Patient-Reported Outcomes in Idiopathic Pulmonary Fibrosis Research
2012; Elsevier BV; Volume: 142; Issue: 2 Linguagem: Inglês
10.1378/chest.11-2602
ISSN1931-3543
AutoresJeffrey J. Swigris, Diane L. Fairclough,
Tópico(s)Occupational and environmental lung diseases
ResumoPatient-reported outcomes (PROs) include questionnaires or surveys that ask patients for their perceptions about things like symptoms they are experiencing or quality of life. For incurable, morbid, life-shortening conditions like idiopathic pulmonary fibrosis (IPF), PROs are particularly germane: They elucidate for clinicians and researchers what it is like for patients to live with such a disease, and they may detect important treatment effects not captured by other metrics (eg, pulmonary physiology). However, a relative paucity of research on PROs in IPF has left significant knowledge gaps in this area and contributed to the timidity investigators have about using PROs as prominent outcomes in IPF drug trials. Additional research on existing instruments is needed to establish or bolster their basic psychometric properties in IPF. When PROs are used as end points in therapeutic trials, analyzing PRO response data can be challenging, but these challenges can be overcome with a transparent, thoughtful, and sophisticated statistical approach. In this article, we discuss some of the basics of PRO assessment, existing knowledge gaps in IPF-related PRO research, and the potential usefulness of using PROs in IPF trials and conclude by offering specific recommendations for an approach to analyzing repeated-measures PRO data from IPF trials. Patient-reported outcomes (PROs) include questionnaires or surveys that ask patients for their perceptions about things like symptoms they are experiencing or quality of life. For incurable, morbid, life-shortening conditions like idiopathic pulmonary fibrosis (IPF), PROs are particularly germane: They elucidate for clinicians and researchers what it is like for patients to live with such a disease, and they may detect important treatment effects not captured by other metrics (eg, pulmonary physiology). However, a relative paucity of research on PROs in IPF has left significant knowledge gaps in this area and contributed to the timidity investigators have about using PROs as prominent outcomes in IPF drug trials. Additional research on existing instruments is needed to establish or bolster their basic psychometric properties in IPF. When PROs are used as end points in therapeutic trials, analyzing PRO response data can be challenging, but these challenges can be overcome with a transparent, thoughtful, and sophisticated statistical approach. In this article, we discuss some of the basics of PRO assessment, existing knowledge gaps in IPF-related PRO research, and the potential usefulness of using PROs in IPF trials and conclude by offering specific recommendations for an approach to analyzing repeated-measures PRO data from IPF trials. a tool to assess quality of life in idiopathic pulmonary fibrosis baseline dyspnea index/transition dyspnea index US Food and Drug Administration health-related quality of life internal consistency reliability idiopathic pulmonary fibrosis last observation carried forward multivariate analysis of variance patient-reported outcome quality of life Medical Outcomes Study 36-Item Instrument St. George Respiratory Questionnaire University of California San Diego Shortness of Breath Questionnaire Patient-reported outcomes (PROs) seek to ascertain information about patients' experiences from their own perspective. Administered as questionnaires or surveys and completed by patients themselves, PROs attempt to quantify a person's perception of things such as health status, symptoms, or quality of life (QOL). PROs can reveal information patients might not disclose spontaneously,1Revicki DA Osoba D Fairclough D et al.Recommendations on health-related quality of life research to support labeling and promotional claims in the United States.Qual Life Res. 2000; 9: 887-900Crossref PubMed Scopus (430) Google Scholar thus strengthening their voices in the often overwhelming realm of their disease. In idiopathic pulmonary fibrosis (IPF), PROs used in either patient-perspectives research settings or therapeutic trials have included dyspnea indexes, cough questionnaires, health status instruments, health-related quality-of-life (HRQL) measures, depression or anxiety questionnaires, and sleep surveys. Although other outcomes (eg, FVC) yield information on disease stage and provide prognostic information, only PROs clue