Public Assessment Report for paediatric studies submitted in accordance with Article 45 of Regulation (EC) No1901/2006, as amended.

Transcription

1 Public Assessment Report for paediatric studies submitted in accordance with Article 45 of Regulation (EC) No1901/2006, as amended Omniscan UK/W/063/pdWS/001 Rapporteur UK Finalisation procedure (day 20) 23 nd October 2013 Date of finalisation of PAR 10 th December 2013 UK/W/063/pdWS/001 Page 1/46

2 TABLE OF CONTENTS I. Executive Summary... 4 II. Recommendation... 5 III. Introduction... 6 IV. SCIENTIFIC DISCUSSION... 9 IV.1 Non-clinical aspects... 9 IV.2 Clinical aspects V. Rapporteur s Conclusion and request for additional clarifications at day VI. MAH RESPONSES VII. Rapporteur s Overall Conclusion and recommendations VIII. List of Medicincal products and marketing authorisation holders involved IX. Literature references UK/W/063/pdWS/001 Page 2/46

3 ADMINISTRATIVE INFORMATION Invented name of the medicinal product(s): INN (or common name) of the active substance(s): MAH (s): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Omniscan See section VIII Paramagnetic Contrast Agent for magnetic resonance tomography. ATC code :VO8CAO2 0.5mmol/ml, solution for injection 5ml,10ml, 15ml or 20ml glass vials UK/W/063/pdWS/001 Page 3/46

4 I. EXECUTIVE SUMMARY This is a data submission for gadodiamide in accordance with Article 45 of Regulation (EC) No 1901/2006, as amended, on medicinal products for paediatric use. The UK is the Rapporteur for this procedure. is a linear non-ionic paramagnetic gadolinium containing contrast agent (GdCA) used during magnetic resonance imaging (MRI) procedures. It is available as 0.5 mmol/ml solution for intravenous use in 5, 10, 15 and 20 ml glass vials. is registered in 96 countries worldwide including all EU member states. is licensed as an MRI contrast agent in all European countries for the following adult indications: examinations of central nervous system (CNS) (brain and spine diseases) examinations of the whole-body (including chest, breast, abdomen, pelvis, kidney, osteo-articular, etc) magnetic resonance angiography (MRA) mammography coronary artery disease (CAD) for evaluation of cardiac perfusion In paediatric patients, is licensed as a contrast agent for central nervous system MRI for children aged 4 weeks to 18 years in all registered countries. It is licensed as a contrast agent for whole body MRI in children from 2 years of age in UK, Romania, New Zealand, India and Nepal and in children from 6 months of age in a number of EU countries. is currently not recommended for use for Magnetic Resonance Angiography (MRA), mammography and cardiac MRI in children under 18 years of age in any MS, due to insufficient data on efficacy and safety for these indications. is used exclusively as a single intravenous dose of 0.1 mmol/kg in children of all age groups for both CNS and whole body MRI. It is contraindicated in neonates up to 4 weeks of age and it should only be used after careful consideration in infants up to 1 year of age due to immature kidney function. Nephrogenic Systemic Fibrosis (NSF) was noted to occur predominantly in patients with endstage renal disease who were administered gadolinium based contrast agents (GdCAs). In December 2007 the Committee for Medicinal Products for Human Use (CHMP) Scientific Advisory Group (SAG) for Diagnostics categorised the gadolinium contrast agents into three NSF risk groups, based on their thermodynamic and kinetic properties. was classified as a high risk agent. A total of 739 adult and 9 paediatric cases of NSF were reported following use of gadodiamide until June For further details please refer to section IV.3.3. The MAH submitted paediatric data for gadodiamide which include synopses of 3 comparative and 6 non-comparative studies conducted by the MAH, a Periodic Safety Update Report (PSUR) with a Data Lock Point (DLP) 31 st January 2011 and 13 relevant abstracts of studies retrieved from the literature. The MAH has submitted data on adverse drug reactions (ADRs) reported in the paediatric population in pre- and post-marketing studies, and from the post-marketing pharmacovigilance database. There were 180 individual safety reports in paediatric patients. Approximately 34 cases had at least one serious ADR, 4 deaths (1 due to NSF and 3 unrelated), 144 cases of UK/W/063/pdWS/001 Page 4/46

5 non-serious ADRs and 2 cases where gadodiamide was ineffective. The safety data analysis conducted by the MAH did not identify any new safety concerns for the paediatric population. Based on the review of the current clinical experience, the post-marketing surveillance data and the published scientific literature, the MAH concluded that gadodiamide continues to have a favourable risk-benefit ratio as a contrast agent for MRI in the paediatric population if used according to the dosage regimen and warning stated in the SmPC. Consequently, no updates to the currently approved SmPC are considered necessary by the MAH. II. RECOMMENDATION Based on the data submitted by the MAH, the diagnostic efficacy of gadodiamide in children is up to 63% and the therapeutic efficacy is up to 72% in CNS and whole body MRI. is classified as a high risk contrast agent for the development of nephrogenic systemic fibrosis by the European Medicines Agency. As part of the EMA Article 31 referral procedure in February 2007, additional safety concerns have been identified regarding potential accumulation in bones and other tissues. The analysis of the identified safety issues is ongoing at European level, therefore no further conclusions on these issues can be drawn at present. Nevertheless, based on the submitted safety data, no new safety concerns for the paediatric population have been identified by the rapporteur. In summary, the rapporteur considers that, taking into account the risk minimisation measures already in place, the benefit:risk balance for the use of gadodiamide in the paediatric population remains unchanged. As a conclusion, the rapporteur considers that no new evidence on gadodiamide safety and efficacy in the paediatric population has been identified from the data submitted by the MAH. Therefore no changes are proposed in the currently approved SmPC. Summary of outcome No SmPC and PL changes are proposed. No change Change New study data UK/W/063/pdWS/001 Page 5/46

