Patient-Reported Outcomes Supporting Anticancer Product Approvals Edwin P

VOLUME 25 ⅐ NUMBER 32 ⅐ NOVEMBER 10 2007

JOURNAL OF CLINICAL ONCOLOGY REVIEW ARTICLE

Patient-Reported Outcomes Supporting Anticancer Product Approvals Edwin P. Rock, Dianne L. Kennedy, Melissa H. Furness, William F. Pierce, Richard Pazdur, and Laurie B. Burke

From the Office of Oncology Drug Prod- ABSTRACT ucts and Study Endpoints and Label Development Team, Center for Drug In 2006, the US Food and Drug Administration (FDA) published draft guidance to provide Evaluation and Research, Food and Drug recommendations for development, validation, implementation, and interpretation of patient- Administration, Silver Spring, MD. reported outcome (PRO) measures that can support treatment benefit claims in product labeling. Submitted February 19, 2007; accepted Here, we summarize and discuss FDA approvals of anticancer products in the context of the draft June 21, 2007. guidance. We identified anticancer product approvals having efficacy claim(s) based at least in part Presented in part at the Patient- on a PRO. In addition, we collated limitations of PRO instruments commonly submitted for Reported Outcomes Assessment in regulatory review over the period from October 1, 2004 to September 30, 2006. From 1995 Cancer Trials (PROACT) Conference in Bethesda, MD, September 20-21, 2006. onward, nine indications were approved for seven anticancer products based at least in part on a PRO. In eight of nine approvals, PRO data supplemented other evidence of clinical benefit. In Opinions expressed in this article are seven approvals, the PRO measured a single symptom or functional domain that was directly the views of the authors and do not reflect the official position of the US attributable to the treatment benefit observed in the disease. The FDA’s draft PRO guidance Food and Drug Administration. describes principles that have been used in anticancer product approvals for more than a decade.

Authors’ disclosures of potential con- PRO end points typically support treatment benefit claims that refer to a patient’s symptoms or flicts of interest and author contribu- ability to function. Single-item PROs may be acceptable. PRO data should be both internally tions are found at the end of this consistent and aligned with other evidence of clinical benefit. The FDA encourages sponsors to article. consult with the FDA early in the process of PRO development. Address reprint requests to Laurie B. Burke, RPh, MPH, Study Endpoints and J Clin Oncol 25:5094-5099. Published by the American Society of Clinical Oncology Label Development, Center for Drug Evaluation and Research, Food and 1 Drug Administration, Bldg 22, 10903 Claims.” This document provides medical product INTRODUCTION New Hampshire Ave, Silver Spring, MD developers, clinicians, and patients with the FDA’s 20993; e-mail: [email protected]. Three pieces of legislation established the frame- current perspective on development and use of Published by the American Society of patient-reported outcome (PRO) measures that are Clinical Oncology work for drug regulation in the United States. First, the 1906 Pure Food and Drug Act mandated truth in intended to support treatment benefit claims in 0732-183X/07/2532-5094/$20.00 drug labeling. Second, the 1938 Food, Drug, and product labeling. The draft guidance outlines meth- DOI: 10.1200/JCO.2007.11.3803 Cosmetic Act instituted the requirement that a ods for development, validation, implementation, drug’s safety be demonstrated before marketing au- and interpretation of reliable and accurate PRO thorization. Finally, the 1962 Harris-Kefauver measures. It advocates clear, prospective delineation amendments to the Food, Drug, and Cosmetic Act of measurement concepts and analysis plans under- mandated preapproval demonstration of substan- lying health labeling claims, regardless of the end tial evidence of product efficacy from adequate and point(s) used. well-controlled investigations. Complementary leg- This article reviews anticancer product approv- islation extends the same requirements to biologic als based at least in part on PRO-based evidence, agents. These laws are integrated into the Code of compares use of PROs in these approvals with prin- Federal Regulations. ciples outlined in the draft PRO guidance, and sum- In addition to the above legal requirements, the marizes limitations of PRO instruments submitted US Food and Drug Administration (FDA) publishes to the FDA for regulatory review. guidance documents to provide current agency perspective on issues of interest to stakeholders. These guidances are not legally binding. Reasonable devi- PRO-BASED ANTICANCER PRODUCT APPROVALS ations are acceptable with adequate justification. In February 2006, the FDA’s Center for Drug Evalua- tion and Research published a draft guidance enti- Standards for demonstrating efficacy of antican- tled “Patient-Reported Outcome Measures: Use in cer drugs have evolved over the last half century.2 Medical Product Development to Support Labeling Tumor response rate (RR), which represents

