public assessment report for paediatric studies submitted ... · sandimmun/sandimmun neoral...

Sandimmun/Sandimmun Neoral D_W_089_pdWS_001 /24

Public Assessment Report for paediatric studies submitted in accordance

with Article 46 of Regulation (EC) No1901/2006, as amended

SANDIMMUN/SANDIMMUN NEORAL Ciclosporin

DE/W/089/pdWS/001

Marketing Authorisation Holder: Novartis Rapporteur: Germany (DE BfArM)

Finalisation procedure (day 120): 30.03.2020

Sandimmun/Sandimmun Neoral DE_W_089_pdWS_001 /24

TABLE OF CONTENTS I. Executive Summary ......................................................................................................... 5

II. RecommendatioN ............................................................................................................ 5

III. INTRODUCTION ............................................................................................................... 5

IV. SCIENTIFIC DISCUSSION ............................................................................................... 5

IV.1 Information on the pharmaceutical formulation used in the studies ............................ 5

IV.2 Clinical aspects ............................................................................................................................ 6

V. INITIAL Rapporteur’s Overall Conclusion AND RECOMMENDATION ...................... 13

VI. INITIAL Request for supplementary information ........................................................ 13

VII. Assessment of response to INITIAL questions .......................................................... 15

VIII. Rapporteur’s DAY 90 Overall Conclusion AND RECOMMENDATION ...................... 17

IX. ASSESSMENT OF APPLICANT’S DAY 90 RESPONSE .............................................. 17

X. Rapporteur’s Overall Conclusion AND RECOMMENDATION .................................... 19

XI. Supplementary information .......................................................................................... 20

XII. ASSESSMENT OF APPLICANT’S DAY 120 RESPONSE ............................................ 21

XIII. Final Rapporteur’s Overall Conclusion AND RECOMMENDATION .......................... 22


ADMINISTRATIVE INFORMATION

Invented name of the medicinal product:

SANDIMMUN/SANDIMMUN NEORAL

INN (or common name) of the active substance(s):

Ciclosporin

MAH: Novartis

Currently approved Indication(s) Transplantation indications Solid organ transplantation Prevention of graft rejection following solid organ transplantation.

Treatment of transplant cellular rejection in patients previously receiving other immunosuppressive agents.

Bone marrow transplantation Prevention of graft rejection following allogeneic bone marrow and stem cell transplantation.

Prevention or treatment of graft-versus-host disease (GVHD).

Non-transplantation indications Endogenous uveitis Treatment of sight-threatening intermediate or posterior uveitis of non-infectious aetiology in patients in whom conventional therapy has failed or caused unacceptable side effects.

Treatment of Behçet uveitis with repeated inflammatory attacks involving the retina in patients without neurological manifestations.

Nephrotic syndrome Steroid-dependent and steroid-resistant nephrotic syndrome, due to primary glomerular diseases such as minimal change nephropathy, focal and segmental glomerulosclerosis, or membranous glomerulonephritis.

Sandimmun can be used to induce and maintain remissions. It can also be used to maintain steroid-induced remission, allowing withdrawal of steroids.


Rheumatoid arthritis Treatment of severe, active rheumatoid arthritis.

Psoriasis Treatment of severe psoriasis in patients in whom conventional therapy is inappropriate or ineffective.

Atopic dermatitis Sandimmun is indicated in patients with severe atopic dermatitis when systemic therapy is required.