6 III. INTRODUCTION On 6 th September 2012, the MAH submitted the following documents for gadodiamide, in accordance with Article 45 of Regulation (EC) No 1901/2006, as amended, on medicinal products for paediatric use: Clinical expert overview use of gadodiamide in the paediatric population Currently approved SmPC and PIL in the UK Periodic Safety Update Report (PSUR) with Data Lock Point (DLP) 31 st January 2011 Synopsis of 3 comparator and 6 non-comparator trials and 13 literature published studies. The clinical expert overview summarizes the currently available evidence on the use of gadodiamide as a contrast agent for MRI in the paediatric population. It concludes that gadodiamide continues to have a favourable risk-benefit profile if used according to the recommended dosage regimen and precautions in the SmPC and therefore no further changes are deemed necessary by the MAH. IV.1 Currently approved SmPC is authorised as a MRI contrast agent in adults for the following indications: MRI of brain and spine MRI of whole body Magnetic Resonance Angiography (MRA) Mammography Coronary artery disease is licensed as a contrast agent for central nervous system MRI in paediatric patients from 4 weeks of age in all EU countries. It is also licensed as a contrast agent for whole body MRI but there are differences in the licensing age across MSs. In the UK and Romania it is licensed in children older than 2 years of age but it is approved from 6 months of age for whole body MRI in a number of MSs. The use of gadodiamide is contraindicated in neonates up to 4 weeks. should only be used in infants up to 1 year of age after careful consideration due to immature renal function in this age group. It is noted overall that there is limited evidence on the use of gadodiamide in children below 2 years of age. is not recommended for MRA, mammography or coronary artery disease in any MS in children under 18 years of age due to lack of safety and efficacy data in children for these indications. The MAH has submitted the currently approved UK SmPC. Section 4.1 Therapeutic indications Contrast medium for cranial and spinal magnetic resonance imaging (MRI) and for general MRI of the body after intravenous administration. The product provides contrast enhancement and facilitates visualisation of abnormal structures or lesions in various parts of the body including the CNS. For cardiac MRI, the product is indicated for the evaluation of coronary artery disease (CAD) by myocardial perfusion imaging MRI (stress/rest and late enhancement examination) for the detection and localization of coronary artery disease (CAD) and differentiation between areas of ischaemia and infarction in subjects with known or suspected CAD. Section 4.2 Posology and method of administration No special preparation of the patient is required. should be drawn into the syringe immediately before use. Both the vial and the bottle are intended for one patient only. Contrast UK/W/063/pdWS/001 Page 6/46

7 medium not used in one examination must be discarded. For both adults and children the required dose should be administered as a single intravenous injection. To ensure complete injection of the contrast medium, the intravenous line may be flushed with sodium chloride injection 0.9%. CNS Dosage for adults and children The recommended dosage is 0.1 mmol/kg body weight (equivalent to 0.2 ml/kg b.w.) up to 100 kg. Above 100 kg body weight 20 ml is usually sufficient to provide diagnostically adequate contrast. Adults only When brain metastases are suspected in patients with equivocal scans after administration of the 0.1 mmol/kg b.w. injection, a second bolus injection of 0.2 mmol/kg b.w. (equiv. to 0.4 ml/kg b.w.) up to 100 kg b.w. may be of additional diagnostic value when administered within 20 minutes of the first injection. Above 100 kg b.w. a second bolus injection of 40 ml should be sufficient to provide diagnostically adequate contrast. Whole body Dosage for adults and children from 2 years of age The recommended dosage is 0.1 mmol/kg b.w. (equiv. to 0.2 ml/kg b.w.) up to 100 kg. Above 100 kg b.w. 20 ml is usually sufficient to provide diagnostically adequate contrast. has also been used in a limited number of children below 2 years of age. CNS and Whole body only Contrast-enhanced MRI should start shortly after administration of the contrast medium, depending on the pulse sequences used and the protocol for the examination. Optimal enhancement is observed within the first minutes after injection (time depending on type of lesion/tissue). Enhancement is generally lasting up to 45 minutes after contrast medium injection. T1-weighted scanning sequences are particularly suitable for contrast-enhanced examinations with. In the investigated range of field strengths, from 0.15 Tesla up to 1.5 Tesla, the relative image contrast was found to be independent of the applied field strength. Angiography Dosage for adults The recommended dosage is 0.1 mmol/kg body weight (equivalent to 0.2 ml/kg b.w.). The efficacy and safety of for use in angiography in children under the age of 18 years has not been established. Mammography Dosage for adults The recommended dosage is mmol/kg body weight (equivalent to ml/kg b.w.). Above 100 kg b.w. 20 ml - 40 ml is usually sufficient to provide diagnostically adequate contrast. Coronary Artery Disease (CAD) Dosage for adults The recommended dosage for evaluation of cardiac perfusion is 0.15 mmol/kg b.w. (equiv. to 0.3 ml/kg b.w.) given as two separate doses of mmol/kg b.w. (equiv. to 0.15 ml/kg b.w.) administered within an interval of 10 minutes; one at pharmacological stress followed by one at rest. For the intravenous bolus injection in cardiac MRI, the use of a suitable injector is recommended at a rate of up to 8 ml/sec. An adequate pharmacological stress agent should be administered via separate intravenous line. For the evaluation of late enhancement only, a total dose of 0.15 mmol/kg b.w. is recommended The CAD indication has not been studied in children. UK/W/063/pdWS/001 Page 7/46