5094 Information downloaded from jco.ascopubs.org and provided by at NIH LIBRARY on December 3, 2010 from 156.40.32.144 Copyright © 2007 American Society of Clinical Oncology. All rights reserved. PROs Supporting Anticancer Product Approvals significant reduction in observable tumor burden after treatment, small-cell lung cancer (NSCLC).”6 Porfimer is administered as an was the basis of all anticancer drug approvals from the 1950s intravenous injection, followed by one or two nonthermal applica- through the 1970s. RR remains an important surrogate of treat- tions of 630-nm laser light and debridement of necrotic tissue. ment benefit and has been a component of more than half of Initial approval was based on a single, multicenter, single-arm anticancer product approvals from 1990 to 2002.3 In the late 1970s, study in patients with completely obstructing esophageal carcinoma. limitations of RR as a sole indicator of clinical benefit from cancer Endoscopically visible tumor response and a PRO Dysphagia Scale treatment were recognized, particularly when tumor responses were assessed at regular follow-up visits, initially at 1 week and then were accompanied by significant treatment toxicity. Subsequently, monthly after the first treatment. Partial response (PR) was defined as demonstration of improvement in overall survival (OS) and symp- appearance of a visible esophageal lumen. Complete response (CR) tom palliation were recognized in the 1980s as directly representa- was defined as absence of endoscopically visible tumor. The dysphagia 4 tive of clinical benefit. Time to tumor progression (TTP), disease- scale was graded as follows: 1 ϭ normal swallowing; 2 ϭ able to free survival, and progression-free-survival (PFS) became accepted swallow semisolids; 3 ϭ able to swallow liquids; 4 ϭ difficulty swal- as additional surrogate end points for anticancer product approv- lowing liquids; and 5 ϭ unable to swallow saliva. 5 als in the 1990s. Seventeen patients with a mean baseline dysphagia grade of 4.6 The first anticancer product approval based on a PRO efficacy were enrolled; patients at baseline typically had difficulty swallowing claim occurred in 1995. Since then, nine treatment indications have any liquids, even saliva. After a single course of therapy, 16 patients been approved for seven anticancer products based either on symp- (94%) were observed to have an objective tumor response. Twelve tom palliation or improvement in a functional end point. These ap- patients (71%) experienced palliation of dysphagia and could swallow provals (Table 1) represent approximately 10% of all treatment liquids without difficulty 1 week after the first treatment. Mean im- indications approved during the past 12 years. provement in dysphagia grade at 1 week and 1 month was 1.4 and 1.5 Porfimer Sodium units, respectively. Two patients had CRs at 1 week with no subse- Porfimer (Photofrin; Axcan Scandipharm Inc, Birmingham, quent follow-up. A third CR, documented after a second course, was AL), a photosensitizing agent used to augment the effect of photody- supported by negative histopathology and was maintained for the namic therapy, was approved in 1995. The initial treatment indication entire 6-month follow-up period. Eight patients (47%) dropped out was for “palliation of patients with completely obstructing esophageal before the 1-month follow-up visit. Clinically important benefit was cancer, or of patients with partially obstructing esophageal cancer defined as CR (three patients), normalization of the dysphagia scale who, in the opinion of their physician, cannot be satisfactorily treated from grade 5 to 1 (two patients), or improvement in dysphagia of at with Nd:YAG laser therapy.”6 In 1997 the product was granted an least two grades (six patients). Median duration of clinically im- additional indication for “reduction of and palliation of symptoms in portant benefit in these 11 patients was 69 days; their median patients with completely or partially obstructing endobronchial non– survival time was 115 days.

