by Christina Bennett, MS
Patients and oncologists have more options than ever when selecting a cancer drug. The problem though is that while oncologists can offer a flurry of metrics—overall survival, tumor shrinkage, disease-free survival—that indicate a drug’s efficacy, they cannot tell patients how they will feel or function on one treatment compared with another because that level of detail is not available.
One way to measure the subjective patient experience is through patient-reported outcomes (PROs), which the U.S. FDA defines as a metric based on feedback directly from the patient about the status of his or her health condition without interpretation from the clinician or any other person.1 PROs have the potential to change cancer care by appearing on product labels or leading to FDA approvals, as was the case for Jakafi® (ruxolitinib), but they need to be properly and consistently captured.² And although more cancer drug companies are including PROs as a measure in their clinical trial designs, most still do not.³
“Collection of the patient-reported experience cannot be an add-on,” stressed Heidi Klepin, MD, Chair of the Cancer Research Committee at ASCO. “It can’t be an afterthought in clinical trials, and I would say in my experience, it feels like that’s where it’s fallen.”
To tease out how best to capture the patient experience, the FDA and the American Society of Clinical Oncology (ASCO) co-sponsored a workshop on June 22 to serve as an open forum for patients, regulators, oncologists, and other key stakeholders.4
The demand for meaningful PRO data was clear throughout the workshop and across the spectrum of stakeholders, but especially so for patients and oncologists who are actually making the treatment decisions.
“When I sit down with a patient to think about starting a new treatment, almost invariably, the first question that they ask is how they will feel with this product,” said Ethan Basch, MD, MSc, Director of the Cancer Outcomes Research Program at the University of North Carolina. “If I don’t have that information from a reliable source, I’m not able to be a good partner in that decision-making.” He added that these decisions aren’t just at the point of care. These are decisions along the “entire continuum.”
Although oncologists can offer patients a drug’s adverse event information, captured via the Common Terminology Criteria for Adverse Events (CTCAE) instrument, this information does not adequately describe how a patient may feel or function on treatment. The CTCAE relies on clinician reporting and, as shown in a study, clinicians are not reliable sources of adverse events, suggesting patients may be the best source.5 Further, even if adverse event information were reliably reported, it would not be enough.
“Patients are all different and they all want different information. A lot of them really want sort of a global knowledge about how am I going to feel compared to how I feel now,” said patient representative Jane Perlmutter, PhD, MBA. She noted that some patients want much more detailed information about specific potential side effects.
The push for meaningful PRO data extends beyond patients and oncologists. Paul Kluetz, MD, Associate Director of Patient Outcomes at the Oncology Center of Excellence at the FDA said, “Everyone’s interested in trying to discriminate between products, we need more data, and so this is another data source that we can use.”
Entities interested include drug companies, regulators, payers, and healthcare systems, each for slightly different reasons, but in general, because healthcare is becoming more value-centric and everyone wants to know a drug’s true value. Part of that value is how well a therapy extends survival or shrinks a tumor, and part is how a patient feels and functions while on therapy, an aspect that is difficult to quantify.
“Skip PROs in cancer drug development at your own peril,” Dr. Basch warned product developers. “If you don’t do this, you will not fully understand your own product. Your product will hit the market and unexpected things will happen, and not only will you not understand your product, but other people who want to know what is going on with your product won’t either.”
Setting Standards, Now
To capture meaningful PRO data, standards need to be set for how PROs are measured, analyzed, and reported because, according to Dr. Kluetz, the FDA is receiving PRO data weekly and there is a lack of standardization.
“We need to strengthen protocol design in clinical trials because if this data is going to be used for major decision-making, it should be captured and analyzed with the same rigor we use for other clinical trial data points,” said Dr. Kluetz.
To start, Dr. Kluetz proposed creating a standard set of core PRO outcomes that can be measured across cancer clinical trials. The standard set of core PRO outcomes could include symptomatic adverse events, overall side effect impact, disease symptoms, and physical function (Figure 1). He said, “They may not be the only concepts to measure, but they would be a good start.”
“If we can come up with standard outcomes, we can come up with standard trial objectives, and then standard analyses,” said Dr. Kluetz.
