Table 1.

Orphan drugs with PRO labelling approved by the EMA.

Generic Name	Marketing Approval Date	Approved Indication	Therapeutic area	No of PRO claims	Symptoms	Functioning	HRQoL	PRO tools named in the SmPC	PRO endpoint status	Statistical significance of PRO results	PRO-related language
ixazomib	11/21/2016	In combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy	Oncology	2	yes	yes	yes	EORTC QLQ-C30 EORTC QLQ-MY20	secondary	HRQoL maintained and no statistically significant difference between study arms.	Quality of life as assessed by global health scores (EORTC QLQ-C30 and MY-20) was maintained during treatment and was similar in both treatment regimens in the Phase 3 study
migalastat	05/26/2016	Long-term treatment of adults and adolescents aged 16 years and older with a confirmed diagnosis of Fabry disease (α-galactosidase A deficiency) who have an amenable mutation	Endocrinology	1	yes	no	no	Gastrointestinal Symptoms Rating Scale	primary	yes	Patient-Reported Outcome – Gastrointestinal Symptoms Rating Scale: In the ERT-naïve trial, analyses of the Gastrointestinal Symptoms Rating Scale demonstrated that treatment with Galafold was associated with statistically significant (p < 0.05) improvements versus placebo from baseline to month 6 in the diarrhoea domain, and in the reflux domain for patients with symptoms at baseline
pitolisant	03/31/2016	Treatment of narcolepsy with or without cataplexy	Neurology	2	yes	no	no	Epworth Sleepiness Scale Weekly cataplexy rate (WCR) recorded in patient diaries	primary	yes	PRO 1: To assess the efficacy of pitolisant on Excessive Daytime Sleepiness (EDS), Epworth Sleepiness Scale (ESS) score was used as the primary efficacy criterion PRO 2: Harmony CTP, a supportive double-blind, randomised, parallel group study of pitolisant versus placebo, was designed to establish pitolisant efficacy in patients with high frequency cataplexy in narcolepsy. The primary efficacy endpoint was the change in the average number of cataplexy attacks per week between the 2 weeks of baseline and the 4 weeks of stable treatment period at the end of the study. On the primary efficacy endpoint, Weekly Rate of Cataplexy episodes (WRC), the results with pitolisant were significantly superior to those in the placebo group (p < 0.0001) (The primary endpoint was the change in the average number of cataplexy attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR]) between the 2 weeks of baseline and the 4 weeks of stable dosing period…)
human coagulation factor X	16/03/2016	Treatment and prophylaxis of bleeding episodes, and perioperative management in patients with hereditary factor X deficiency	Haematology	1	yes	no	no	Pre-determined bleed-specific ordinal rating scale	primary	yes	The efficacy of Coagadex in treating bleeding episodes was assessed by the subject and/or investigator for each new bleeding episode, using a pre-determined bleed-specific ordinal rating scale of excellent, good, poor and unassessable.
carfilzomib	11/19/2015	In combination with either lenalidomide and dexamethasone or dexamethasone alone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy	Oncology	1	yes	yes	yes	EORTC QLQ-C30	secondary	yes	Patients treated with KRd reported improved Global Health Status, with higher Global Health Status/Quality of Life (QoL) scores compared with Rd over 18 cycles of treatment (multiplicity unadjusted 1 sided p-value = 0.0001) measured with the EORTC QLQ-C30, an instrument validated in multiple myeloma. The p-values for ORR and Global Health Status/Quality of Life (QoL) scores are descriptive based on the pre-specified multiplicity adjustment plan.
tasimelteon	03/07/2015	Treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) in totally blind adults	Endocrinology	1	yes	no	no	patient-recorded sleep diaries	primary	yes	SET and RESET evaluated the duration and timing of nighttime sleep and daytime naps via patient-recorded diaries.
nintedanib	15/01/2015	Treatment of Idiopathic Pulmonary Fibrosis (IPF)	Respiratory	1	yes	no	yes	Saint George’s Respiratory Questionnaire (SGRQ)	secondary	yes	SGRQ total score measuring health-related quality of life (HRQoL) was analysed at 52 weeks (in both trials INPULSIS-1 and INPULSIS-2)
olaparib	16/12/2014	As monotherapy for maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy	Oncology	3	yes	no	yes	FOSI (FACT/NCCN Ovarian Symptom Index) Trial Outcome Index (TOI) Functional Analysis of Cancer Therapy–Ovarian total score (FACT-O total)	secondary	no	No statistically significant differences were observed between olaparib and placebo in patient-reported symptoms or HRQoL as measured by improvement and worsening rates in the FACT/NCCN Ovarian Symptom Index (FOSI), Trial Outcome Index (TOI) and Functional Analysis of Cancer Therapy–Ovarian total score (FACT-O total)
obinutuzumab	23/07/2014	In combination with chlorambucil for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) and with comorbidities making them unsuitable for full-dose fludarabine-based therapy	Oncology	2	yes	yes	yes	EORTC QLQ-C30 QLQ-CLL-16	secondary	no	In the QLQC30 and QLQ-CLL-16 questionnaires conducted during the treatment period, no substantial difference in any of the subscales was observed
obinutuzumab	23/07/2014	In combination with bendamustine followed by obinutuzumab maintenance for the treatment of patients with follicular lymphoma (FL) who did not respond to or progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen	Oncology	2	yes	yes	yes	FACT-Lym EQ-5D	secondary	HRQoL maintained and no statistically significant difference between study arms.	Based on the FACT-Lym questionnaire and EQ-5D index scale collected during the treatment and during follow-up periods, health-related quality of life was generally maintained in the pivotal study with no significant difference between the arms. However, in patients with FL the addition of Gazyvaro to bendamustine delayed the time to worsening of health-related quality of life as measured by the FACT-Lym TOI score by 2.2 months (median 5.6 versus 7.8 months for B and G + B respectively HR = 0.83; 95% CI: 0.60, 1.13)
macitentan	12/20/2013	As monotherapy or in combination for long-term treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III.	Respiratory	1	yes	yes	yes	SF-36	secondary	yes	Macitentan 10 mg improved quality of life assessed by the SF-36 questionnaire (A 36-item, patient-reported survey of patient health)
brentuximab vedotin	10/25/2012	Treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL): 1. following autologous stem cell transplant (ASCT) or 2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option. Treatment of adult patients with CD30+ HL at increased risk of relapse or progression following ASCT	Oncology	1	no	no	yes	not specified	tertiary	no	Study SGN35-005 No differences were observed in quality of life between the treatment and placebo arms.
ivacaftor	07/23/2012	Treatment of patients with cystic fibrosis (CF) aged 6 years and older and weighing 25 kg or more who have one of the following gating (class III) mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R; treatment of patients with cystic fibrosis (CF) aged 18 years and older who have an R117H mutation in the CFTR gene.	Respiratory	1	yes	no	no	Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain	secondary	no	Mean absolute change from baseline in CFQ-Rb respiratory domain score was evaluated at weeks 24 and 48 CFQ-R: Cystic Fibrosis Questionnaire-Revised is a disease-specific, health-related quality-of-life measure for CF