Table 1. PROs in Efﬁcacy Claims of Approved Anticancer Products Approval No. of No. of Product and Indication Year Measured PRO Concepts Domains Patients R B M Context

Porfimer Obstructing esophageal cancer 1995 Dysphagia 1 17 N N Y Complement to endoscopic RR Obstructing NSCLC 1998 3 NSCLC symptoms: dyspnea, cough, 1 211 Y N Y Complement to bronchoscopic hemoptysis RR Gemcitabine Complement to OS, TTP ءN; N ءY; N ءY; N ءLocally advanced or metastatic 1996 Pain/analgesic use 1 126; 63 pancreatic cancer, first-line or after FU NSCLC 1998 Health-related quality of life Multiple 657 Y N Y Complement to safety data Mitoxantrone Y N Y Primary evidence of efficacy ءHormone-refractory prostate cancer 1996 Pain/analgesic use 1 161; 242 Topotecan Recurrent, chemotherapy-sensitive SCLC 1998 9 SCLC symptoms: shortness of breath, 1 211 Y N Y Complement to RR interference with daily activities; fatigue, hoarseness, cough, insomnia, anorexia, chest pain, hemoptysis Amifostine Amelioration of xerostomia from 1999 Xerostomia 1 315 Y N N Complement to measurement radiotherapy for head and neck cancer of saliva production Imatinib Philadelphia chromosome–positive 2003 Symptoms of interferon toxicity Multiple 1,067 Y N Y Complement to safety data chronic myeloid leukemia Palifermin Y ? N Primary evidence of efficacy ءPrevention of oral mucositis after bone 2004 Mucositis 1 212; 169 marrow ablation Abbreviations: PRO, patient-reported outcome; R, randomized study; B, blinded study; M, missing data; N, no; Y, yes; RR, response rate; FU, fluorouracil; NSCLC, non–small-cell lung cancer; OS, overall survival; TTP, time to tumor progression; SCLC, small-cell lung cancer. .The first value is for study 1, and the second value is for study 2ء

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An additional indication was supported by two randomized mul- of 63 patients on gemcitabine had CBRs compared with three (5%) of ticenter studies comparing safety and efficacy of porfimer versus laser 63 patients on FU (P ϭ .004, two-sided test for difference in binomial therapy alone for reduction of obstruction and palliation of symptom- proportions). Of patients on gemcitabine, criteria for CBR included atic patients with partially or completely obstructing endobronchial reduced pain or analgesic use with stable performance status (11 NSCLC. Bronchoscopically visible tumor response, improvement of patients), improved pain or analgesic use with improved performance atelectasis, and patient-reported pulmonary symptoms (dyspnea, status (one patient), and improved pain, analgesic use, and perfor- cough, and hemoptysis) were assessed at regular visits, initially at 1 mance status (one patient). No patient achieved a CBR based on week and then 1 month after initial treatment. PR was defined as at weight gain. Study 2 was a single-arm trial of gemcitabine in 63 least a 50% increase in the smallest luminal diameter or, for com- patients with advanced pancreatic cancer after either FU or an FU- pletely obstructing tumors, any visible lumen. CR was defined as containing regimen. Median survival time was 3.9 months, and the absence of bronchoscopically visible tumor. Dyspnea was graded clinical benefit RR was 27%. on a 6-point severity scale; cough and hemoptysis were graded on a A second indication with PRO label information is for gemcitab- 5-point scale. Improvements of two or more grades were consid- ine “in combination with cisplatin for the first-line treatment of pa- ered clinically significant. tients with inoperable, locally advanced (stage IIIA or IIIB), or Results were combined for 211 patients who were randomly metastatic (stage IV) non–small-cell lung cancer.”7 Approval was sup- assigned in the two studies. Objective RR (CR ϩ PR) was 59% for ported by two randomized studies of 657 patients showing that gem- porfimer and 58% for laser therapy alone at week 1. At 1 month or citabine plus cisplatin produced statistically significant improvements later, 60% of patients treated with porfimer and 41% treated with in TTP and RR when compared with single-agent cisplatin. The larger neodymium-doped yttrium aluminium garnet (Nd:YAG) laser alone trial (N ϭ 522) of gemcitabine plus cisplatin versus cisplatin alone also had responses. Because of a large amount of missing data at and showed an advantage in OS associated with the addition of gemcitab- beyond 1 month, statistical comparisons could not be made. Twenty- ine. Patient-reported health-related quality of life (HRQOL) was a eight percent of patients treated with porfimer and 38% of patients secondary end point in both studies. The larger study used the Func- treated with Nd:YAG alone dropped out before the 1-month evalua- tional Assessment of Cancer Therapy–Lung for assessment of physi- tion. Of 60 patients with baseline atelectasis assigned to porfimer, 21 cal, social, emotional, and functional well-being, as well as lung (35%) were considered to have had improvement compared with 14 cancer–specific symptoms. The second study used the European Or- (20%) of 71 patients with baseline atelectasis assigned to Nd:YAG. In ganisation for Research and Treatment of Cancer Quality of Life a retrospective risk/benefit analysis, 36 of 99 porfimer-treated Questionnaire C30 with the lung cancer supplement LC13; these patients obtained clinically important benefit with minimal or assess physical and psychological functioning and symptoms related moderate toxicities of short duration compared with 23 of 99 to both lung cancer and its treatment. In both studies, no significant Nd:YAG-treated patients. differences were observed in HRQOL between the treatment arms.