8 Special Populations Neonates up to 4 weeks of age and infants up to 1 year of age is contraindicated in neonates up to 4 weeks of age (see section 4.3). Due to immature renal function in infants up to 1 year of age, should only be used in these patients after careful consideration at a dose not exceeding 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, injections should not be repeated unless the interval between injections is at least 7 days. Section Contraindications should not be used in patients known to have hypersensitivity to or its constituents. is contraindicated in patients with severe renal impairment (GFR <30ml/min/1.73m2), in patients in the perioperative liver transplantation period and in neonates up to 4 weeks of age (see section 4.4). Section 4.4 Warning and precautions for use Neonates and Infants: is contraindicated in neonates up to 4 weeks of age (see section 4.3). Due to immature renal function in infants up to 1 year of age, should only be used in these patients after careful consideration. 5.3 Preclinical Safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and local tolerance. Toxicological studies have demonstrated a high acute tolerance of gadodiamide. The common finding after high single dose or repeated dose toxicology studies was proximal tubular vacuolation, which was reversible, and was not associated with altered renal function. had no effects on fertility, reproductive performance or peri- post-natal development in rats, or in teratology studies in rats and rabbits at doses not associated with paternal or maternal toxicity. In pregnant rabbits reduced fetal weights and skeletal anomalies were observed after repeated administration of doses of 0.5 mmol/kg/day and above (approximately 2 times the maximum human cumulative dose of 0.3 mmol/kg based on a mmol/kg comparison). The transfer of maternally administered gadodiamide into milk was small in lactating rats injected intravenously with gadodiamide. It is noted during this procedure that there is difference in the licensing age of gadodiamide as contrast agent for whole body MRI among MSs. The MAH did not provide detailed information on gadodiamide s licensing status across all MSs. During a national procedure in the UK in 1997 it was concluded that there was not enough evidence to support the use of gadodiamide as a whole body contrast agent below 2 years of age. Therefore in the UK it is licensed for whole body MRI in children older than 2 years of age. IV.2 The MAH s recommendations for updating the product information The MAH concluded that no further changes to the SmPC are needed based on the review of paediatric data. UK/W/063/pdWS/001 Page 8/46

9 IV. SCIENTIFIC DISCUSSION IV.1 Non-clinical aspects The effect of as a contrast enhancing agent during MRI has been investigated in a series of animal studies. Safety pharmacology studies in dogs and rats have demonstrated that has no significant effects on the cardiovascular system. The vitro studies have demonstrated no or insignificant effects on mast cell histamine release, human serum complement activation factors, human erythrocyte cholinesterase activity, lysozyme activity, human erythrocyte fragility and morphology, and on tension in isolated bovine blood vessels. No evidence of antigenicity was seen in a dermal test in guinea pigs. Pharmacokinetic studies in several animal species have demonstrated to be rapidly distributed in the extracellular volume, and quantitatively excreted via the kidneys by glomerular filtration. The elimination half-lives in man and monkey are similar and are approximately 70 minutes. The calculated distribution volume is approximately 25% of the body size. Toxicological studies have suggested a high acute tolerance of ; the approximate LD50 in mice was > 30 mmol/kg. The common finding after high single doses or repeated dosing was proximal tubular vacuolation, which was reversible, and was not associated with altered renal function. was found to be non-irritating after intravenous, intra-arterial, paravenous, intramuscular and subcutaneous administration, or when applied to the skin or the eye. had no effects on fertility or reproductive performance in rats or in teratology studies in rats and rabbits at doses that did not cause maternal toxicity. The MAH has continued its programme of preclinical research in 2011 and 2012 due to case reports of nephrogenic systemic fibrosis (NSF). In 2006 Gadolinium-based contrast agents (GdCAs) including have been associated with this potentially fatal condition. The MAH noted that the results of this research programme and the survey of published data support the position that high GdCA exposure, severe renal impairment (SRI) and end stage renal disease (ESRD) are the key predisposing factors in the development of NSF. It is concluded by the MAH that there is nothing in the nonclinical literature or in studies conducted by the MAH that indicates either a new safety signal or need for revision to approved labelling. The MAH claims that there are no new safety signals and therefore no need for revision of the approved SmPC. It is noted that a literature review has not been conducted by the MAH to identify preclinical studies relevant for the paediatric use of gadodiamide. In July 2010 the EMA published the assessment report of gadolinium-containing contrast agents (GdCAs). was classified as high risk for the development of NSF. Based on the 580 unconfounded cases reported up to February 2009 and the GdCA usage, the EMA calculated that the estimated relative risk for NSF for gadodiamide is 100%, 94% for gadoversetamide, and 10% for gadopentetic acid and <1% for gadoteridol and gadoteric acid. The above mentioned EMA assessment report refers to four relevant non-clinical studies. In two non-clinical studies by Pietsch et al (2009, 2010), skin biopsies were taken from rats (normal renal function and nephrectomised, respectively) treated for 5 consecutive days with 2.5 mmol GdCA/kg of seven different GdCAs including gadodiamide. Gadolinium could be detected in the skin of animals treated with high risk GdCAs (gadodiamide, gadoversetamide and gadopentetic acid) for up to one year. NSF skin lesions were only seen in gadodiamide-treated animals, in nephrectomised as well as normal renal function rats. Studies by Moran et al (2002) and Gibby UK/W/063/pdWS/001 Page 9/46

