There is substantial and growing interest in measuring patient-reported outcomes in drug development trials, for example, to understand the effects of treatment on tumor-associated pain. Although there is enthusiasm at the US Food and Drug Administration (FDA) for such a patient-centered approach, evidenced by guidance for industry published on this topic in 2009, most oncology trials and FDA-approved medication labels still do not include information on patient-reported outcomes

Atkinson, T.M.

Basch, E.

Wagner, J.-S.

PubMed

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Trustworthiness of Patient-Reported Outcomes in Unblinded Cancer Clinical TrialsThomas M. Atkinson, PhD,Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, New York; and Cancer Outcomes Research Program, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel HillJan-Samuel Wagner, MPH, andCancer Outcomes Research Program, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill; and Enterra Solutions, Newtown, PAEthan Basch, MD, MScCancer Outcomes Research Program, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill; and Outcomes Research Group, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New YorkThere is substantial and growing interest in measuring patient-reported outcomes in drug development trials,1 for example, to understand the effects of treatment on tumor-associated pain. Although there is enthusiasm at the US Food and Drug Administration (FDA) for such a patient-centered approach, evidenced by guidance for industry published on this topic in 2009,2 most oncology trials and FDA-approved medication labels still do not include information on patient-reported outcomes.3Several reasons for the limited inclusion of patient-reported outcomes in cancer trials and drug labels have been cited, including cost and logistics, but the barrier that has most prevented progress in this area is the FDA’s concern that patients cannot provide unbiased reports of their own symptoms if a trial is unblinded to study treatment allocation.3 For example, the FDA asserts that patients with pain associated with metastatic prostate cancer might be inclined to report improvements in their pain based simply on the knowledge that they have been assigned to receive a novel therapeutic agent, regardless of the actual properties of that drug or of their actual pain responses.2,3 The FDA extends this concept to encompass single-arm trials, open-label trials, and blinded trials in which they believe study arm allocation has likely been unmasked owing to imbalances in readily apparent toxic effects between arms. Indeed, in oncology, this scenario now represents most pivotal registration trials.However, there is no empirical evidence that this type of bias exists, or, if it does, that it is sufficient to meaningfully affect results of clinical trials. Findings from published Corresponding Author: Ethan Basch, MD, MSc, Cancer Outcomes Research Program, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 170 Manning Dr, Campus Box 7305, Chapel Hill, NC 27599 (ebasch@med.unc.edu). Conflict of Interest Disclosures: None reported.HHS Public AccessAuthor manuscriptJAMA Oncol. Author manuscript; available in PMC 2017 June 08.Published in final edited form as:JAMA Oncol. 2017 June 01; 3(6): 738–739. doi:10.1001/jamaoncol.2016.3328.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptpsychobehavioral literature suggest that cognitively, respondents are not prone to altering the content of their self-reports of symptoms associated with treatments that they are receiving.4How might one empirically evaluate whether this type of bias exists, or at least whether it is sufficient to meaningfully affect results of analyses of patient-reported outcomes in clinical trials? One approach is to identify published double-blind controlled trials with negative efficacy results for primary clinical end points that had substantial imbalances of readily apparent toxic effects on patients between arms that might inadvertently unblind participants to their study arm allocations, which also included patient-reported outcomes as secondary end points. In such cases, we would expect the patient-reported outcome end points to yield negative results (unless they pertained directly to the imbalanced toxic effects). If the patient-reported outcomes differed between arms, it would suggest that bias may indeed meaningfully affect the results. Conversely, if patient-reported outcomes did not differ between arms, it would suggest that inadvertent unblinding is not a meaningful source of bias.Indeed, a structured literature review identified 5 randomized, double-blind negative trials with imbalances by 10% or more in at least 3 symptomatic toxic effects between arms (as measured by the National Cancer Institute’s Common Terminology Criteria for Adverse Events), and at least 1 secondary patient-reported outcome end point that included pain (Table).5–9 In these trials, despite imbalances in multiple toxic effects, no significant differences in patient-reported outcomes were detected between study arms. This result suggests that, in cases of inadvertent unblinding associated with readily apparent toxic effects, there is not a sufficient bias to affect patient-reported outcomes between arms. Moreover, these findings also support the notion that this type of bias is not sufficiently present to meaningfully affect patient-reported outcomes in open-label studies.To further explore this question in the future, prospective or retrospective analyses could be conducted of drug development programs that include both an open-label trial and a blinded controlled trial with inclusion of the same patient-reported outcome measure in both trials, to evaluate whether differences