Gemcitabine Mitoxantrone Gemcitabine (Gemzar; Eli Lilly and Co, Indianapolis, IN), a Mitoxantrone (Novantrone; Serono Inc, Rockland, MA), a syn- nucleoside analog, was approved in 1996 for initial treatment of “pa- thetic antineoplastic anthracenedione, was approved in 1996 “as ini- tients with locally advanced (nonresectable stage II or stage III) or tial chemotherapy for the treatment of patients with pain related to metastatic (stage IV) adenocarcinoma of the pancreas,”7 including advanced hormone-refractory prostate cancer”8 in combination with those previously treated with fluorouracil (FU). Two trials, each in- corticosteroids. Two randomized trials supported approval. The first, corporating a prospective clinical benefit response (CBR) end point, CCI-NOV22, was a multicenter trial of mitoxantrone plus low-dose were submitted. This composite end point, comprising patient- prednisone (N ϩ P) versus low-dose prednisone alone (P). Eligible reported analgesic consumption, patient-reported pain intensity, per- patients had either metastatic or locally advanced disease that had formance status, and weight change, was defined as follows. Response progressed on standard hormonal therapy, a castrate serum testoster- occurred when at least a 50% reduction in either pain intensity (Me- one level, and at least mild pain at study entry. Mitoxantrone was morial Pain Assessment Card) or analgesic consumption or a 20-point administered intravenously every 3 weeks; prednisone was taken or greater improvement in Karnofsky performance status was noted orally twice daily. Patients randomly assigned to P alone were crossed for at least 4 consecutive weeks without sustained worsening of any over to N ϩ P if they experienced progression or had not improved other parameter. Sustained worsening was defined as 4 consecutive after a minimum of 6 weeks of study therapy. A primary palliative weeks with either any increase in pain intensity or analgesic consump- response was defined as a 2-point decrease in patient-reported pain tion or a 20-point decrease in performance status that occurred during intensity on a 6-point scale associated with stable patient-reported the first 12 weeks of therapy. Alternatively, response occurred when a analgesic use and lasting a minimum of 6 weeks. A secondary palliative patient remained stable on all of the aforementioned parameters with response was defined as at least a 50% decrease in analgesic use with sustained weight gain, which was defined as at least a 7% increase for at stable pain intensity of at least 6 weeks in duration. Progression was least 4 weeks, that was not attributed to fluid accumulation. defined as a 1-point increase in pain intensity, a 25% or greater in- Study 1 was a single-blind, two-arm, randomized comparison of crease in analgesic use, radiographic evidence of disease progression, gemcitabine and FU in first-line locally advanced or metastatic pan- or requirement for radiotherapy. creatic cancer. Sixty-three patients were enrolled onto each arm. Sta- One hundred sixty-one patients were randomly assigned (80 to N tistically significant increases in OS, TTP, and CBR were observed in ϩP and 81 to P). A primary palliative response was achieved in 29% of the gemcitabine arm. Median survival time and TTP were prolonged patients assigned to N ϩ P compared with 12% assigned to P alone by 1.5 and 1.2 months, respectively, on gemcitabine. Fourteen (22%) (P ϭ .011). Median primary palliative response duration was 7.6 and

5096 JOURNAL OF CLINICAL ONCOLOGY Information downloaded from jco.ascopubs.org and provided by at NIH LIBRARY on December 3, 2010 from 156.40.32.144 Copyright © 2007 American Society of Clinical Oncology. All rights reserved. PROs Supporting Anticancer Product Approvals