Pharmaco-therapeutic group (ATC Code):

Immunosuppressive agents, calcineurin inhibitors (L04AD01)

Pharmaceutical form(s) and strength(s):

25 mg, 50 mg soft gelatin capsules, 100 mg/mL oral solution, 50 mg/mL concentrate for solution for infusion for Sandimmun, 10 mg, 25 mg, 50 mg soft gelatin capsules 100 mg/mL oral solution for Sandimmun Neoral


I. EXECUTIVE SUMMARY No SmPC and PL changes were proposed at the start of the procedure. In response to the draft AR the MAH proposed in response to the day 90 AR the following SmPC change (subheading 5.1): ‘A post-marketing surveillance study conducted in 92 lung transplant Japanese patients (including 13 paediatric patients) has shown a statistically significant difference in rejections that occurred in patients less than 15 years old, when compared to patients aged 15 years and older. However, these results are considered inconclusive and cannot be generalized to the overall paediatric transplant population.’ After the MAH was requested to provide clarification on the data submitted and the clinically relevance for the change, the MAH proposed to not implement the SmPC wording. It was recommended to the applicant conducting a cumulative review of all post-marketing and clinical studies involving paediatric and adult lung transplantation, and to submit a type II variation provided that the requested review would require an update of the SmPC. The MAH has submitted a comprehensive review of all post-marketing and clinical studies involving paediatric and adult lung transplantation II. RECOMMENDATION1 No SmPC changes are required. III. INTRODUCTION On 05 May 2015, the MAH submitted 4 Japanese post-marketing surveillance studies (PMS), partially as complete reports in Japanese language, partially as synopses in English language (study codes COLO400EJP06, COLO400EJP08, COLO400D1401and COLO400JJP15) investigating Sandimmun and/or Sandimmun Neoral, in accordance with Article 46 of Regulation (EC) No1901/2006, as amended, on medicinal products for paediatric use. A short critical expert overview has also been provided. The MAH stated that the submitted paediatric studies do not influence the benefit risk for Sandimmun and/or Sandimmun Neoral and that there is no consequential regulatory action. IV. SCIENTIFIC DISCUSSION IV.1 Information on the pharmaceutical formulation used in the studies The MAH provided a summary of Post Marketing Surveillance studies (PMS) in Japan. According to the MAH, a PMS is non-interventional surveillance under normal medical practice unlike a Clinical trial which is an interventional study. In addition, marketed drug are purchased by patients in a PMS, whereas drug for clinical trial is provided by the Sponsor.

1 The recommendation from section V can be copied in this section


These PMS included adult and pediatric patients treated with either Sandimmun or Sandimmun Neoral for cardiac transplantation (study code COLO400EJP06), lung transplantation (study code COLO400EJP08), and with Sandimmun Neoral for treatment of atopic dermatitis (study code COLO400D1401) and treatment of systemic myasthenia gravis (study code COLO400JJP15). IV.2 Clinical aspects

1. Introduction Of note, the definition of the pediatric population is different in Japan (age <15 years) than in Europe (age <18 years). The pediatric population reported in Japanese studies is therefore more restricted than in Europe. For this reason and for the sake of completeness, a separate description of the events reported in patients of 15-17 years of age is also provided for each study. The MAH submitted 4 (Japanese) reports/ (English) synopses for:

• study COLO400EJP06: in cardiac transplantation • study COLO400EJP08: in lung transplantation • study COLO400D1401: treatment of atopic dermatitis • study COLO400JJP15: treatment of systemic myasthenia gravis

The following table provides an overview of studies submitted, as well as the density of information available in English and Japanese language each:


2. Clinical studies Study COLO400EJP06: Special Drug Use Observational Study of Neoral® / SANDIMMUN® on Japanese heart transplantation patients (title according to the synopsis) Description The COL0400EJP06 is a Japanese post marketing surveillance (J-PMS) which is required by the Pharmaceutical Affairs Law and must be conducted in accordance with GPSP, Japanese regulations. The design is multi-centre, open-label, not-control, multiple doses, non-interventional, prospective observational study. Prior to the site initiation of this J-PMS, the contract for the surveillance must be concluded between NPKK and the medical institution. After the contract was concluded, the patient registration form and this investigation form are filled in for the patients planned to begin receiving treatment with this marketed drug. The patient registration form, with necessary entries and signature or seal, is immediately mailed to the Case Registration Center to complete the registration. In principle, the observation period for each new transplant patient is 3 years (at time of transplantation, 1-, 3-, and 6-months post-transplantation and, if possible, 1-, 2-, and 3-years post transplantation for maintenance/long-term results) and, for previous transplantation patients, until the time of registration (if possible, at time of transplantation, 1-, 3-, and 6-months