10 et al (2004) have shown that gadolinium is retained following the use of GdCAs in animals and humans in bone and in other tissues such as the liver, kidney, muscle and spleen. The EMA report on GdCAs identified other contributing risk factors for NSF such as higher cumulative doses of gadodiamide (Collidge et al, 2007), dosing interval and high levels of ionised calcium and phosphorus. Consequently the EMA requested all GdCA MAHs to conduct studies of gadolinium accumulation in human bones with samples from hip and knee replacement surgery. Co-factors that may increase the risk of NSF, such as calcium and phosphate levels at the time of administration of a gadolinium contrast agent were also requested to be studied and biomarkers need to be evaluated. The MAHs were also requested to submit a cumulative review on NSF cases annually for 3 years from IV.2 Clinical aspects 1. Introduction is a linear non-ionic gadolinium containing contrast agent (GdCA) used during magnetic resonance imaging (MRI) procedures. Due to its paramagnetic properties it shows up as bright on T1- weighted images. The aim is to provide diagnostic information, including differentiation of tumour from oedema and inflammation, and soft tissue from scar tissue. It is also intended to facilitate the assessment of lesion types (for example hepatic hemangiomas vs. hepatocellular carcinoma). In the brain, gadolinium-enhancement reveals areas where the blood-brain barrier has been breached, providing information on patients with tumours and other pathologic processes i.e. meningoencephalitis. It is used exclusively by intravenous route with 0.1mmol/kg as a single dose in most of the MRI procedures. Nephrogenic Systemic Fibrosis (NSF) was noted to occur predominantly in patients with endstage renal disease who were administered gadolinium based contrast agents (GdCAs). In December 2007 the Committee for Medicinal Products for Human Use (CHMP) Scientific Advisory Group (SAG) for Diagnostics categorised the gadolinium contrast agents into three groups of NSF risk based on their thermodynamic and kinetic properties. was classified as a high risk agent by the CHMP SAG. 2. Clinical studies The MAH submitted the following data: Synopsis of nine clinical studies conducted by the MAH. Abstracts of 13 relevant studies published in the literature on the efficacy of gadodiamide in children. Periodic Safety Update Report (PSUR) with a Data Lock Point (DLP) 31 st January SW 1357 Phase III This was a Phase III, double-blind, randomized, parallel-group, multicenter, comparative study conducted to evaluate the safety and efficacy of gadodiamide, compared to gadopentetate, when administered intravenously for MRI of the central nervous system (CNS) in paediatric patients. Study centers were randomized to one of two groups (A and B) to be analysed and reported as two independent studies. This report summarized the results from Study A. Each center was stratified by age (2 to <7 years and 7 to 18 years) to ensure the equal distribution of and gadopentetate patients across the full range of ages and to ensure that the minimum number of patients in UK/W/063/pdWS/001 Page 10/46

11 each age group received contrast agent. Results from the companion study (Study B) are reported in Study Report and gadopentetate were administered as a single peripheral bolus injection at a dose of 0.1 mmol/kg (0.2 ml/kg). In this study, 40 patients received and 43 patients received gadopentetate. All efficacy results for the brain and spine were pooled together. provided added diagnostic value for 79% (31/39) of all patients and for 89 % (24/27) of patients with an abnormality. Gadopentetate provided added diagnostic value for 77% (33/43) of all patients and for 77% (24/31) of patients with an abnormality. There was a statistically significant increase in the grading of the quality of delineation from pre- to postinjection in both contrast agent groups. New information was obtained on post-injection scans that assisted in patient management for 72% (28/39) of the patients in the group and for 65% (28/43) of the patients in the gadopentetate group. Both and gadopentetate were well-tolerated. One of the 40 patients (3%) in the group (7 to 18 years of age) was reported to have experienced 1 severe adverse event (abnormal hepatic function) which was considered to be of uncertain relationship to the study drug. Six of the 43 patients (14%) in the gadopentetate group reported a total of 8 adverse events (2 to <7 year age group: 4 patients, 6 events; 7 to 18 year age group: 2 patients, 2 events). AEs reported by patients in the gadopentetate group included two reports of nausea and single reports of diarrhoea, epistaxis, fever, maculo-papular rash, vertigo, and vomiting. The one episode of vertigo was the only adverse experience considered by the investigator to be related to study drug. No statistically significant differences were observed between contrast agent groups in the overall proportion of patients reporting AEs. Two of 40 patients (5%) who received and 2 of 43 patients (5%) who received gadopentetate reported injection-associated discomfort of a sensation of cold. No clinically significant trends were observed in vital signs. In both contrast agent groups, the majority of laboratory value changes from pre- to post-injection in haematology and biochemistry parameters remained within the reference range. This was a phase III, double blind, multicentre, comparator trial for the analysis of safety and efficacy of gadodiamide in 83 children ( 40, gadopentetate 43) from 2 to 18 years of age. The MAH has submitted only a synopsis of the trial report as this has been assessed previously as a part of the MA application. The trial documented that gadodiamide had a diagnostic efficacy of 79% and a therapeutic efficacy of 72%. There were only commonly known ADRs reported in the trial for both and gadopentetate. The study had the following limitations in the design and analysis: - It was not designed to establish the superiority or non- inferiority of gadodiamide compared to gadopentetate. - The synopsis does not mention any power analysis for sample size calculation and there was no statistical analysis mentioned in the report. In summary, despite these limitations, it provided evidence on the efficacy and safety of gadodiamide in children from 2 to 18years of age. SW1358 Phase III This report summarizes the results from Study B. This was a Phase III, double-blind, randomized, parallel-group, multicenter, comparative study conducted to evaluate the safety and UK/W/063/pdWS/001 Page 11/46