2.1 months for patients randomly assigned to N ϩ P and P alone, all symptoms, and not all patients responded to all questions. Limita- respectively (P ϭ .0009). An overall palliative response (primary plus tions in interpretability of the rating scale and missing data precluded secondary responses) was achieved in 38% of patients assigned to N ϩ formal statistical analysis. P compared with 21% assigned to P (P ϭ .025). Median overall palliative response duration was 5.6 and 1.9 months for N ϩ P and P Amifostine alone, respectively (P ϭ .0004). Median TTP for all patients was 4.4 Amifostine (Ethyol; MedImmune Oncology Inc, Gaithersburg, and 2.3 months for N ϩ P and P alone, respectively (P ϭ .0001). MD), an organic thiophosphate cytoprotective agent, was approved in Median survival time was 11.3 and 10.8 months for all patients on the 1999 “to reduce the incidence of moderate to severe xerostomia in N ϩ P arm and P alone arm, respectively (P ϭ .2324). Forty-eight patients undergoing postoperative radiation treatment for head and ϩ neck cancer, where the radiation port includes a substantial portion of patients on the P arm crossed over to receive N P. Nine of these 10 patients (19%) demonstrated a palliative response on N ϩ P after they the parotid glands.” A single randomized trial in head and neck crossed over. cancer supported approval. One treatment group received standard A second study, Cancer and Leukemia Group B trial 9182, com- fractionated radiation alone, whereas the other arm received radiation pared mitoxantrone plus hydrocortisone (N ϩ H) versus hydrocorti- plus amifostine before each radiation treatment. At least 75% of both sone alone (H) in patients with hormone-refractory prostate cancer. parotid glands were required to be located in the radiation field. Eligible patients had metastatic disease after progression on at least Incidence of grade 2 or higher acute (90 days or less from start of one hormonal therapy. Progression at baseline was defined as progres- radiation) and late patient-reported xerostomia (9 to 12 months after sive symptoms, increased measurable or osseous disease, or increasing radiation) was assessed. prostate-specific antigen. Mitoxantrone was administered intrave- Three hundred fifteen patients were enrolled. After 1 year of nously every 21 days, and daily hydrocortisone was administered follow-up, the two arms were comparable in locoregional control, disease-free survival, and OS. Incidence of grade 2 or higher acute orally. Patient-reported analgesic use was measured in this study using xerostomia was 51% in the amifostine plus radiation arm and 78% in a 5-point scale. Patient-reported pain intensity was measured using the radiation alone arm (P Ͻ .0001). Similarly, incidence of late the Symptom Distress Scale Pain Item 2 (a 5-point scale). xerostomia was 35% in the amifostine plus radiation arm and 57% in Two hundred forty-two patients were randomly assigned (119 to the radiation arm (P ϭ .0016). At 1 year after radiation, patients on NϩH and 123 to H alone). Approximately 60% on each arm required amifostine had higher median saliva production than patients on baseline analgesics. Best percent change from baseline in mean anal- amifostine plus radiation (0.26 v 0.1 g, respectively), although there gesic use was Ϫ17% for 61 patients with available data on N ϩ H was no difference in stimulated saliva collections. compared with ϩ17% for 61 patients on H alone (P ϭ .014). Best percent change from baseline in mean pain intensity was Ϫ14% for 37 Imatinib ϩ ϩ patients with available data on N H compared with 8% for 38 Imatinib (Gleevec; Novartis Pharmaceuticals Corp, East Hanover, patients on H alone (P ϭ .057). Partial tumor responses were noted in NJ), an inhibitor of the bcr-abl protein tyrosine kinase, received accel- 10 patients (8.4%) on N ϩ H compared with two (1.6%) treated with erated approval in 2001 “for treatment of adult patients with Philadel- H alone (P ϭ .018). Median TTP was 7.3 and 4.1 months for patients phia chromosome positive chronic myeloid leukemia (CML).”11 assigned to the N ϩ H arm and H alone arm, respectively (P ϭ .0654). Initial marketing authorization was based on cytogenetic and hema- Median survival time was 11.1 and 12 months in the N ϩ H and H tologic responses in three single-arm studies.12 Conversion to regular arms, respectively (P ϭ .3298). approval occurred in 2003 after demonstration of improved response duration and OS.13 Topotecan To support approval of imatinib for use in newly diagnosed, Topotecan (Hycamtin; GlaxoSmithKline, Research Triangle chronic-phase chronic myeloid leukemia, an open-label, multicenter, Park, NC), a topoisomerase I inhibitor, was approved in 1998 for randomized phase III study in 1,106 patients was conducted to com- treatment of “small cell lung cancer (SCLC) sensitive disease after ␣ 9 pare imatinib with the combination of interferon-alfa (IFN- ) plus failure of first-line chemotherapy.” Sensitive disease was defined as cytarabine. The primary end point was PFS. PFS was longer on the responding to chemotherapy before progressing at least 60 days (in the imatinib arm (log-rank, P Ͻ .0001). Hematologic and cytogenetic phase III study) or 90 days (in phase II studies) after chemotherapy. A responses were consistently and significantly higher on the imatinib randomized phase III trial compared intravenous topotecan with cy- arm. The PRO Functional Assessment of Cancer Therapy–Biologic clophosphamide, doxorubicin, and vincristine (CAV). End points Response Modifier was used to assess physical, functional, and included RR, TTP, OS, and improvement in nine patient-reported treatment-specific biologic response modifier scales. After 1 small-cell lung cancer–related symptoms. These included shortness of month of therapy to 6 months of therapy, median scores decreased breath, interference with daily activity, fatigue, hoarseness, cough, by 13% to 21%, respectively, from baseline in patients treated with insomnia, anorexia, chest pain, and hemoptysis. Each symptom was IFN-␣. There was no change from baseline noted in the imatinib- rated on a 4-point scale, with improvement defined as a change in one treated patients. These observations were consistent with known category from baseline sustained over two courses. IFN-induced toxicities. One hundred seven patients were randomly assigned to topotecan, and 104 patients were assigned to CAV. The RR was 24% on Palifermin topotecan and 18% on CAV (P ϭ not significant). Response duration, Palifermin (Kepivance; Amgen, Inc, Thousand Oaks, CA), a TTP, and OS were similar between the two treatment groups. Of the purified, recombinant preparation of human keratinocyte growth nine disease-related symptoms, each reportedly improved in a greater factor, is indicated “to decrease the incidence and duration of severe percentage of patients on topotecan than on CAV. Not all patients had oral mucositis in patients with hematologic malignancies receiving www.jco.org 5097 Information downloaded from jco.ascopubs.org and provided by at NIH LIBRARY on December 3, 2010 from 156.40.32.144 Copyright © 2007 American Society of Clinical Oncology. All rights reserved. Rock et al myelotoxic