Patient Reported Outcomes Are Changing Drug Trials and Clinical Oncology
With encouragement from the U.S. Food and Drug Administration (FDA), patient-reported outcome measures (PROMs) of symptoms are increasingly included as secondary end points in clinical trials for cancer treatments; these outcomes are likely to become important drug label criteria for treatment planning in the clinic.
Patient-reported outcome questionnaires have been developed to measure patient symptoms, treatment adherence, function and health-related quality of life, and satisfaction with treatment regimens. Due to their importance in clinical trials and gradually becoming part of daily clinical practice, PROMS are also encouraging better communication with patients and even guiding adjustments in chemotherapy dosing decisions.
Patient-reported outcomes (PROs) are subjective status reports that help describe patient's current disease- or drug-related condition or recent experiences. Familiar examples are patient pain scale reports and health-related quality of life (HRQOL) self-reports about the physical, emotional, and social impact of a disease or therapy.1,2 Although PROs will often correlate with objective test outcomes, PROs offer insight into a patient's status that are not easily measured with objective clinical tests or medical imaging (eg, PRO pain status and bone metastasis).
While numerous cancer clinical trials include PROs as secondary outcome measures, few cancer drugs have yet been granted FDA permission to include symptom outcomes on their drug labeling.3 This is a very different situation compared with the almost 25% of noncancer drugs that have label information about medication effects on patient symptoms or function.4
“That disparity is surprising, given how common symptoms and functional impairment are in patients with cancer and how toxic oncology drugs can be,” reports Ethan Basch, MD, of the Cancer Outcomes Research Program at the University of North Carolina at Chapel Hill, NC.4 Basch is a pioneer in the field of PRO measurement.
“As an oncologist, when I sit with patients to discuss starting a new chemotherapy regimen, their first questions are often, ‘how will it make me feel?',” Dr. Basch wrote in a recent commentary for The New England Journal of Medicine.4 “Regrettably, this information is generally missing from US drug labels and from published reports of clinical trials…of cancer drugs.”
That situation is quickly changing, thanks in part to longer patient survival times and the resulting need to balance the efficacy of cancer drugs with their long-term effects.4 Some newly approved drugs, such as targeted agents, that might represent small additional survival benefits over existing treatments, may also offer significant improvements in PROMs—offering important potential considerations when making clinical decisions.4
PROs and Product Labeling: A New Wave
The federal government is encouraging drug developers to include more measures of patient experiences in clinical studies. In 2009, the FDA released guidance to industry that outlined how PRO measuring tools like questionnaires will be evaluated for product labeling.5
Two years later, ruxolitinib (JAKAFI®) became the first cancer therapy in a decade to include symptom information on its drug label.4 Another example is abiraterone acetate, approved in 2013, carries label descriptions of the drug's PROM-based associations with delayed time to pain progression and time to need for opioid pain control, among patients diagnosed with metastatic prostate cancer.4
Topotecan has also been granted FDA permission to include symptom-improvement labeling claims, based on an as-yet modestly validated Symptom Distress Scale PRO questionnaire, for patients diagnosed with small-cell lung cancer. The instrument measures self-reported changes in shortness of breath, interference with daily activity, fatigue, hoarseness, cough, anorexia, insomnia, bloody cough, and chest pain.2
Efforts are under way to validate and standardize PROMs, but inconsistencies persist between clinical trials' implementation and guidelines meant to harmonize methods across trials. For example, according to the research literature, caregivers or clinicians are allowed to act as surrogates, answering PRO questions for the patient in some cases.6 Formal PRO extension guidelines for the Consolidated Standards of Reporting Trials (CONSORT) statement discourages such surrogate or proxy reporting, and instead recommends that proxy outcomes reporting standards be developed.1 (See Box.)
Patient-reported outcome (PRO): Self-reported patient status that is recorded without interpretation or alteration by a clinician, such as pain or depression.6
PRO Measure (PROM): A questionnaire or other scale or instrument used to elicit a patient-reported statement of status, such as the Patient Health Questionnaire-9 (PHQ-9).6
PRO Performance Measure (PRO-PM): Statistical summary measures based on aggregate PROM data from across a patient population, such as the proportion of patients with a particular cancer at a treatment center who report depression.6
The FDA is participating in collaborations with industry through the PRO Consortium, which develops well-validated symptom-measuring instruments.4
The reauthorized US Prescription Drug User Fee Act (PDUFA) authorized the FDA's hiring of additional experts on PROM development, but in the current fiscal sequestration, Congress has withheld the funding allocated in PDUFA for patient-centered programs.4
PROMs have been used primarily in clinical research and are increasingly recognized as important secondary trial end points.1,7 However, there is increasing interest in their use as clinical tools to help guide clinicians' understanding of their patients' concerns and challenges, and to improve communication with patients.8
Several electronic PRO questionnaires are already coming into use for patients with cancer, both in remote and in-clinic settings.9 One of Dr. Basch's studies found that PRO symptom severity affects clinicians' chemotherapy dosing decisions, for example.8,10
A group that has not been addressed in relation to PROMs includes the managed care organizations. The implications of PROMs for reimbursement practices remain unclear. It has yet to be determined how insurance companies and other health care payers will respond to PRO findings when making reimbursement decisions.2
“Payers may dismiss PROs that do not independently predict improved outcomes,” cautions Erin Zagadailov, PharmD, MS, of the pharmaceuticals industry consultancy Xcenda, and coauthors, in a 2013 review of PROs in clinical trials and its implications for payers.2 Clearly, further discussion is warranted regarding standardization of PROMs as well as the value and impact of the information that PROMs would yield in a clinical setting.
1. Calvert M, Blazeby J, Altman DG, Revicki DA, Moher D, Brundage MD. Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA. 2013;309(8):814-822.
2. Zagadiailov E, Fine M, Shields A. Patient-reported outcomes are changing the landscape in oncology care: challenges and opportunities for payers. Am Health Drug Benefits. 2013;6(5):264-274.
3. Gnanasakthy A, Mordin M, Clark M, DeMuro C, Fehnel S, Copley-Merriman C. A review of patient-reported outcome labels in the United States: 2006 to 2010. Value in Health. 2012;15:437-442.
4. Basch E. Toward patient-centered drug development in oncology. New Engl J Med. 369(5):397-400.
5. U.S. Food and Drug Administration (FDA). Guidance for industry: patient-reported outcomes measures: use in medical product development to support labeling claims. Silver Spring, MD: FDA; December 2009. http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. Accessed August 15, 2013.
6. Basch E, Torda P, Adams K. Standards for patient-reported outcome-based performance measures. JAMA. 2013;310(2):139-140.
7. Gnanasakthy A, Lewis S, Clark M, Mordin M, DeMuro C. Potential of patient-reported outcomes as nonprimary endpoints in clinical trials. Health Qual Life Outcom. 2013;11:83. www.hqlo.com/content/11/1/83.
8. Snyder CF, Blackford AL, Aaronson NK, et al. Can patient-reported outcomes measures identify cancer patients' most bothersome issues? J Clin Oncol. 2011;29(9):1216-1220.
9. Bennett AV, Jensen RE, Basch E. Electronic patient-reported outcome systems in oncology clinical practice. CA Cancer Journal Clin. 2012;62:336-347.
10. Basch E, Artz D, Dulko D, et al. Patient online self-reporting of toxicity symptoms during chemotherapy. J Clin Oncol. 2005;23:3552-3561.