post transplantation and 1-, 2-, 3-, 5-, and 10-years [at time of final observation] post-transplantation for maintenance/long-term results). The investigators describe the safety and efficacy data into the CRFs as soon as completion of observation period and NPKK collects CRFs from the investigators. NPKK carries out the statistical analysis and prepare the interim report, and it is submitted to PMDA annually. Methods

Measurement • Patient's background • Status of administration of Neoral®/Sandimmun® • Drug withdrawal status, drug withdrawal period, reason for withdrawal • Status of administration of concomitant medications • Blood concentration of cyclosporine • NYHA functional classification • Cardiac function tests • Blood pressure • Renal function tests • Periodic endomyocardial biopsy • Rejection • Engraftment of heart • Discontinuations/withdrawals • Adverse events

Results

• Recruitment/ Number analysed A total of 78 cardiac transplant patients participated in a Japanese PMS study of Sandimmun and Sandimmun Neoral (study code COLO400EJP06).

• Baseline data 22 were pediatric patients of less than 15 years of age (age 7.2±4.9 years, [mean±SD] range 1-15 years).

• Efficacy results

Graft survival was 100 % in pediatric patients (22/22 patients) and showed no difference as compared to 98.11% graft survival (52/53 patients) in patients aged 15 years and older. Also, the incidence of rejection in pediatric patients was 47.62% (10/21 patients), a rate similar to that in patients aged 15 years and older (38.46%, 20/52 patients). Patients in the 15-17 years age range One male and one female patient were 16 years old. One adverse reaction of renal failure (not recovered) was reported at month 36 in the male subject. No efficacy data was available.

• Safety results

The incidence of adverse drug reactions (ADRs) in pediatric patients less than 15 years was 54.55% (12/22 patients), no different from that in patients aged 15 years and older, which was 50.94% (27/53 patients).


In pediatric patients less than 15 years of age, 31 ADRs were noted in 12 patients. Among them, serious ADRs were pneumonia (2 events), and gastroenteritis, tonsillitis, lung infection, oral herpes, lymphomas, breast fibroma, Epstein-Barr virus associated lymphoproliferative disorder, pancytopenia, renal tubular acidosis, and renal impairment (1 event each). There were no particular ADRs that occurred more frequently in pediatric patients. Non-serious ADRs were hypertension (5 events), sinusitis (2 events), and Epstein-Barr virus infection, otitis media, anemia, hypercholesterolemia, hyperuricaemia, hyperlipidemia, renal impairment, developmental delay, blood creatine phosphokinase increased, blood creatinine increased, drug level increased, and immunosuppressant drug level decreased (1 event each). Unknown ADRs were as follows: breast fibroma (outcome: resolving); pancytopenia (outcome: resolved); developmental delay (outcome: unknown because of company’s discretion).

Study COL0400EJP08: Special Drug Use Observational Study of Neoral® I SANDIMMUN® on Japanese Jung transplantation patients (title according to the synopsis) Description The COL0400EJP08 is the Japanese post marketing surveillance (J-PMS) which is required by the Pharmaceutical Affairs Law and must be conducted in accordance with GPSP, Japanese regulations. The design is multi-center, open-label, not-controlled, multiple doses, non-interventional, prospective, observational study. Prior to the site initiation of this J-PMS, the contract for the surveillance must be concluded between NPKK and the medical institution. After the contract was concluded, the patient registration form and this investigation form are filled in for the patients planned to begin receiving treatment with this marketed drug. The patient registration form, with necessary entries and signature or seal, is immediately mailed to the Case Registration Center to complete the registration. The observation period is 10 years at maximum (until the end of re-examination period). The investigators describe the safety and efficacy data into the CRFs as soon as completion of observation period and NPKK collects CRFs from the investigators. NPKK carries out the statistical analysis and prepare the interim report, and it is submitted to PMDA annually. Methods