12 efficacy of gadodiamide injection, compared to gadopentetate, when administered intravenously for MRI of the central nervous system (CNS) in paediatric patients. and gadopentetate were administered as a single peripheral bolus injection at a dose of 0.1 mmol/kg (0.2 ml/kg) to 45 and 46 patients respectively. All efficacy results for the brain and spine were pooled together. provided added diagnostic value for 73% (33/45) of all patients and for 81 % (21/26) of patients with an abnormality. Gadopentetate provided added diagnostic value for 74 % (34/46) of all patients and for 80% (24/30) of patients with an abnormality. There was a statistically significant increase in the grading of the quality of delineation from pre- to postinjection in both contrast agent groups. New information was obtained on post-injection scans that assisted in patient management for 36% (16/45) of the patients in the group and for 26% (12/46) of the patients in the gadopentetate group. Both and gadopentetate were well-tolerated. None of the 45 patients in the group reported any adverse event. Two of the 46 patients (4%) in the Gadopentetate group reported an adverse event only one of which, in the 7 to 18 year age, group (urticaria) was considered related to the study drug Gadopentetate. No statistically significant differences were observed between contrast agents groups in the overall proportion of patients reporting adverse experiences. Three of 45 patients (7%) who received and 3 of 46 patients (7%) who received gadopentetate reported injection-associated discomfort, i.e. sensation of cold, warmth and pain. No clinically significant trends were observed in vital signs. In both contrast agent groups, the majority of laboratory value changes from pre- to post-injection in haematology and biochemistry parameters remained within the reference range. This is the part B of the previous trial. This was a phase III, double blind, multicentre, comparator trial for analysis of safety and efficacy of gadodiamide in 91 children ( 45, gadopentetate 46) from 2 to 18 years of age. The MAH has submitted only a synopsis of the trial report as this has been assessed previously as a part of the MA application. The trial documented that gadodiamide had a diagnostic efficacy of 73% and a therapeutic efficacy of 36%. There were only commonly known ADRs reported in the trial for both and gadopentetate. This study had similar limitations in the design and analysis as discussed above. The MAH did not provide the reasons for the very low therapeutic efficacy of gadodiamide identified in this study (36% compared to 72% in the previous study), even though the study design, conduct and analysis were the same across both studies. SOV033 Phase IV This was a phase III, double-blind, parallel-group, randomized, comparative, two-centre study of gadodiamide injection and Gadopentetate at 0.1 mmol/kg in MRI examinations of the CNS in children and adolescents between 2 and 18 years of age who had a proven or suspected CNS tumour. The study was conducted at Hamburg (0.5 T MRI unit) and at Cologne (1.5T MRI unit), Germany. The trial was designed to include 60 patients in group and 40 patients in Gadopentetate group; at the end of the trial, the patients included were 57 and 39 respectively. The main parameter in this study related to safety and measurements of heart rate were obtained, 2 measurements were before and 5 after contrast injection. Other safety parameters were the occurrence of adverse events, injection associated discomfort and changes in blood pressure variables (diastolic, systolic and mean arterial blood pressure). The efficacy was evaluated by the ability of the contrast media to visually enhance lesions/tumours and from the UK/W/063/pdWS/001 Page 12/46

13 amount of diagnostic information provided. T1-weighted images were obtained before and after injection of contrast; T2-weighted images were obtained before contrast injection. There was only one AE of mild diarrhoea of relatively short duration (30 mins) reported in a patient in the gadodiamide group which was classified as uncertain. The main aim of the statistical analysis was to estimate the expected difference between the two contrast media in the extent of the change in heart rate immediately after their administration. The analysis showed that, with a 95% level of confidence, the difference would lie within the range of to beats per minute concluding that the difference would be of no clinical relevance. Contrast enhancement was seen in the region of interest in 46% and 39% of the patients who received and Gadopentetate respectively. The diagnostic efficacy post-contrast compared to pre-contrast was 48 and 39% respectively in patients who received and Gadopentetate. The injection of gadodiamide was helpful for determining tumour/lesion size, vascularisation and internal structure in 50, 65 and 81% of the cases in which there was contrast enhancement in the region of interest; the respective figures in the Gadopentetate group were 60, 40 and 73%. injection, at a dose of 0.1 mmol/kg, was shown to be very safe, well tolerated and effective in MRI examinations of the CNS in this population of children and adolescents. There was no statistical difference between the two contrast media as regards changes in heart rate immediately after injection. This was a phase III study which has been evaluated before by a competent authority (CA) as a part of the MA dossier. The study included 96 children (57 in the and 39 in the Gadopentetate group) aged 2 to 18 years and was designed for safety analysis as a primary endpoint and efficacy as the secondary endpoint. Analysis of changes in heart rate, pre and post contrast injection, showed no statistical difference. There were no significant adverse events reported. There was contrast enhancement in the region of interest in only 46% of children receiving gadodiamide and 39% of children receiving Gadopentetate. The study reports a diagnostic efficacy of 48% in gadodiamide group and 39% in Gadopentetate group. This study was specifically designed for safety analysis which was conducted and presented very well. This study proved that both gadodiamide and Gadopentetate had no effect on the heart rate and blood pressure of children treated with these agents. The MAH did not discuss the reasons for the significantly lower diagnostic efficacy in both groups of contrast agents compared to previous studies in children and adults. However, it is acknowledged that the trial was not designed for efficacy analysis. In summary, the study provided evidence on the immediate safety of the use of gadodiamide in children from 2 to 18 years of age. SW1356 Phase III This was a Phase III, open-label, multicenter study conducted to evaluate the safety and efficacy of gadodiamide injection for MRI of the central nervous system (CNS) in children less than 2 years of age. was administered at a dose of 0.1 mmol/kg (0.2 ml/kg) to 13 children with a mean age of 9.1 months (SD of 5.8months), enrolled at four study centres. All pre- and post-injection images were evaluated for efficacy by the on-site investigator as well as by an independent blinded reviewer (see Figure 1 below). These results reflect the differences in the approach and in the interpretation of the findings by the on-site investigator and the independent blinded reviewer. The MAH states that the evaluation of the MRI scans by UK/W/063/pdWS/001 Page 13/46

