promising and illuminating. First, they found that the most common type of clinical trial impact of PROs was through informing clinical decision-making. That alone is a testament to the power of PROs, that they do affect how clinicians make decisions (more on this later). Of all the eligible evaluated case studies, 34% showed evidence that PROs had a direct or indirect impact. At first glance, that figure might sound disheartening and in a way it is, but not for the reason you might expect: The remaining 64% didn’t explicitly state that PROs didn’t have an impact — they simply didn’t provide any evidence of impact. This highlights exactly why the researchers conducted this study — it’s very possible that the trial investigators themselves didn’t quite fully understand the extent that the PROs had an impact and therefore didn’t include that evidence. Again, disheartening in a way, but promising as it means that continued research into PROs and the development of guidance can only be a benefit.
Lastly, possibly the most exciting lesson of their review. They found that trials that included PROs as primary endpoints were more likely to report that PROs had a direct impact than trials that had them as a secondary endpoint. PROs, under more scrutiny and higher expectations, demonstrated that they can meet the challenge.
To further support the benefit of including PROs in clinical trials, in a paper reviewing the use of PROs in studies in infectious diseases, the authors explicitly emphasize that PROs when developed and used correctly “can increase the efficiency and clinical relevance of clinical trials.” Patient-centered approaches to clinical trials don’t just benefit the patients, they benefit the researchers by making clinical trials more effective, an outcome that makes things better for patients, researchers, clinical trial sponsors, and clinicians alike.
Patient-reported outcomes are also useful as tools that provide caregivers and researchers with a more intimate understanding of the behavior and psychology of patients with a given condition. It’s challenging for anybody to imagine how they would act in a specific circumstance, such as being diagnosed or living with a neurological condition. This includes anticipating how people will respond to dosages of interventions. PROs can add helpful context — and potentially guide subsequent trials. So while evaluating the safety and efficacy of medications through established primary endpoints, PROs can provide additional context into the trade-offs and unseen burdens of the intervention. For safety and efficacy to be truly evaluated, it should be assumed that clinical trial conditions won’t perfectly mirror the eventual real-world data. With the help of patient-reported outcomes, clinical researchers can better ascertain what those real-world conditions will look like.
Much remains to be understood about PROs, but they are already making a difference in the world of neurology.
PROs in Neurology
The Quality of Life in Neurological Disorders instrument, known as the Neuro-QOL, is a validated PROM used to evaluate how neurological conditions affect more than twenty measures across the physical, mental, and social health domains of children and adults. Some PROMs are general, such as the Patient-Reported Outcome Measurement Information System (PROMIS), developed and validated to measure the physical, mental, and social domains of anybody, regardless of if they have a chronic condition or not. Disease-specific PROMs also exist. The Neuro-QOL is less specific — and therefore more generalizable — than the PROMIS, but is more specific — and therefore more useful for comparing similar conditions — than the PROMIS. A strength of PROMs is in their diversity and variety, offering researchers different options for different research goals.
A single patient-reported outcome measure in acquired brain injury, multiple sclerosis, and Parkinson’s disease
In some circumstances, there may be a need for a patient-reported outcome measure for a few different conditions. In this case, researchers sought to develop a PROM that allowed for a more specific comparison across acquired brain injury (ABI), multiple sclerosis (MS), and Parkinson’s disease, even though disease-specific PROMs exist. Their rationale — and as mentioned in part one, there has to be an unmet need before it makes sense to develop and validate a PROM — was that ABI, MS, and PD often present with overlapping symptoms, and since PROMs vary in length, complexity, and extent of validation, it would be valuable to have a PROM to make a direct comparison more accessible. They found that their newly-developed PROM — itself born out by two already-validated instruments, including the aforementioned PROMIS instrument — performed as well as the disease-specific instruments, indicating its utility, generalizability, and relevance to AB, MS, and PD.
The Patient-Reported Outcome for Multiple Sclerosis (PROMS) Initiative
A current limitation of PROMs is that there can be a gap in understanding how to utilize PROs as effectively as possible. In a condition like multiple sclerosis, which affects at least 2.8 million people across the world, patient-reported outcomes hold remarkable promise, offering illuminating possibilities into the variations of the types of MS, the care in different nations or states, and how to develop drugs using different therapeutic approaches. The European Committee for Treatment and Research in MS (ECTRIMS) set out to resolve this issue in 2019 when they established the Patient-Reported Outcome for Multiple Sclerosis (PROMS) initiative, not to be confused with either PROMIS or PROMs. ECTRIMS had two primary goals when they mapped out PROMS: To “maximize the impact of science” of PROs, and to “represent a unified view [on PROs for MS] to people affected by MS, healthcare providers, [and] regulatory agencies.” Necessary goals to be sure, but also ambitious, only possible to attain by being international and interdisciplinary. The PROMS Initiative has not concluded, but they have made progress.