are comparable between arms. Regardless, in the interim, based on the information described above, we believe that inadvertent unblinding should not be considered a meaningful source of bias, and patient-reported outcomes should be included in cancer drug development trials and FDA drug labels regardless of blinding status. Patient-reported outcomes provide essential information that cannot be reliably captured any other way about the patient experience with products, and are necessary for complete evaluations of risks and benefits and the value of cancer therapeutics.10 In light of the value of this information, in the absence of compelling evidence that a bias associated with knowledge of treatment allocation exists, there is little justification for withholding patient-reported outcomes from drug development trials or FDA drug labeling.References1. Basch E, Geoghegan C, Coons SJ, et al. Patient-reported outcomes in cancer drug development and US regulatory review: perspectives from industry, the Food and Drug Administration, and the patient. JAMA Oncol. 2015; 1(3):375–379. [PubMed: 26181187] Atkinson et al. Page 2JAMA Oncol. Author manuscript; available in PMC 2017 June 08.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscript2. US Department of Health and Human Services. Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf. Published December 2009. Accessed June 22, 20163. Gnanasakthy A, DeMuro C, Clark M, Haydysch E, Ma E, Bonthapally V. Patient-reported outcomes labeling for products approved by the Office of Hematology and Oncology Products of the US Food and Drug Administration (2010–2014). J Clin Oncol. 2016; 34(16):1928–1934. [PubMed: 27069082] 4. Hagger MS, Orbell S. A meta-analytic review of the common-sense model of illness representations. Psychol Health. 2003; 18(2):141–184. DOI: 10.1080/0887044031000813215. Eckhardt SG, De Porre P, Smith D, et al. Patient-reported outcomes as a component of the primary endpoint in a double-blind, placebo-controlled trial in advanced pancreatic cancer. J Pain Symptom Manage. 2009; 37(2):135–143. [PubMed: 18723314] 6. Kindler HL, Ioka T, Richel DJ, et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011; 12(3):256–262. [PubMed: 21306953] 7. Michaelson MD, Oudard S, Ou YC, et al. Randomized, placebo-controlled, phase iii trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer. J Clin Oncol. 2014; 32(2):76–82. [PubMed: 24323035] 8. Natale RB, Thongprasert S, Greco FA, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non–small-cell lung cancer. J Clin Oncol. 2011; 29(8):1059–1066. [PubMed: 21282542] 9. Sonpavde G, Matveev V, Burke JM, et al. Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. Ann Oncol. 2012; 23(7):1803–1808. [PubMed: 22112969] 10. Banerjee AK, Okun S, Edwards IR, et al. Patient-Reported Outcome Measures in Safety Event Reporting: PROSPER Consortium guidance. Drug Saf. 2013; 36(12):1129–1149. [PubMed: 24092596] Atkinson et al. Page 3JAMA Oncol. Author manuscript; available in PMC 2017 June 08.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAtkinson et al. Page 4TableResults of Patient-Reported Outcome Comparisons in Randomized Clinical TrialsaSource/NCT (if applicable) ComparisonAbsolute Between-Arm Differences in Patients With Toxic Effects, % Patient-Reported Outcome MeasuresResults of Patient-Reported Outcome ComparisonsEckhardt et al,6 2009 Tipifarnib + gemcitabine vs placebo + gemcitabineAnorexia, 31Diarrhea, 10Rash, 14MPAC pain intensity; VAS Daily diaries of pain intensity showed no differences between armsKindler et al,7 2011 NCT00471146Axitnib + gemcitibine vs placebo + gemcitabineAnorexia, 10Diarrhea, 11Dysphonia, 18Hypertension, 19Mucositis, 13Nausea, 10EORTC QLQ-C30; EORTC QLQ-PAN26Patients in both arms reported ≥5-point mean improvement from baseline pain on the EORTC QLQ-C30 and pancreatic pain on the EORTC QLQ-PAN26Michaelson et al,8 2014 NCT00676650Sunitinib + prednisone vs placebo + prednisoneAnorexia, 23Diarrhea, 31Dysgeusia, 20Fatigue, 26Hand-foot syndrome, 26Hypertension, 17Mucositis, 24Nausea, 22mBPI-SF worst pain score No difference in percentage of patient-reported pain between arms at 2 mo (17.3% vs 12.5%; P = .25), 4 mo (20.9% vs 16.3%; P = .32), or 6 mo (21.4% vs 17.3%; P = .39)Natale et al,9 2011 NCT00364351Vandetanib vs erlotinib Diarrhea, 12Hypertension, 14Rash, 10EORTC QLQ-C30 No significant differences between study arms in time to deterioration of disease-associated symptoms for patient-reported pain (HR, 0.96; 95% CI, 0.83–1.11; P = .58), cough (HR, 0.94; 95% CI, 0.80–1.09; P = .40), or dyspnea (HR, 1.08; 95% CI, 0.93–1.25; P = .33)Sonpavde et al,10 2012 NCT00286793AT-101 + docetaxel + prednisone vs placebo + docetaxel + prednisoneDehydration, 10Nausea, 15Peripheral neuropathy, 12PPI Patient-reported pain response rates did not differ significantly between study arms across all postcycle assessments (29% vs 28%)Abbreviations: AT-101, R-(–)-gossypol acetic acid; EORTC QLQ-C30, European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EORTC QLQ-PAN26, European Organisation for the Research and Treatment of Cancer Pancreatic Cancer Module; HR, hazard ratio; mBPI-SF, Modified Brief Pain Inventory-Short Form; MPAC, Memorial Pain Assessment Card; NCT, clinicaltrials.gov registration number; PPI, Present Pain Index; VAS, visual analog scale.aTrials had negative efficacy results but imbalances in toxic effects between arms by ≥10% for at least 3 toxic effects.JAMA Oncol. Author manuscript; available in PMC 2017 June 08.

Trustworthiness of patient-reported outcomes in unblinded cancer clinical trials

http://dx.doi.org/10.1001/jamaoncol.2016.3328

Trustworthiness of patient-reported outcomes in unblinded cancer clinical trials

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