14 the on-site investigator, having full access to clinical information, mirrors that of the true clinical situation and these results are the primary focus of this report. The primary efficacy parameters were the presence or absence of abnormalities, contrast enhancement, value of contrast agent in patients with normal post-injection scans, added diagnostic value, change in diagnostic confidence, and patient management. The on-site investigator s review of the pre-injection T1 and post-injection T1 scans assessed the presence or absence of abnormal structures or lesions in all 13 patents. Five patients (38%) had no abnormalities seen on any scan and eight patients (62%) had lesions/abnormalities observed on both pre-injection T1, and post-injection T1 scans. Contrast enhancement was reported for 54% (7/13) of all patients and for 38% (3/8) of patients with an abnormality. For the five patients with normal post-injection scans, the investigator determined to be of value for four patients (80%). There were six patients with no contrast enhancement. This lack of enhancement confirmed a normal preinjection diagnosis for one patient by increasing the confidence that no regions of encephalitis were observed. The investigator offered no comments as to the benefits associated with the lack of contrast enhancement for the remaining five patients, all of whom had abnormal preinjection diagnoses. Of the seven patients with enhancement, there was enhancement of an abnormality (a cyst wall) in only one patient (14%), while all seven patients had enhancement of normal tissue. Lack of enhancement of an abnormality indicated that there was no active inflammatory process, such as ventriculitis, for one patient whose pre-injection diagnosis was cystic encephalomalacia. In addition, lack of enhancement of an abnormality made the presence of cerebral haemophagocytic lymphohistiocytosis (HLH) less likely for another patient whose pre-injection diagnosis was mildly delayed myelination with no evidence of HLH. provided added diagnostic value for 77% (10/13) of all patients and for 63% (5/8) of patients with an abnormality. There was a statistically significant difference (p=0.003) between the proportion of patients with an increase in diagnostic confidence (69%, 9/13) from pre- to post-injection. New information was obtained on the post-injection scans that assisted in patient management for 54% (7/13) of the patients. The new information included the lack of enhancement of an abnormality as confirmation of a normal pre-injection diagnosis for four patients and as indicative of no active inflammatory processes, such as ventriculitis, in one patient. was well-tolerated. One AE was reported in 2 of 13 patients (15%). One patient experienced fever that was considered by the investigator to be of mild intensity and of uncertain relationship to. The patient was treated with paracetamol. The other patient experienced a rash that was considered by the investigator to be of mild intensity and related to. The onset of this event occurred approximately 6 hours following the administration of, and continued for 1.5 hours. No treatment was required. Both patients recovered from these events. No patient was discontinued from the study due to an adverse experience or had an adverse experience that was considered by the sponsor or investigator to be serious and no patient deaths were reported. Injection-associated discomfort was not reported for any patient by the physician administering the contrast agent. No clinically important trends in vital sign changes were apparent after the administration of. UK/W/063/pdWS/001 Page 14/46

15 Figure 1: Efficacy analysis for study SW1356 This was a phase III efficacy trial of gadodiamide for CNS lesions in 13 children under 2 years of age. The pre and post contrast images were reviewed by an onsite investigator with access to full clinical information and by a blinded off-site investigator (no access to clinical information) which has led to discrepancies in the analysis. Blinded image evaluations by independent readers are recommended for phase III efficacy trials, with the use of appropriate reading grids and an overall evaluation of accordance should be proposed e.g. using the kappa coefficient. The MAH has discussed discrepancies in interpretations between the readers and their potential consequences in terms of patient management. Thus there was a diagnostic efficacy range from 54 to 77% and therapeutic efficacy of 54% in the study. The study had one related and one unrelated adverse event, both of which are known and well described in the SmPC. There was no influence from the contrast agent on vital signs and biochemical laboratory parameters. The study has following limitations in the design and analysis: - There is no power analysis or justification given for the study population. UK/W/063/pdWS/001 Page 15/46