us in to what patients with IPF are actually experiencing and how, in turn, that experience affects any number of life domains. At the core of PROs, and the thing that distinguishes them from other outcomes, is their incorporation of patients' values and judgments—the traits most influential in shaping patients' perceptions of what it is like to live with IPF.1Revicki DA Osoba D Fairclough D et al.Recommendations on health-related quality of life research to support labeling and promotional claims in the United States.Qual Life Res. 2000; 9: 887-900Crossref PubMed Scopus (430) Google Scholar, 2Gill TM Feinstein AR A critical appraisal of the quality of quality-of-life measurements.JAMA. 1994; 272: 619-626Crossref PubMed Scopus (1749) Google Scholar None of the primary outcomes commonly used in IPF trials has anything to do with patient values or judgments: FVC is important to patients only in so far as it quantifies disease severity; it is the downstream effects of a low FVC (eg, activity limitation, dyspnea), rather than the FVC value itself, that influence patients' perceptions of their disease. In some IPF studies, PRO scores have correlated with other outcomes (eg, FVC); in other studies (and quite often within an individual), PRO scores do not correlate with other outcome measures. Consider a 64-year-old woman with severe IPF who is perfectly content if she is able to sit at her computer and e-mail her friends. Although her FVC is only 30% of predicted for her age and height, and she requires supplemental oxygen 24 h per day, she is not necessarily bothered by these, because her perception is that she is still able to do the one thing she values most—e-mail her friends. An outsider, even a physician caring for this patient, might ask how she can be at ease, even content, with her current situation. Although her FVC reveals she has very severe IPF, her values and judgments shape her perception that things are not too bad. Other patients with IPF with the same FVC and oxygen requirements may perceive things quite differently. Because each patient formulates his or her own unique perceptions, and because those perceptions (and scores from PROs that capture them) may not parallel other outcome measures, PROs can identify differences between groups of patients with IPF undetected by physiologic or radiologic measures. For patients with life-shortening diseases that have no curative therapies (like IPF), on the face of it, PROs would seem to be the ideal outcome measures.1Revicki DA Osoba D Fairclough D et al.Recommendations on health-related quality of life research to support labeling and promotional claims in the United States.Qual Life Res. 2000; 9: 887-900Crossref PubMed Scopus (430) Google Scholar Without medicinal therapies to prolong the lives of patients with IPF, perhaps the most important objective for practitioners is to identify ways to improve the QOL of patients with IPF—to manage and limit dyspnea, cough, and fatigue; to enable them to be as physically and socially active as possible; and to ease the frustration and anguish they endure living with IPF. There are PROs available to assess these things. However, to date, investigators have not used a PRO as a primary end point, or as a component of a composite primary end point, in a multicenter therapeutic trial in IPF. This likely stems from several factors, including the following: the incorrect perception among IPF trial designers that PROs are "soft" end points and, even if met, would not be recognized as meaningful by the US Food and Drug Administration (FDA) in the drug-approval process; because of the relative paucity of research on PROs in IPF, investigators have not developed confidence in what PRO scores really mean; and until recently, IPF-specific PROs had not been developed. Recently, the FDA began formalizing recommendations for how a PRO might qualify (in their view for the drug indication approval process) as a valid, reliable outcome measure whose scores have "interpretable meaning" and one whose usefulness need not be reconfirmed when used again in the same target population.3Food and Drug Administration, Center for Drug Evaluation and Research Guidance for Industry: Qualification Process for Drug Development Tools. US Department of Health and Human Services, Silver Spring, MD2010Google Scholar To qualify, the PRO (or the idea for one) is submitted to the FDA, which essentially vets the instrument if various criteria are viewed as acceptable, including the following: (1) the overall goal of the PRO, (2) the conceptual framework for the attribute