therapy requiring hematopoietic stem cell support.”14 when patients or care providers have prior knowledge of assigned These malignancies include non-Hodgkin’s lymphoma, Hodgkin’s therapy. Blinding patients and health care providers to assigned ther- disease, acute myeloid leukemia, acute lymphocytic leukemia, chronic apies in randomized oncology drug trials may be impractical because myelogenous leukemia, chronic lymphocytic leukemia, and multiple of different toxicities and administration routes and schedules in the myeloma. Approval was based on two clinical studies. study’s treatment arms. In these situations, the effects of unblinding Two randomized, placebo-controlled clinical trials supported may be minimized by the selection of a PRO instrument that asks for approval. In the first study, all patients received high-dose cytotoxic current status rather than recall of past experiences, that prevents therapy, including fractionated total-body irradiation, high-dose eto- patient access to previous responses, and that contains multiple cor- poside, and high-dose cyclophosphamide, followed by peripheral- roborating questions regarding the same concept. blood progenitor cell support. Patients were randomly assigned to Patients may miss study visits and PRO assessments, withdraw either palifermin (n ϭ 106) or placebo (n ϭ 106). The primary end from the study, or die for unknown reasons during the study. Large point was the number of days patients experienced patient-reported amounts of missing data may introduce bias and prevent credible severe oral mucositis (grade 3 or 4 on the WHO scale). Oral mucositis comparisons of treatment groups. Missing PRO data are generally ϭ ϭ grades were as follows: 1 soreness/erythema; 2 ulcers present, can informative and may stem from poor outcome or dissatisfaction with ϭ ϭ eat solids; 3 ulcers, tolerates liquid diet only; and 4 alimentation the experimental treatment. Assumptions underlying imputation of not possible. Other end points included incidence, duration, and missing values can seldom be verified. Prospective plans for PRO severity of oral mucositis and opioid analgesia requirements. Patients measurements should establish methods for minimizing patient recorded daily the amount of mouth and throat soreness in a diary. dropouts before trial completion and documenting reasons for pa- Study 1 enrolled 212 patients; 106 were randomly assigned to tient withdrawal. A trial incorporating PRO measures should describe each arm. Median days of severe oral mucositis were 3 and 9 days in prospective methods for prevention of missing data and interpreta- Ͻ the groups treated with palifermin and placebo, respectively (P .001, tion of missing data and, optimally, a process by which PRO data are Cochran-Mantel-Haenszel test stratified for study center). Secondary obtained either before or shortly after patient withdrawal. end points supporting this primary end point included the incidence When incorporating a PRO instrument into a clinical trial, the and median days of grade 4, grades 3 and 4, and grades 2, 3, and 4 oral statistical plan should describe an ordered analysis of the PRO in mucositis and median days and cumulative usage of opioid analgesics. relation to other study end points. An end point hierarchy determined Despite blinding of patients to study treatment, altered oral sensations by the trial’s primary and secondary objectives should specify the in the patients receiving palifermin may have led to unintentional order of end point interpretation. A PRO instrument could be the unblinding of the assigned treatment. Study 2 was a prior dose- trial’s primary end point, a coprimary end point, or a secondary end escalation trial in the same population that generated supportive re- point whose analysis would be ordered by a prospective hierarchical sults in patients who received palifermin. sequence. The statistical analysis plan should clearly identify the con- ditions for a positive study conclusion. DISCUSSION In all approvals, except mitoxantrone, more commonly used end points, such as OS, TTP, or RR, were assessed in addition to the PRO Since 1995, seven anticancer products (nine approvals) were based at measure. Approval of mitoxantrone was based on an improvement in least in part on a PRO measure, representing approximately one tenth pain. The FDA recommends that timing of pain assessments be closely of oncologic drug approvals. These nine approvals incorporated PRO related to time period of interest. Recall periods that assess past distant data to support either efficacy or safety. PRO instruments supporting pain experiences should be minimized by asking patients to record the anticancer product efficacy measured diverse symptoms and/or func- immediate time period rather than recording distant past experiences. tional deficit(s) that were directly attributable to the disease being A measure of worst pain over no longer than a 24-hour period may be treated. Most PRO instruments assessed only one symptom domain. considered. When rescue pain medication is allowed, the pain assess- To address potential sources of bias, the draft PRO guidance ment should be made before receiving a rescue dose. advocates random assignment, blinding, minimization of missing Labeling for two approvals, gemcitabine and imatinib, incorpo- data, and prospectively identified hypotheses in clinical studies incor- rated information about adverse effects or safety benefit taken from porating PRO measures. However, in three of seven approvals sup- HRQOL measures. HRQOL is a multidomain concept representing a ported by PRO-based evidence of treatment efficacy (porfimer, patient’s perception of the overall impact of an illness and its treatment 15 topotecan, and amifostine), data submitted included nonrandomized on the individual’s life. Each HRQOL domain needs to capture and/or unblinded studies with significant amounts of missing data. important aspects of illness and both benefits and risks of treatment in Two of these three approvals (porfimer in NSCLC and topotecan) the population studied. Component items of each domain (eg, pain lacked prospectively defined hypotheses and statistical plans to guide intensity in a symptoms domain) should be measured by currently PRO analyses. FDA approvals of anticancer products are based on an accepted standards for each component item when used alone. overall assessment of the risks and benefits of a treatment. If a large, None of the approved indications described in this article clinically significant treatment effect with a favorable toxicity pro- are based on a PRO measure of fatigue. Fatigue, like HRQOL, is file is observed, limitations in PRO study design or the data col- a multidomain concept that includes both mental and physical lected may be overcome. components. However, the critical domains of fatigue have not Because responses to PRO measures are subjective assessments, been standardized. New instruments to assess how patients single-arm and open-label randomized studies are seldom credible. experience and interpret changes in fatigue as a result of treat- Randomized, blinded trials minimize bias that may be introduced ment are needed.