16 - The study should have appropriate primary efficacy endpoints, mainly in terms of diagnostic performance (sensitivity and specificity), predictive values, likelihood ratios, prognostic evaluation, impact on diagnostic thinking and/or on patient management or on clinical outcome. - Although the technical performance and the diagnostic impact of the contrast agent is analysed in the study, it was only done with percentages rather than sensitivity/specificity or Positive Predictive Value/Negative Predictive Values (PPV/NPV). In summary, the study has several limitations in design and analysis hence it provides limited efficacy data on the use of gadodiamide in children under 2 years of age. Nevertheless, gadodiamide was safely administered to the children included in the study. ISOVO26 Phase II/III An open phase II/III study was performed to evaluate the safety and contrast enhancing ability of gadodiamide injection when injected intravenously as a bolus for MRI imaging of the musculoskeletal system at a dose of 0.3mmol/kg. (0.6ml/kg). Fifty patients mean age 41 years (SD 18.6 years) were enrolled in the trial. Adverse events other than discomfort were reported in two patients. One severe deep venous thrombosis occurred the night after the MRI examination and was considered as a serious disease-related ADR, caused by the enormous tumour compressing the veins. The other patient reported a strange taste of mild intensity. This was considered as related to the contrast medium. Thirty-four patients experienced discomfort, described mainly as sensation of warmth or coldness, and related to the rapid injection of the contrast medium followed by the saline flush. All but one patient had abnormal findings on both pre- and post-contrast scans and contrast enhancement in the region of interest was usually seen. The injection of contrast medium improved lesion delineation in 65% of the cases subject to improvement. The proportion of patients presenting more diagnostic information on post- compared to pre-contrast T1-weighted scan was 88% [95% CI ]. The diagnosis was modified as a consequence of contrast injection in 24% of the patients and confirmatory information was obtained in the follow-up period for 96% of the patients. The MAH concluded that the dose of 0.3 mmol/kg gadodiamide injection was safe and well tolerated and useful for the diagnosis and characterization of the lesions in this patient population with musculoskeletal pathology. This study was conducted in adults and no specific demographic profile of the participants was presented in the synopsis. Furthermore, the dose used for the MRI scan was 0.3 mmol/kg, which is higher than the currently recommended dose (0.1mmol/kg) for the paediatric population. Therefore this study does not provide any relevant paediatric information. SOVO32 Phase III An open phase III study was conducted to evaluate the efficacy and safety of gadodiamide injection at a dose of 0.1 mmol/kg in MRI examination of the CNS and whole body in children between 6 months and 12 years of age. Fifty patients were included, 18 with CNS pathology and 32 with pathology in other body areas. The main aim of this study related to safety and on whether gadodiamide injection influenced the heart rate. Other safety parameters were percentage venous blood oxygen saturation, and adverse events including injection-associated discomfort/distress. The usefulness of administration of the contrast medium (i.e. efficacy) was evaluated from the ability of gadodiamide injection to visually enhance lesions/tumours and from the amount of diagnostic information provided (see Figure 2 below). UK/W/063/pdWS/001 Page 16/46

17 T1-weighted images were obtained at 0.5 T before and after injection of contrast, and in three cases T2-weighted images were also obtained before contrast injection. One adverse event was recorded for each of seven patients; two of those events (headache and cutaneous flush) were considered as of uncertain relationship and five of no relationship to the injection of contrast medium. The statistical analysis performed on heart rate data obtained from the entire trial population revealed no overall variation in heart rate over time (p-0.63) i.e., administration of gadodiamide injection had no significant effect on heart rate. Figure 2: Results for the SOV032 study This was a phase III study to evaluate safety (i.e. influence on HR) of gadodiamide as a primary endpoint and efficacy as a secondary endpoint in children from 6 months to 12 years. The study concluded that there was no statistically significant change in the heart rate. There were no significant or unknown adverse events reported in the study and the incidence was comparable to the other studies. The report does not mention monitoring of biochemical parameters. The secondary endpoint was evaluated by comparing only pre and post-contrast T1 images in the majority of the children, as only 3 children had pre contrast T2 images. Despite this major limitation, there is no difference in the number of patients with abnormal structures detected in pre and post contrast scans (first line in Figure 2 above). There was contrast enhancement reported in 70% of children. Comparing the quality of tumour/lesion delineation in post T1 vs. pre T1 scans, there was improvement in 23 out of 41 cases. Since the study was not designed for evaluation of the therapeutic efficacy, this is not reported. In summary, the study provided safety information regarding the heart rate and vital signs immediately following the use of gadodiamide as a contrast agent for MRI in children from 6 months to 12 years of age. SOVO31 Phase III This open non-comparative phase III study was conducted to evaluate the safety and efficacy of gadodiamide injection in 100 children between 6 months and 14 years of age, at a dose of 0.1 mmol/kg during CNS MRI examination. The main parameter in this study was related to safety and six measurements of heart rate were obtained, 3 before and 3 after contrast injection to analyse whether gadodiamide injection influenced the heart rate. The occurrence of adverse events was recorded. The usefulness of administration of the contrast medium (i.e. efficacy) was evaluated from the ability of gadodiamide injection to visually enhance lesions/tumours and from the amount of diagnostic information provided. T1-weighted images were obtained before and after injection of contrast; T2-weighted images were obtained only before contrast injection. UK/W/063/pdWS/001 Page 17/46