to be measured, (3) the context of its use, (4) the developmental process, (5) various measurement properties (eg, reliability, construct validity), (6) score interpretation, and (7) language translation and cultural adaptation. It depends. To our knowledge, there are no FDA-qualified PROs for IPF. We are not suggesting that only FDA-qualified PROs be used in IPF research, but if qualified, researchers could at least be confident that certain fundamental psychometric properties of the PRO have been met. For several PROs used in IPF trials, these properties are not known (Table 1),4King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (468) Google Scholar, 5Raghu G Brown KK Bradford WZ Idiopathic Pulmonary Fibrosis Study Group et al.A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2004; 350: 125-133Crossref PubMed Scopus (632) Google Scholar, 6Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (297) Google Scholar, 7King Jr, TE Brown KK Raghu G et al.BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2011; 184: 92-99Crossref PubMed Scopus (398) Google Scholar, 8Zisman DA Schwarz M Anstrom KJ Collard HR Flaherty KR Hunninghake GW Idiopathic Pulmonary Fibrosis Clinical Research Network A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis.N Engl J Med. 2010; 363: 620-628Crossref PubMed Scopus (482) Google Scholar, 9King Jr, TE Albera C Bradford WZ INSPIRE Study Group et al.Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial.Lancet. 2009; 374: 222-228Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar, 10Demedts M Behr J Buhl R IFIGENIA Study Group et al.High-dose acetylcysteine in idiopathic pulmonary fibrosis.N Engl J Med. 2005; 353: 2229-2242Crossref PubMed Scopus (856) Google Scholar but must be before their scores can be interpreted with confidence.Table 1Psychometric Properties of Various PROs Used in Published IPF TrialsPROInternal Consistency in IPFTest-Retest in IPFEvidence to Support Ability to Detect Change in IPFEvidence to Support Construct Validity for Use in IPFDyspnea BDI/TDI4King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (468) Google Scholar, 5Raghu G Brown KK Bradford WZ Idiopathic Pulmonary Fibrosis Study Group et al.A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2004; 350: 125-133Crossref PubMed Scopus (632) Google Scholar, 6Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (297) Google Scholar, 7King Jr, TE Brown KK Raghu G et al.BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2011; 184: 92-99Crossref PubMed Scopus (398) Google ScholarUnknownUnknownSomeSome Borg4King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (468) Google Scholar, 8Zisman DA Schwarz M Anstrom KJ Collard HR Flaherty KR Hunninghake GW Idiopathic Pulmonary Fibrosis Clinical Research Network A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis.N Engl J Med. 2010; 363: 620-628Crossref PubMed Scopus (482) Google ScholarUnknownUnknownNoneNone UCSD5Raghu G Brown KK Bradford WZ Idiopathic Pulmonary Fibrosis Study Group et al.A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2004; 350: 125-133Crossref PubMed Scopus (632) Google Scholar, 8Zisman DA Schwarz M Anstrom KJ Collard HR Flaherty KR Hunninghake GW Idiopathic Pulmonary Fibrosis Clinical Research Network A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis.N Engl J Med. 2010; 363: 620-628Crossref PubMed Scopus (482) Google Scholar, 9King Jr, TE Albera C Bradford WZ INSPIRE Study Group et al.Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial.Lancet. 2009; 374: 222-228Abstract Full Text Full Text PDF PubMed Scopus (439) Google ScholarUnknownUnknownNoneSomeQOL/HRQL EQ5D7King Jr, TE Brown KK Raghu G et al.BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2011; 184: 92-99Crossref PubMed Scopus (398) Google Scholar, 8Zisman DA Schwarz M Anstrom KJ Collard HR Flaherty KR Hunninghake GW Idiopathic Pulmonary Fibrosis Clinical Research Network A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis.N Engl J Med. 2010; 363: 620-628Crossref PubMed Scopus (482) Google ScholarUnknownUnknownNoneNone SF-364King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (468) Google Scholar, 6Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (297) Google Scholar, 7King Jr, TE Brown KK Raghu G et al.BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2011; 184: 92-99Crossref PubMed Scopus (398) Google Scholar, 8Zisman DA Schwarz M Anstrom KJ Collard HR Flaherty KR Hunninghake GW Idiopathic Pulmonary Fibrosis Clinical Research Network A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis.N Engl J Med. 2010; 363: 620-628Crossref PubMed