Abbreviations: ASCT-autologous stem cell transplant; CF-Cystic Fibrosis; CFQ-R-Cystic Fibrosis Questionnaire-Revised; DSSS-Diary Symptom Sum Score; EORTC QLQ-European Organization for Research and Treatment Quality of Life Questionnaire; FACT-Lym- Functional Assessment of Cancer Therapy – Lymphoma; FOSI-FACT/NCCN Ovarian Symptom Index; EQ-5D-EuroQol-5- Dimensional; FACT-O-Functional Analysis of Cancer Therapy–Ovarian; GNDS-Guy’s Neurological Disability Scores; HRQoL-Health-Related Quality of Life; IPF-Idiopathic Pulmonary Fibrosis; MSCS-Mean Symptom Complex Severity; MSCS-Mean Symptom Complex Severity; nOH-neurogenic symptomatic orthostatic hypotension; OHQ-Orthostatic Hypotension Questionnaire; PI-NRS-Pain Intensity Numerical Rating Scale; PI-Package Insert; PRO-Patient Reported Outcome; SF-Short Form; SGRQ-Saint George’s Respiratory Questionnaire; TEQ-Treatment Effect Questionnaire; TOI-Trial Outcome Index; TOS-Treatment Outcome Score; WCR-Weekly cataplexy rate; VAS-Visual Analogue Scale