5098 JOURNAL OF CLINICAL ONCOLOGY Information downloaded from jco.ascopubs.org and provided by at NIH LIBRARY on December 3, 2010 from 156.40.32.144 Copyright © 2007 American Society of Clinical Oncology. All rights reserved. PROs Supporting Anticancer Product Approvals

PRO instruments intended to support product labeling AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS claims should have content validity—evidence supporting that the OF INTEREST instrument’s domains and items are appropriate and comprehensive relative to the intended measurement concept(s), population, and use. Employment: Edwin P. Rock, GlaxoSmithKline Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: N/A Documentation of content validity should include focus group or Testimony: N/A Other: N/A cognitive debriefing transcripts, and these materials should be provided to the FDA. PRO end points support treatment benefit claims that describe a AUTHOR CONTRIBUTIONS patient’s symptoms or ability to function. Most PRO measures that are Conception and design: Edwin P. Rock, Laurie B. Burke included in product labeling claims provide information that supple- Administrative support: Dianne L. Kennedy ments other oncology clinical trial end points, such as improvements Collection and assembly of data: Edwin P. Rock, Dianne L. Kennedy, in OS, TTP, or RR. PRO claims provide additional information re- Melissa H. Furness, William F. Pierce garding treatment effects that should be consistent with other mea- Data analysis and interpretation: Edwin P. Rock, Melissa H. Furness, William F. Pierce, Richard Pazdur, Laurie B. Burke sures of clinical benefit. The FDA encourages anticancer product Manuscript writing: Edwin P. Rock, Dianne L. Kennedy, Richard sponsors to consult with the agency early in the process of PRO Pazdur, Laurie B. Burke instrument development. Final approval of manuscript: Edwin P. Rock, Richard Pazdur, Laurie B. Burke