Scopus (482) Google ScholarDomains vary, 0.67–0.90UnknownSomeSome SGRQ4King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (468) Google Scholar, 5Raghu G Brown KK Bradford WZ Idiopathic Pulmonary Fibrosis Study Group et al.A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2004; 350: 125-133Crossref PubMed Scopus (632) Google Scholar, 6Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (297) Google Scholar, 8Zisman DA Schwarz M Anstrom KJ Collard HR Flaherty KR Hunninghake GW Idiopathic Pulmonary Fibrosis Clinical Research Network A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis.N Engl J Med. 2010; 363: 620-628Crossref PubMed Scopus (482) Google Scholar, 9King Jr, TE Albera C Bradford WZ INSPIRE Study Group et al.Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial.Lancet. 2009; 374: 222-228Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar, 10Demedts M Behr J Buhl R IFIGENIA Study Group et al.High-dose acetylcysteine in idiopathic pulmonary fibrosis.N Engl J Med. 2005; 353: 2229-2242Crossref PubMed Scopus (856) Google ScholarDomains vary, 0.66–0.85UnknownSomeSomeBDI/TDI = baseline dyspnea index/transition dyspnea index; Borg = Borg dyspnea scale; EQ5D = EuroQOL 5 dimension instrument; IPF = idiopathic pulmonary fibrosis; PRO = patient-reported outcome; QOL/HRQL = quality of life/health-related quality of life; SF-36 = Medical Outcomes Study 36-Item Instrument; SGRQ = St. George Respiratory Questionnaire; UCSD = University of California San Diego Shortness of Breath Questionnaire. Open table in a new tab BDI/TDI = baseline dyspnea index/transition dyspnea index; Borg = Borg dyspnea scale; EQ5D = EuroQOL 5 dimension instrument; IPF = idiopathic pulmonary fibrosis; PRO = patient-reported outcome; QOL/HRQL = quality of life/health-related quality of life; SF-36 = Medical Outcomes Study 36-Item Instrument; SGRQ = St. George Respiratory Questionnaire; UCSD = University of California San Diego Shortness of Breath Questionnaire. As seen in Table 1, we do not know a lot about how existing PROs perform in IPF, at least not in longitudinal studies. At a minimum, to be deemed useful in IPF, and to yield scores in whose meaning we can be highly confident, internal consistency reliability (ICR) and test-retest for the PRO should be proved acceptable, and data to support its validity for use as a longitudinal outcome measure in IPF must be published. The ICR (ie, Cronbach α)—a measure of the interrelatedness of items composing an instrument—for a multidimensional instrument, used in research, should be > 0.7, and Streiner and Norman11Streiner D Norman G Reliability.in: Health Measurement Scales: a Practical Guide to Their Development and Use. 4th ed. Oxford University Press, New York2010: 104-126Google Scholar recommend that it should not exceed 0.9. A test-retest (intraclass correlation) coefficient > 0.7 is considered psychometrically acceptable.1Revicki DA Osoba D Fairclough D et al.Recommendations on health-related quality of life research to support labeling and promotional claims in the United States.Qual Life Res. 2000; 9: 887-900Crossref PubMed Scopus (430) Google Scholar, 12Hays RD Anderson RT Revicki DA Assessing reliability and validity of measurement in clinical trials.in: Staquet M Hays R Fayers P Quality of Life Assessment in Clinical Trials. Oxford University Press, New York1998: 169-182Google Scholar, 13Nadorra RL Landing BH Pulmonary lesions in childhood onset systemic lupus erythematosus: analysis of 26 cases, and summary of literature.Pediatr Pathol. 1987; 7: 1-18Crossref PubMed Google Scholar, 14Nunnally J Bernstein J The assessment of reliability.in: Psychometric Theory. 3rd ed. McGraw-Hill, New York1994: 248-292Google Scholar For comparison, in IPF, the test-retest correlation coefficient for FVC is 0.93.15du Bois RM Weycker D Albera C et al.Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference.Am J Respir Crit Care Med. 2011; 184: 1382-1389Crossref PubMed Scopus (365) Google Scholar Besides ensuring that ICR and test-retest are acceptable, PRO users must confirm that the aggregate of items from a PRO match the expected levels of the attribute in the target population.1Revicki DA Osoba D Fairclough D et al.Recommendations on health-related quality of life research to support labeling and promotional claims in the United States.Qual Life Res. 2000; 9: 887-900Crossref PubMed Scopus (430) Google Scholar For example, a PRO that contains only items focused on the ability to perform very strenuous physical activity (eg, carry a heavy load one city block, running a mile, digging a ditch) would