Perspectives in clinical gastroenterology and hepatology
Patient-Reported Outcomes as Primary End Points in Clinical Trials of Inflammatory Bowel Disease

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The Food and Drug Administration (FDA) is moving from the Crohn’s Disease Activity Index to patient-reported outcomes (PROs) and objective measures of disease, such as findings from endoscopy. PROs will become an important aspect of assessing activity of inflammatory bowel disease (IBD) and for labeling specific drugs for this disease. PROs always have been considered in the management of patients with rheumatoid arthritis or multiple sclerosis, and have included measurements of quality of life, disability, or fatigue. Several disease-specific scales have been developed to assess these PROs and commonly are used in clinical trials. Outcomes reported by patients in clinical trials of IBD initially focused on quality of life, measured by the Short-Form 36 questionnaire or disease-specific scales such as the Inflammatory Bowel Disease Questionnaire or its shorter version. Recently considered factors include fatigue, depression and anxiety, and work productivity, as measured by the Functional Assessment Chronic Illness Therapy-Fatigue, the Hospital Anxiety Depression, and the Work Productivity Activity Impairment Questionnaire, respectively. However, few data are available on how treatment affects these factors in patients with IBD. Although disability generally is recognized in patients with IBD, it is not measured. The international IBD disability index currently is being validated. None of the PROs currently used in IBD were developed according to FDA guidance for PRO development. PROs will be a major primary end point of future trials. FDA guidance is needed to develop additional PROs for IBD that can be incorporated into trials, to better compare patients’ experience with different therapies.

Section snippets

Methods

See the Supplementary Materials and Methods section for more detail.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23

Food and Drug Administration Guidance for Developing Patient-Reported Outcomes

Recently, the FDA proposed guidance for the development of PROs with the ultimate goal of supporting labeling claims.24 An overview of this guidance is shown in Figure 1. Importantly, PROs should not be confused with patient-based outcomes, which are developed by and/or collected by practitioners; PROs should be obtained from validated self-administered questionnaire(s) using items that are generated solely by patients.24 A PRO is any report that comes directly from a patient about a health

Experience From Other Chronic Conditions

See the Supplementary Materials and Methods section.25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49

Quality of Life in Inflammatory Bowel Disease

The definition and epidemiology4, 50, 51, 52, 53, 54, 55 and available tools to assess quality of life in IBD (Table 1) can be found in the Supplementary Materials and Methods section.3, 4, 5, 13, 14, 15, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82

Work Productivity in Inflammatory Bowel Disease

The definition and epidemiology106, 107 and available tools to assess work productivity in IBD (Table 2) can be found in the Supplementary Materials and Methods section.7, 8, 70, 71, 92, 108, 109, 110, 111, 112

Disability in Inflammatory Bowel Disease

The definition and epidemiology12, 107, 116, 117, 118, 119 and available tools to assess disability in IBD (Table 3) can be found in the Supplementary Materials and Methods section.12, 120, 121, 122, 123, 124, 125

Fatigue in Inflammatory Bowel Disease

The definition and epidemiology126, 127, 128 and available tools to assess fatigue in IBD (Table 4) can be found in the Supplementary Materials and Methods section.6, 20, 21, 22, 127, 129, 130, 131, 132, 133

Depression and Anxiety in Inflammatory Bowel Disease

The definition and epidemiology135, 136, 137, 138, 139, 140 and available tools to assess depression and anxiety in IBD (Table 5) can be found in the Supplementary Materials and Methods section.9, 10, 11, 23, 136

Relationships Between Patient-Reported Outcomes and Disease Activity in Inflammatory Bowel Disease

See the Supplementary Materials and Methods section for more detail.67, 71, 74, 76, 77, 78, 83, 85, 86, 88, 89, 91, 94, 99, 103, 142, 143

Conclusions and Perspectives

There is a growing interest for PROs in IBD. In the future, physicians managing patients with IBD may evaluate a variety of PROs that assess fatigue, disability, quality of life, work productivity, anxiety, and depression, with the final aim of improving patients’ lives. However, none of the existing IBD PROs were developed according to FDA guidance, and thus cannot lead to PRO labeling. Available questionnaires such as the IBDQ assessing quality of life in IBD and the IBD Disability Index do

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  • Conflicts of interest These authors disclose the following: Laurent Peyrin–Biroulet has received consulting and/or lecture fees from Merck, Abbott, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, and Takeda. William Sandborn has received consulting fees from ActoGeniX NV, AGI Therapeutics, Inc, Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys, Inc, Atlantic Healthcare Limited, Axcan Pharma (now Aptalis), BioBalance Corporation, Boehringer-Ingelheim, Inc, Bristol Meyers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research, Inc, Elan Pharmaceuticals, EnGene, Inc, Eli Lilly, Enteromedics, Exagen Diagnostics, Inc, Ferring Pharmaceuticals, Flexion Therapeutics, Inc, Funxional Therapeutics Limited, Genzyme Corporation, Genentech (now Roche), Gilead Sciences, Given Imaging, Glaxo Smith Kline, Human Genome Sciences, Ironwood Pharmaceuticals (previously Microbia, Inc), Janssen (previously Centocor), KaloBios Pharmaceuticals, Inc, Lexicon Pharmaceuticals, Lycera Corporation, Meda Pharmaceuticals (previously Alaven Pharmaceuticals), Merck Research Laboratories, MerckSerono, Millennium Pharmaceuticals (subsequently merged with Takeda), Nisshin Kyorin Pharmaceuticals Co, Ltd, Novo Nordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Limited, Purgenesis Technologies, Inc, Receptos, Relypsa, Inc, Salient Pharmaceuticals, Salix Pharmaceuticals, Inc, Santarus, Schering Plough Corporation (acquired by Merck), Shire Pharmaceuticals, Sigmoid Pharma Limited, Sirtris Pharmaceuticals, Inc (a GSK company), S.L.A. Pharma (UK) Limited, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co, Ltd), TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Limited, Warner Chilcott UK Limited, and Wyeth (now Pfizer); has received lecture fees from Bristol Meyers Squibb and Janssen (previously Centocor); and has received research support from Bristol Meyers Squibb, Genentech, Glaxo Smith Kline, Janssen (previously Centocor), Millennium Pharmaceuticals (now Takeda), Novartis, Pfizer, Procter and Gamble Pharmaceuticals, Shire Pharmaceuticals, and UCB Pharma. The remaining author discloses no conflicts.

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