18 Two adverse events were recorded one each for two patients; both events (i.e. bradycardia and shortness of breath) were present before contrast injection and they were classified as having no relationship to gadodiamide. Heart rate data from 97 patients were included in the statistical analysis. Of these patients, 61 underwent general anaesthesia before the MRI examination was started. The difference in mean heart rate at the start of the procedure (i.e. before eventual anaesthesia) between the anaesthetized and non-anaesthetized groups was statistically significant (p<0.001); the patients in the group to be anaesthetized had on average a higher (15 beats per minute) heart rate. The main endpoint for statistical analysis was the changes in heart rate after injection of contrast and variations in heart rate over time by repeated measures analysis of variance. All mean changes in heart rate were not clinically significant. The statistical analysis revealed no overall variation in heart rate over time (p=0.70); i.e. injection of gadodiamide overall had no statistically significant effect on heart rate. Ninety-nine patients were included in the efficacy analysis and lesions/tumours were detected pre- or post-contrast in 80 patients. More diagnostic information was acquired in 42 patients following injection of contrast. Comparing pre- and post-contrast T1-weighted images, in 15 patients more lesions were seen; in 14 cases lesion/tumour delineation was improved; in 8 patients the diagnosis was modified; in 20 cases evaluation of the internal structure of the tumour/lesion was aided; in 25 patients evaluation of tumour/lesion size was aided and in 11 cases patient management was influenced. injection at a dose of 0.1 mmol/kg was shown to be safe and effective in MRI examinations in this population of children. No post-injection change in heart rate the main safety parameter - was considered as clinically important or associated with the injection of gadodiamide. This was a phase III study evaluating the safety (i.e. influence on heart rate) of gadodiamide as a primary endpoint and efficacy as a secondary endpoint in children between 6 months and 14 years of age. The study concluded that there was no statistically significant change in heart rate. There were no significant or unknown adverse events reported in the study and the incidence was comparable to other paediatric studies. The report does not mention whether any biochemical parameters were monitored. The efficacy of the images was analysed by comparing post-contrast T1 and pre-contrast T2 images. The study reports a diagnostic efficacy of 29-42% and therapeutic efficacy of about 11%. The study was not powered to analyse the efficacy of the drug and hence the results need to be interpreted with caution. UK/W/063/pdWS/001 Page 18/46

19 Figure 3: Efficacy results in studysov031 SOVO35 Phase II/III This was a open label, non-comparative phase II/III study conducted to evaluate the diagnostic utility, safety and tolerability of gadodiamide injection when used at a dose of 0.1 mmol/kg in MRI examinations of the body (excluding the CNS) in children and adolescents. Fifty patients between 2 and 17 years of age were included. As a minimum, T1-weighted images were obtained before and after injection of contrast and in many cases, T2-weighted images were obtained before contrast injection. The main question of this study related to efficacy and was whether administration of gadodiamide injection influenced the amount of useful diagnostic information in MRI images. For this purpose, pre-contrast images (both T1W and T2W, where available) and post-contrast T1W images were compared. Diagnostic information was assessed separately by both an investigator (observer 1) and another independent radiologist (observer 2). In all patients, safety and tolerability were assessed based on the occurrence of adverse events and the changes in heart rate after contrast injection. In patients up to 15 years old, safety was also assessed by monitoring post-contrast injection changes in clinical chemistry parameters in blood and urine. The main aim of the statistical analysis was to estimate the probability of contrast-enhanced images obtained per patient providing more diagnostic information than the unenhanced images. The study reported diagnostic efficacy to be 70.4% with 95% confidence interval (59% to 81.7%). No adverse events were recorded. There was no significant change in the heart rate on pre and post-contrast measurements. None of the post-injection changes in biochemistry parameters UK/W/063/pdWS/001 Page 19/46

20 monitored in blood and serum or urine was considered as clinically important or as related to the injection of gadodiamide. The MAH concluded that gadodiamide injection at a dose of 0.1 mmol/kg was shown to be safe and effective in MRI examinations in children between 2 to 17years of age. Both observer 1 and observer 2 agreed that injection of gadodiamide improved the amount of diagnostic information - the main trial parameter - in the majority of cases; 80 and 61% respectively. This is a well conducted open label, non-comparative, phase II/III study in children aged 2 to 17 years. The MAH has provided an explanation for the non-comparative trial as there was no comparative drug registered at the time of the trial. The study design is also considered appropriate; images were read by 2 readers, the procedure and reporting and predetermined criteria of the efficacy are well defined. Analysis of safety parameters is also considered acceptable. Although the study was not powered for an efficacy analysis, the reporting of the confidence interval for efficacy provides assurance for the interpretation of the results. The study reports a diagnostic efficacy of about 70% with no significant change in vital parameters and laboratory findings. There were no significant adverse events reported in the trial. In summary, the rapporteur considers this study to be well designed and it provided data on safety and efficacy of gadodiamide as a contrast agent for MRI of whole body in children from 2 to 17 years of age. SOVO51 Phase III This was a phase III open multicentre study conducted to evaluate the safety and efficacy of at 0.1 mmol/kg used for MRI in children below six months of age 59 patients were analyzed: 39 with contrast and 20 without contrast. MRI examination, pre- and post-image evaluation, blood and urine sampling before sedation and after examination, heart rate and oxygen saturation during examination, adverse events and efficacy parameters were documented. The following criteria were used for evaluation of efficacy: The diagnostic utility of the MRI examination with or without contrast medium (control group) was based on the following set of recordings: 1) Pre-contrast diagnosis based on unenhanced MRI only 2) Post-contrast diagnosis modified from pre-contrast diagnosis (yes/no) 3) Detection of abnormal structures or lesions (yes/no) for each pulse sequence 4) Number of lesions for each pulse sequence 5) Grading of quality of lesion delineation (poor, adequate, excellent) for each pulse sequence 6) Contrast enhancement in the pathological area of interest (yes/no) 7) Diagnostic information comparing post- to pre-contrast images (less, equal, more) 8) New information affecting patient management (yes/no for post-contrast images) 9) Overall quality of the images 10) Diagnostic gain of the contrast-enhanced MRI compared to non-contrast enhanced MRI 11) Confidence in diagnosis (low, moderate, high) for non-contrast enhanced and contrast enhanced MRI The independent reader answered the same questions concerning the efficacy as the onsite investigator. However the independent reader received only the images and no further information about the patient. The safety parameters recorded in this study were serum parameters (Serum creatinine, ASAT, ALAT, bilirubin, alkaline phosphatase) and urine parameters (proteins, blood, others) and heart UK/W/063/pdWS/001 Page 20/46