likely be irrelevant to many, if not most, patients with IPF. These items connote a level of physical functioning far beyond that of an average patient with IPF and would be too difficult for the majority of the IPF population.16Rasch G Probabilistic Models for Some Intelligence and Attainment Tests. Danish Institute of Educational Research, Copenhagen, Denmark1960Google Scholar Such a scale would not be able to differentiate patients with IPF on physical functioning, because responses would almost certainly be skewed toward the "easiest" of all items. This skew, caused by lack of congruence between item difficulty and respondent ability, can also lead to floor and ceiling effects and poor sensitivity to change over time.1Revicki DA Osoba D Fairclough D et al.Recommendations on health-related quality of life research to support labeling and promotional claims in the United States.Qual Life Res. 2000; 9: 887-900Crossref PubMed Scopus (430) Google Scholar Investigators wanting to use a PRO in IPF research will need to assess whether there are data to support its validity for use in IPF. Validation is the process of building understanding in the meaning of the scores of a PRO so they can be used to make accurate inferences about a person in the target population. It takes time and hypothesis testing, in multiple studies, to amass data to support validity of a PRO. As more studies that include a PRO are conducted, greater understanding of (and confidence in) the meaning of different scores from the PRO is gained. A mistake that has been perpetuated in the medical literature is that one cross-sectional correlation study "validates" an instrument.1Revicki DA Osoba D Fairclough D et al.Recommendations on health-related quality of life research to support labeling and promotional claims in the United States.Qual Life Res. 2000; 9: 887-900Crossref PubMed Scopus (430) Google Scholar Data from such studies, assuming correlations are significant and in the expected (hypothesized) directions, may support the so-called "concurrent validity" of the instrument, but more data are needed before the instrument could be used confidently to assess change in longitudinal studies.11Streiner D Norman G Reliability.in: Health Measurement Scales: a Practical Guide to Their Development and Use. 4th ed. Oxford University Press, New York2010: 104-126Google Scholar, 17Hays RD Hadorn D Responsiveness to change: an aspect of validity, not a separate dimension.Qual Life Res. 1992; 1: 73-75Crossref PubMed Scopus (220) Google Scholar, 18Patrick DL Chiang YP Measurement of health outcomes in treatment effectiveness evaluations: conceptual and methodological challenges.Med Care. 2000; 38: II14-II25PubMed Google Scholar According to Nunnally,19Nunnally J Introduction to Psychological Measurement. McGraw-Hill, New York, NY1970Google Scholar "one validates not a measurement instrument but rather some use to which the instrument is put." For the majority of PROs in Table 1, there are numerous studies whose results support concurrent validity20Swigris JJ Gould MK Wilson SR Health-related quality of life among patients with idiopathic pulmonary fibrosis.Chest. 2005; 127: 284-294Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 21Swigris JJ Kuschner WG Jacobs SS Wilson SR Gould MK Health-related quality of life in patients with idiopathic pulmonary fibrosis: a systematic review.Thorax. 2005; 60: 588-594Crossref PubMed Scopus (191) Google Scholar, 22Nishiyama O Taniguchi H Kondoh Y et al.Health-related quality of life in patients with idiopathic pulmonary fibrosis. What is the main contributing factor?.Respir Med. 2005; 99: 408-414Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar; for example, patients with IPF who score high on the St. George Respiratory Questionnaire (SGRQ) or low on the Medical Outcomes Study 36-Item Instrument (SF-36) (both indicating impairments in HRQL) tend to have significant dyspnea. Although gaps remain in our knowledge of PROs in IPF, recently, a growing interest in PRO research in IPF has generated limited data that support the validity of the baseline dyspnea index/transition dyspnea index (BDI/TDI), University of California San Diego Shortness of Breath Questionnaire (UCSD), SGRQ, and SF-36 for use as longitudinal outcomes in IPF trials.23du Bois RM Weycker D Albera C et al.Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2011; 184: 459-466Crossref PubMed Scopus (329) Google Scholar, 24du Bois RM Weycker D Albera C et al.Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference.Am J Respir Crit Care Med. 2011; 183: 1231-1237Crossref PubMed Scopus (332) Google Scholar, 25Swigris JJ Brown KK Behr J et al.The SF-36 and SGRQ: validity and first look at minimum important differences in IPF.Respir Med. 2010; 104: 296-304Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar Although the question of how many data (or studies) are needed to validate an instrument ignores the basic premise that validation is a process, when a PRO is being considered for use as an outcome measure in a trial, we believe the ability of the PRO to track change over time needs to have been well demonstrated in at least one previous study (eg, using data from a previously conducted therapeutic trial or a longitudinal observational study) in the target population. If a PRO has acceptable psychometric properties (ICR, test-retest reliability, and data to support its validity for the intended purpose in the target population), then investigators will need to decide whether it adequately addresses all the domains (or aspects of an individual domain) they are interested in examining in their study. For example, if dyspnea is the outcome of interest, do the investigators want to know its severity, how burdensome or intrusive it is, how it impacts emotional health, or some other aspect? If they are most interested in the effect of dyspnea on emotional well-being (ie, whether it induces anxiety, frustration, fear, low mood), then they may wish to consider a dyspnea questionnaire other than the BDI/TDI or UCSD, because these instruments don't fully tap that aspect of dyspnea. Assuming more than one psychometrically acceptable PRO is available to give them the data they desire, investigators must review the candidate instruments and draw on their scientific curiosity, clinical experience, work done previously by other investigators, and perhaps even patient input to help shape their decision of which PRO(s) to use. Because of lack of data to support the longitudinal validity of more than a handful of PROs, investigators should be prepared to choose from a limited number of candidate instruments (acceptable to use at this time), to perform the preliminary studies necessary to build a foundation of validity for an instrument, or to develop a new one. Although it is impossible for us to make recommendations about which PROs to use in a trial without knowing the specific goals of the trial, prior research has revealed that patients with IPF have impaired QOL, they cough, and they are dyspneic and fatigued. These are domains an investigator may wish to assess as outcomes in a trial. A generally accepted rule is that investigators use both a generic and a disease-specific instrument: The generic instrument allows comparisons to be made with other patient populations, and the disease-specific instrument is included in the hopes of maximizing the ability to capture change over time. Whatever instruments they choose, investigators should follow the same principles of trial design that guide them in their selection and formulation of efficacy end points. Importantly, hypotheses about PRO end points and data analysis plans should be developed and clearly stated a priori.1Revicki DA Osoba D Fairclough D et al.Recommendations on health-related quality of life research to support labeling and promotional claims in the United States.Qual Life Res. 2000; 9: 887-900Crossref PubMed Scopus (430) Google Scholar We are aware of four IPF-specific PROs (all HRQL instruments) that have been developed (or are in the developmental phase), two of which have been published.26Swigris JJ Wilson SR Green KE Sprunger DB Brown KK Wamboldt FS Development of the ATAQ-IPF: a tool to assess quality of life in IPF.Health Qual Life Outcomes. 2010; 8: 77Crossref PubMed Scopus (57) Google Scholar, 27Yorke J Jones PW Swigris JJ Development and validity testing of an IPF-specific version of the St George's Respiratory Questionnaire.Thorax. 2010; 65: 921-926Crossref PubMed Scopus (110) Google Scholar The SGRQ-I is an IPF-specific variation of the original SGRQ, developed by applying Rasch analysis to SGRQ response data acquired in a multinational trial.4King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (468) Google Scholar, 27Yorke J Jones PW Swigris JJ Development and validity testing of an IPF-specific version of the St George's Respiratory Questionnaire.Thorax. 2010; 65: 921-926Crossref PubMed Scopus (110) Google Scholar In Rasch analysis, response data are fit to a mathematical model, the results of which place instrument items and respondents on the same scale
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