Using PROs to Establish a Core Outcome Set (COS) in Childhood Epilepsy
A Core Outcome Set (COS) is an accepted, standardized group of outcomes used in a specific condition for clinical trials. They reduce uncertainty and bias and improve clinical relevance, especially because — much like PROMs — they are developed only after enlisting the perspectives of patients, caregivers, and health professionals. One group of researchers, after performing a systematic review of childhood epilepsy-specific PROMs, “mapped” the PROMs to a proposed core outcome set to guide future research in childhood epilepsy clinical trials.
What do neurologic providers think about patient-reported outcomes?
We’ve discussed PROs in clinical trials and specific examples of PROs in neurological clinical trials, but how do providers view PROs and how do PROs shape how clinicians provide care? One group set out to answer this question, which included 11 questions asking providers a series of questions including how they talked to patients about PRO results, how the results shaped their care, and their general perspective on how useful PROs are. While only 40% of providers responded that they directly discussed the PROs with their patients, more than 70% responded that PROs informed their patient management at least some of the time. Overall, the researchers concluded that clinicians by and large have a favorable view of PROs. Given what we’ve talked about regarding the gaps in understanding of PROs, this study underscores that PROs, while providers already see them as positive, can be even more impactful.
Patient-reported outcomes offer a powerful, insightful way to better center patients in the healthcare system. PROs empower patients by giving them an avenue to report their perspectives, which serves to benefit their care, improve clinician understanding, and inform research in a more nuanced, quantitative, and qualitative. While there are gaps, PROs have already demonstrated remarkable impact and promise — through initiatives like PROMS, their impact is likely to only grow. Patients deserve to feel empowered and centered in their care — PROs are a scientific, necessary tool to doing just that.
- Birch, N., Graham, J., Ozolins, C., Kumarasinghe, K., & Almesfer, F. (2022). Home-Based EEG Neurofeedback Intervention for the Management of Chronic Pain. Frontiers in Pain Research (Lausanne, Switzerland), 3, 855493.
- Carter, B., Hayes, C., Smith, A., Pennington, A., Price, M., Pearson, O., Vitoratou, S., & Hewitt, J. (2021). A single patient reported outcome measure for acquired brain injury, multiple sclerosis & Parkinson’s disease. PLoS ONE, 16(6), e0251484.
- Crudgington, H., Collingwood, A., Bray, L., Lyle, S., Martin, R., Gringras, P., Pal, D. K., & Morris, C. (2020). Mapping epilepsy-specific patient-reported outcome measures for children to a proposed core outcome set for childhood epilepsy. Epilepsy & Behavior, 112, 107372.
- Katzan, I. L., Thompson, N. R., Dunphy, C., Urchek, J., & Lapin, B. (2018). Neurologic provider views on patient-reported outcomes including depression screening. Neurology: Clinical Practice, 8(2), 86–92.
- Neurology, T. L. (2019). Patient-reported outcomes in the spotlight. The Lancet Neurology, 18(11), 981
- Newey, C. R., Thompson, N. R., George, P., Punia, V., Hantus, S., Lapin, B., Gomes, J., & Katzan, I. (2020). Patient-Reported Outcomes (PROs) in Acute Symptomatic Seizure (ASyS) Versus Patients With Established Epilepsy. The Neurohospitalist, 10(3), 193–200.
- Powers, J. H., Howard, K., Saretsky, T., Clifford, S., Hoffmann, S., Llorens, L., & Talbot, G. (2016). Patient-Reported Outcome Assessments as Endpoints in Studies in Infectious Diseases. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 63(Suppl 2), S52–S56
- Rivera, S. C., Kyte, D. G., Aiyegbusi, O. L., Slade, A. L., McMullan, C., & Calvert, M. J. (2019). The impact of patient-reported outcome (PRO) data from clinical trials: A systematic review and critical analysis. Health and Quality of Life Outcomes, 17(1), 156.
- Zaratin, P., Vermersch, P., Amato, M. P., Brichetto, G., Coetzee, T., Cutter, G., Edan, G., Giovannoni, G., Gray, E., Hartung, H. P., Hobart, J., Helme, A., Hyde, R., Khan, U., Leocani, L., Mantovani, L. G., McBurney, R., Montalban, X., Penner, I.-K., … PROMS Initiative Working Groups. (2022). The agenda of the global patient reported outcomes for multiple sclerosis (PROMS) initiative: Progresses and open questions. Multiple Sclerosis and Related Disorders, 61, 103757.
- Crudgington, H., Rogers, M., Morris, H., Gringras, P., Pal, D. K., & Morris, C. (2020). Epilepsy-specific patient-reported outcome measures of children’s health-related quality of life: A systematic review of measurement properties. Epilepsia, 61(2), 230–248.