While instruments, like the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), are available and can capture the patient experience, fine tuning of these tools is needed.6
Medical officer in the Division of Oncology Products 1 in the Center for Drug Evaluation and Research at the FDA, Lynn Howie, MD, said that applications submitted to the FDA have “plenty” of PRO data, but the current PRO strategies involve “lots” of questions, often more than 50 questions for patients. “Despite this, there are still critical questions missing, meaning that many instruments ask no questions about the most common symptomatic adverse effects from a drug or common disease-related symptoms.”
By not having questions about important symptomatic adverse events, trial sponsors may miss and bias the patient perspective about which therapy is more tolerable, noted Dr. Howie.
“We also want to limit the amount of questions assessing locoregional effects because these are not likely affected by the treatment that’s being evaluated,” she said. “It’s not to say that these are not important things to patients living with these diseases. It’s just from a regulatory perspective, if you can reduce question burden and be able to tease out the effects of the drug, you want to do this with as few questions as possible.”
Patient advocate and CEO of LUNGevity, Andrea Ferris offered the patient perspective on asking the right questions. “You’re asking really sick patients to give you their time and to share their experiences with you. Make sure it’s something that they can then use, or other patients can then use.”
Another aspect to fine tune is making sure the patient understands the purpose of the PRO instrument. Otherwise, they may respond in a fashion that biases results. Ms. Ferris recalled talking with a focus group of patients and learning that they thought the PRO data were used for clinical care and would affect whether they stayed on the trial. “They had no concept that this was for future patients to understand how somebody taking this drug is experiencing it. That’s a big, big issue because then there’s a lot of underreporting.”
A Path Forward
After the workshop, Dr. Kluetz told OBR, “My feeling is that we have proposed core outcomes to measure, we have clarified that there are several measurement systems that have characteristics that are suitable for regulatory use, and that we now need to focus on creating the standard trial objectives, endpoint definitions, and analytic methods to create a set of consistent and interpretable metrics.”
An effort underway to standardize analytic methods is SISOQAL, which is short for Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Endpoints.7 Analytic methods are necessary to interpret the results and apply these symptom and function results to important treatment and healthcare policy decision-making, said Dr. Kluetz.
Although we do not have the standards for analyzing today, we will in five years, Dr. Kluetz said, but we won’t have the data in five years if we don’t get the trials designed correctly now. “If we can start getting the right questions in trials and the right assessment frequencies, we can do a lot with the data when they come in.”
Dr. Basch echoed a similar sentiment, “If we don’t go to the trouble to capture this information directly from patients in our trials, particularly before marketing, it will be lost forever.”
“I feel it’s time for a culture change,” said Dr. Klepin. “I think clinicians and patients should be expecting these types of data now, going forward, from clinical trials and that we should be incentivizing and facilitating research to be able to do this, and I look forward to several years from now going to clinic and actually being able to provide the most meaningful data to my patients, which they ask me for every week.”
- US. FDA. Guidance for industry patient-reported outcome measures: Use in medical product development to support labeling claims. https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf. December 2009. Accessed June 28, 2018.
- Zagadailov E, Fine M, and Shields A. Patient-reported outcomes are changing the landscape in oncology care: Challenges and opportunities for payers. Am Health Drug Benefits. 2013;6:264-274.
- Vodickaa E, Kimb K, Devine EB, et al. Inclusion of patient-reported outcome measures in registered clinical trials: Evidence from ClinicalTrials.gov (2007–2013). Contemp Clin Trials. 2015;43:1-9.
- FDA.gov. FDA public workshop: 2018 clinical outcome assessments in cancer clinical trials. https://www.fda.gov/NewsEvents/MeetingsConferencesWorkshops/ucm602540.htm. Accessed June 28, 2018.
- Atkinson TM, Yuelin Li Y, Coffey CW, et al. Reliability of adverse symptom event reporting by clinicians. Qual Life Res. 2012;21:1159-1164.
- National Cancer Institute. Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™). https://healthcaredelivery.cancer.gov/pro-ctcae/. Accessed June 28, 2018.
- EORTC Quality of Life. SISAQOL project. http://groups.eortc.be/qol/sisaqol-project. Accessed June 28, 2018.