5. O’Shaughnessy JA, Wittes RE, Burke G, et al: 11. US Food and Drug Administration: Gleevec REFERENCES Commentary concerning demonstration of safety product label. http://www.fda.gov/cder/foi/label/ and efﬁcacy of investigational anticancer agents in 2006/021588s009lbl.pdf 1. US Food and Drug Administration: Guidance clinical trials. J Clin Oncol 9:2225-2232, 1991 12. Cohen MH, Williams G, Johnson JR, et al: for Industry. Patient-reported outcome measures: 6. US Food and Drug Administration: Photofrin Approval summary for imatinib mesylate capsules in Use in medical product development to support product label. http://www.fda.gov/cder/foi/label/ the treatment of chronic myelogenous leukemia. labeling claims. http://www.fda.gov/cder/guidance/ 2003/20451s012_photofrin_lbl.pdf Clin Cancer Res 8:935-942, 2002 5460dft.pdf 7. US Food and Drug Administration: Gemzar 13. Pazdur R: U.S. Food and Drug Administration 2. US Food and Drug Administration: Draft FDA product label. http://www.fda.gov/cder/foi/label/ Drug Approval Summary.Cohen MH, Johnson JR, Guidance for Industry: Clinical trial end points for the 2005/020509s033lbl.pdf Conversion of imatinib mesylate (STI571; Gleevec) approval of cancer drugs and biologics. http://www- 8. US Food and Drug Administration: Nov- tablets from accelerated approval to full approval. .fda.gov/cder/guidance/6592dft.pdf antrone product label. http://www.fda.gov/cder/foi/ Clin Cancer Res 11:12-19, 2005 3. Johnson JR, Williams G, Pazdur R: End points nda/2000/21120.pdf_Novantrone_Prntlbl.pdf 14. US Food and Drug Administration: Kepivance and United States Food and Drug Administration 9. US Food and Drug Administration: Hycamtin product label. http://www.fda.gov/cder/foi/label/ approval of oncology drugs. J Clin Oncol 21:1404- product label. http://www.fda.gov/cder/foi/label/ 2005/125103s0010lbl.pdf 1411, 2003 2006/020671s014lbl.pdf 15. Rock EP, Scott JA, Kennedy DL, et al: Chal- 4. Johnson JR, Temple R: Food and Drug Ad- 10. US Food and Drug Administration: Ethyol lenges to use of health-related quality-of-life for FDA ministration requirements for approval of new anti- product label. http://www.fda.gov/cder/foi/label/ approval of anticancer products. J Natl Cancer Inst cancer drugs. Cancer Treat Rep 69:1155-1159, 1985 2003/20221slr017_ethyol_lbl.pdf (in press)

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www.jco.org 5099 Information downloaded from jco.ascopubs.org and provided by at NIH LIBRARY on December 3, 2010 from 156.40.32.144 Copyright © 2007 American Society of Clinical Oncology. All rights reserved.