From The Editor | March 2, 2020

Are You Missing Out On Critical Adverse Event Information?

Ed Miseta

By Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @EdClinical

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The Association of Community Cancer Centers (ACCC) presented its 2019 Clinical Research Award to Dr. Ethan Basch during its 36th National Oncology Conference. Basch is the Director of the Cancer Outcomes Research Program and is professor of hematology and oncology at the University of North Carolina Lineberger Comprehensive Cancer Center.

The ACCC noted in a release that as a medical oncologist and health services researcher, Basch has focused on developing methods to bring the patient perspective into cancer clinical research and routine care delivery. For over a decade, his group has developed and implemented patient-reported outcomes tools and worked closely with public and private agencies to effect policy changes based on their findings.

I took this opportunity to speak to Basch about his work and how far the industry has advanced with the collection of patient reported outcomes (PRO) and the and use of ePRO.

Ed Miseta: Please tell us about the Cancer Outcomes Research Program.

Dr. Ethan Basch: The UNC Cancer Outcomes Research Program is a large, university-wide program for bringing together investigators who do cancer related outcomes or health services research. That is similar to what you might call public health research or regulatory science research. We have individuals performing pharmacoepidemiology research and patterns of care research. Some of our faculty are methodologists who do applied work on how care is delivered, such as access, cost, quality disparities, and more.

Miseta: One aspect of your work involves developing methods to bring the patient perspective into cancer clinical research and routine care delivery. Why is that patient perspective so important?

Basch: I'm an oncologist and have been involved with clinical trials for many years. A limitation that became apparent to me early on is that we were not adequately capturing comprehensive information in the data about the patient experience. This was particularly true when it came to toxicities or adverse events. Many of us perceived what was going on with patients, but the data were not conveying that accurately. For example, the extent of severe nausea, diarrhea, fatigue, or pain in patients. I became interested in this problem and started systematically studying whether having patients report on their own adverse events would allow us to pick up on information that we were missing.

Miseta: What were you able to find out?

Ethan Basch

Dr. Ethan Basch, Director of the Cancer Outcomes Research Program and professor of hematology and oncology at the University of North Carolina Lineberger Comprehensive Cancer Center

Basch: We determined that investigators and clinicians were missing up to 50 percent of the symptoms that patients were experiencing. Many of those symptoms were adverse reactions attributable to the drug products being used. That meant there was a large underestimation of the impact of products on patients.

It also meant there might be a large under-detection of baseline symptoms that patients experience. In clinical trials, we sometimes end up misattributing reactions to a drug when in fact they were preexisting and related to other factors. In the work I was doing I began to recognize that by using standardized tools for patients to self-report on their own adverse events, we could improve the accuracy and the precision of adverse event detection. What we've subsequently found is that when we use some of these standardized tools that we've created with the National Cancer Institute (NCI), we can better detect adverse events both at baseline and during studies.

This effort also allows us to be more patient centric. We care about patients and want to act in their best interests. To do so, clinical trials must have comprehensive and accurate data about the impact of products on patients. When we ask patients directly about their experiences, we can be more patient centric and at the same time improve the quality of the data we collect.

Miseta: Many in the industry have long felt that if we ask patients to tell us what they experienced since their last visit, there is a lot we will miss. 

Basch: Exactly. Something is always better than nothing, so asking people that question at the time of their visit is better than not asking at all. But between those visits, when patients are out of sight and out of mind, we are missing out on much of what is going on.

Patients will often have reactions to a medication when they are not at the clinic. Memory degrades over time, and patients forget many of their reactions by the time they see us again in clinic.  There are studies that show people will start to forget details about their condition after about a week.  

Nurses and doctors do not detect everything. When we have conversations with patients in the clinic, we will ask how the patient is doing but for a myriad of reasons may not pick up on certain things. Sometimes we are simply not able to elicit the full amount of information we need in the time we have. Patients may also not want to disclose information because they fear receiving a reduced dosage or being taken off a drug altogether. We know that clinicians can also gloss over discussion details because we need to talk about scans or test results. So, what we see and hear in the clinic can often be an incomplete picture.

