Summer 2013    |
TRI - A Full Service CRO+

Turning on the Patient's Microphone in AE Reporting for Cancer Clinical Trials: the PRO-CTCAE

Turning on the Patient's Microphone in AE Reporting for Cancer Clinical Trials

Symptoms and functional impairment in cancer patients are common, and oncology drugs can yield substantial symptomatic toxicity, especially when compared to drugs for other diseases. So it is not surprising that patients deliberating whether to start a new chemotherapy regimen ask, “How will this treatment make me feel? What side effects did patients like me have with this treatment?” For people trying to understand the clinical effects of drugs, U.S. drug labels and published reports of clinical trials are the go-to sources, but symptom information is often lacking in these sources. For patients enrolled in investigational studies sponsored by the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP), possible risks and side effects of therapeutic agents are discussed in the informed consent process. However, all of these sources of information are derived almost entirely from clinicians’ interpretations of patients’ symptoms rather than from patients’ own firsthand reports of their experiences with a drug. To amplify the voice of the patient in drug development,1 the Food and Drug Administration (FDA) has recently taken several steps, including issuing guidance on the use of patient-reported outcomes (PROs) in drug development and collaborating with the Critical Path Institute and industry to form a PRO Consortium for the development of robust tools to measure symptoms. The NCI is also seeking to turn on the patient’s microphone in clinical research by converting its current clinician-based adverse event measurement system, the Common Terminology Criteria for Adverse Events (CTCAE), to the PRO-CTCAE.2 The rationale and the development of the PRO-CTCAE initiative,3 presented at this year’s annual American Society of Clinical Oncology (ASCO) meeting in Chicago, Illinois, are discussed here.


What is the PRO-CTCAE, and how does it work?

The CTCAE is a lexicon used by clinicians to describe and document AEs for both federally-sponsored and industry-sponsored oncology studies, and it is regularly used in FDA labeling. AEs are any unfavorable signs temporally associated with the use of medical treatment or intervention that may or may not be considered related to the medical treatment or intervention under investigation, and they are graded on a scale of 1 (mild) to 5 (death related to AE) using the CTCAE. Of approximately 800 CTCAE items that include laboratory or clinically measured values (e.g., a decrease in white blood cells or hypertension) and observable symptoms (e.g., wound infection), 10% are subjective symptoms making them candidates for the PRO-CTCAE. The PRO-CTCAE system will present patients with easily comprehensible questions via a secure web-based platform to elicit information about patients’ experiences with symptoms such as fatigue, nausea, vomiting, pain, and anorexia. The PRO-CTCAE terminology and symptom severity will be mapped to that of the CTCAE for official AE reporting to the FDA. Targeting the severity, frequency, and the degree to which symptoms interfere with everyday life, sample questions include:



Patients could complete the PRO-CTCAE survey using a wireless tablet computer; an interactive voice response telephone system is also a feasible option for survey administration. The overall goal of the PRO-CTCAE initiative is to create a system for patient self-reporting of AEs in oncology trials that is widely accepted and used; generates useful data for investigators, regulators, clinicians, and patients; and is compatible with existing AE reporting systems.


What is wrong with the current AE reporting system?


There may be some critics of the PRO-CTCAE—those who feel that the clinician is best equipped to assess all toxicities (even symptomatic ones), and those who wonder about the reliability of patient reporting and whether it may create noise in the system. However, there is evidence that the current system of clinician-only AE reporting in oncology is inadequate. Mechanistically, clinicians document adverse symptoms in charts, and then nonclinical data managers abstract this information and map verbatim symptom terms to the CTCAE (or to another lexicon known as the Medical Dictionary of Regulatory Activities or MedDRA). During this process, data are often lost or transformed, potentially diminishing the value of reported AE information as well as the downstream ability of regulators to fully appreciate the symptom toxicity profiles of drugs. It has also been shown that clinicians frequently underreport and downgrade patients’ symptom severity. The underestimating of oncology products’ true symptomatic toxicities during early drug development can lead to much more symptomatic toxicity than expected when products hit the market, and ultimately lower compliance or greater use of healthcare services. Studies have not only shown disagreement about symptomatic toxicities between clinicians and patients, but they have also demonstrated disagreement between clinicians themselves.4 In one case, independent clinicians examined patients receiving active chemotherapy in close time proximity (within 10 to 15 minutes), without access to each other’s reports, and with no intervention in between. The clinicians used the CTCAE to determine the severity of symptoms, such as constipation, diarrhea, fatigue, nausea, and vomiting. To quantify the level of agreement between independent clinicians, interclass correlation coefficients (ICCs) were calculated; higher values corresponded to greater agreement, and lower values corresponded to lesser agreement. Analysis revealed ICCs much lower than what would be considered ideal for AE severity data in clinical trials and showed clinician colleagues disagreeing with each other after seeing the same patient on the same trial at the same time.