Miseta: Are patient-reported outcomes the answer?

Basch: I think so. The best way to obtain information about the subjective patient experience is to systematically ask patients about it. One approach is to collect this information from patients via the use of questionnaires. We also need to understand that it’s not just a matter of asking questions. We must ask questions the right way, and do it on a regular basis, not just when the patient visits the clinic.

Miseta: Once you realized that clinicians were missing half of patients’ symptoms, how did you solve this problem? 

Basch: The missing information was clearly a problem but presented an opportunity to improve our processes by developing new ways to capture this information. Approximately 15 years ago we started building software to elicit the right information from patients. We developed questionnaires that were patient versions of the Common Technology Criteria for Adverse Events (CTCAE), which is the standard adverse event reporting questionnaire system for oncology. The NCI learned what we were doing and expressed interested in this work. They the contracted my group to develop and test an official patient version of the CTCAE, called the PRO-CTCAE.

Miseta: Tell us about the work you did.

Basch: I realized that these tools needed to be fully integrated into trials. I also felt they needed to be used early in development programs. 

Sometimes there is a new drug product being tested in humans for the first time. Other times sponsors might be testing a product in a new indication or a new population. In early-phase clinical studies, it’s important to integrate assessments to examine the patient perspective. This can be as interviews or broad questionnaires that attempt to identify key adverse symptoms patients are experiencing. A sponsor may also want to learn if there are symptoms of disease that might be improving with use of a product. Once one has that information, one can construct more targeted questionnaires to be used in later-phase trials to characterize what's going on in a broader population. Then, when a drug is being reviewed or marketed, there is a better understanding of what people are going to experience, ultimately enabling clinicians to explain to them what to expect.

Miseta: Were you looking for ways to better implement commercially available PRO tools or were you hoping to develop your own?

Basch: If we consider patient-reported adverse events, when we started there was no tool available for that. We felt that such a tool needed to be created but we also felt the tool needed to be created in a way that was complimentary to the CTCAE. Since the NCI has the CTCAE, it made sense for the tool to be housed there.

The rating system needed to be adapted for patient use, which we did. In addition to NCI, my group worked closely with the FDA and multiple pharmaceutical manufacturers, technology vendors, and advocacy organizations to advance awareness of the importance of bringing the patient voice into trials.

Miseta: Will digital devices play a role in this effort?

Basch: Absolutely. I think large pharma companies should be thinking about building digital therapeutics groups that will use patient-reported outcomes in novel ways to monitor patients’ symptoms. This will better allow us to integrate patient-reported outcomes into clinical care with new or existing drugs to catch problems early.

Many companies now have digital therapeutics arms and they're thinking about companion digital therapeutics, which would entail a specific patient reported outcome questionnaire that might be a companion to a specific drug. It would ask about the side effects of that particular drug or the symptoms of the disease. We should also be thinking about integrating patient-reported adverse events in every clinical trial. Whenever investigator-reported adverse events are being collected, patient-reported adverse events should be collected as well. Patient-reported data should be a part of the assessment of tolerability of a product.

Miseta: Do you see this effort changing how we think about patient centricity?

Basch: I hope so. We used to hear pharma talk about patient centricity or patient-reported outcomes as something that was nice to do or the right thing to do. I believe we have come a long way since then. Today, I believe there is a business case for hearing the patient voice and understanding the patient experience. If patient-reporting tools are not used, companies will lack a complete understanding of the impacts of their products, or patient supportive care needs. They will also be at a disadvantage compared to their competitors who are patient focused. It is at a sponsor’s own peril if they don't use patient-reported outcomes tools.


Dr. Ethan Basch is Director of the Cancer Outcomes Research Program and professor of hematology and oncology at the University of North Carolina Lineberger Comprehensive Cancer Center