What are some potential benefits of patient AE reporting?


Even if clinician-based AE reporting needs to be improved, is patient reporting the way to go? The phase 3 trial that led to the indication for oxaliplatin (Eloxatin®) in metastatic colorectal cancer mandated both patients and clinicians to report the potentially problematic symptom of diarrhea, which was viewed as a potential issue. Clinicians reported diarrhea symptoms every cycle using the CTCAE, and patients reported diarrhea symptoms every other cycle using a paper questionnaire; only the clinician reports were officially reported during the course of the trial and reviewed by the FDA and other regulatory authorities. In this study, which compared the efficacy of three different treatments, unexpected early deaths due to gastrointestinal syndrome associated with severe diarrhea, dehydration, and hospitalization were observed in one of the treatment arms. Although clinicians adequately detected diarrhea, patients reported cumulative diarrhea, and much more of it, throughout the study than did clinicians.5 Thus, patient reporting appears to detect potentially serious AE symptoms earlier than clinician reporting. Another study demonstrated that patient reports of symptom information are more highly correlated with measures of underlying health state and functional status than are clinician reports.6 Furthermore, there is evidence that both patients and clinicians provide valuable information in AE reporting, which when combined provides a more accurate understanding of the patient’s symptoms. The predictive accuracy of Cox models to predict overall survival among cancer patients improved when patient and clinician scores were considered together than when they were considered alone; the adjusted C-index increased from 0.63 to 0.67 for fatigue and from 0.62 to 0.65 for nausea.7 Because the PRO-CTCAE would inform oncology clinicians of patient-reported symptoms in real time, the system could potentially augment the patient-clinician relationship, allow for prompt mitigation of toxicities, promote timely and accurate interdisciplinary communication, and ultimately improve the quality and safety of care.


What research is ongoing and still needed?


The NCI has conducted several studies to determine the analytic validity and usability of the PRO-CTCAE, and continues to do so. Additional studies include analysis of the data from validation testing in a large cancer cohort; translation to Spanish, German, Chinese, and Japanese; feasibility testing of the PRO-CTCAE system in two cooperative group treatment trials; and comparison of alternate models to integrate patient and clinician reporting of AE data for toxicity grading, dose modifications, and cancer care improvement. The PRO-CTCAE must:



It is not yet clear how trials will interpret and yield meaningful information using the PRO-CTCAE, but the aim is to improve the accuracy, precision, and validity of AE reporting. TRI’s regulatory and safety support services, which include the monitoring of AEs, to NCI-CTEP’s investigational therapeutics program will likely be impacted, and TRI is ready and poised to adapt to this promising method of collecting AE information. Perhaps as we move further into the 21st century, patients using personal smartphones or other computer devices to report their symptoms and any other patient-reported outcome will become the norm. The voices of patients in clinical research would then be heard loudly and clearly.


1  Guidance for industry - patient-reported outcomes measures: use in medical product development to support labeling claims. Silver Spring, MD: Food and Drug Administration, December 2009 (
2  Patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). Bethesda, MD: National Institutes of Health, May 2013 (
3  Basch, E. Scientific Rationale for the PRO-CTCAE. Chicago, IL: 2013 ASCO Annual Meeting Education Session.

4  Basch, E., A. Iasonos, T. McDonough, et al. (2006). Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: results of a questionnaire-based study. Lancet Oncol. 7:903-909.

5  Atkinson, T.M., Y. Li, C.W. Coffey, et al. (2012). Reliability of adverse symptom event reporting by clinicians. Qual Life Res. 21:1159-1164.

6  Basch, E., X. Jia, G. Heller, et al. (2009). Adverse symptom event reporting by patients vs clinicians: relationships with clinical outcomes. J Natl Cancer Inst. 101:1624-1632.

7  Quinten, C., J. Maringwa, C.C. Gotay, et al. (2011). Patient self-reports of symptoms and clinician ratings as predictors of overall cancer survival. J Natl Cancer Inst. 103:1851-1858.


About the Author

Kristie Magee, PhD ,(Medical Writer and Clinical Research Specialist) has a background in cellular and molecular biology. .

TRI - Challenge Convention. Exceed Expectations. © Technical Resources International, Inc.  •  •  Phone: 301-564-6400