Measurement • Patient's background • Status of administration of Neoral®/Sandimmun® • Clinical course: Body weight, blood concentration • Other immunosuppressant agents, concomitant drugs and therapies • Efficacy evaluation: Confirm patient survival status and rejection response status at • completion of the observation period • Rejection response • Discontinuation I withdrawal • Adverse events

Results

• Recruitment/ Number analysed


In the drug use-result surveillance specified for Jung transplantation, of 92 patients enrolled, safety and efficacy were assessed on 91 patients as subjects for safety and efficacy analyses except for 1 patient due to duplication.

• Baseline data Among the patients included in the safety analysis set, there were 12 pediatric patients (aged less than 15 years).

• Efficacy results

Survival of pediatric patients was 91.67% (11/12 patients) and showed no difference with the rate of 86.08% (68/79 patients) in patients aged 15 years and older. The percentage of paediatric patients in whom rejection occurred was 91.67% (11/12 patients) while rejection episodes occurred in 56.96% (45/79 patients) of patients aged 15 years and older. Patients in the 15-17 years age range One male patient was 15 years old and experienced an adverse reaction of renal impairment (improving) at month 22. No efficacy data was available.

• Safety results The incidence of adverse drug reactions (ADRs) in pediatric patients less than 15 years of age was 58.33% (7/12 patients) and was no difference from that in patients aged 15 years and older (46.84%, 37/79 patients). Twelve ADRs were noted in 7 pediatric patients less than 15 years of age. Among them, serious ADRs were pneumonia and hepatic function abnormal (2 events each), and aspergillosis, stenotrophomonas sepsis, renal failure, platelet count decreased, leukopenia, and function disorder after bronchotomy (1 event each). Non-serious ADRs were pneumonia and goiter (1 event each). There were no particular ADRs that occurred more frequently in pediatric patients. Unknown ADRs were as follows: goitre (outcome: resolving); function disorder after bronchotomy (outcome: resolved).

Study COLO400D1401 COLO400EJP06: No study title applicable Description The special-use-result survey was conducted in patients who have used Neoral for their “atopic dermatitis (patients not adequately responding to existing treatment)”, an indication of Neoral. The survey was conducted in the institutions supplied of Neoral and available for survey contract, where the enrollment period initiated from 1 December 2008 to 30 June 2010, and survey period from 1 December 2008 to the termination date of the re-examination, 15 October 2012. In this survey, among 245 institutions contracted, 1,201 patients were registered from 227 institutions, and 1,159 CRFs were collected from 223 institutions except for uncollected 30 patients and hospital-transferred 12 patients (the 2 data of before and after the transfer was integrated into 1). Methods


Section methods of the report mentions only that “the Survey method is in accordance with special-use-result survey plan”. Results

A total of 1159 patients suffering from atopic dermatitis participated in a Japanese PMS study of Sandimmun Neoral (study code COLO400D1401), of whom 11 were paediatric patients younger than 15-year old (age 12.7±2.3 years, range 8-15) who were treated with a dose of Sandimmun Neoral of 2.7±0.3 mg/kg for a median duration of 43 days (range 13-804 days). No adverse event was reported in this pediatric population. Patients in the 15-17 years age range There were 26 patients in the 15-17 age range (20 males, 6 females) who were treated with a dose of Sandimmun Neoral of 2.5±0.5 mg/kg for a median duration of 116 days (range 14-564 days). Two adverse reactions were reported, both in male subjects: (i) palpitations on day 28 (recovered) in one case and (ii) hepatic function abnormal (not recovered) on day 141 in the other case. No efficacy data was available.

Study COLO400JJP15: Special Drug Use Observational Study of Neoral® on Japanese Systemic myasthenia gravis patients (title according to the synopsis) Description The COL0400JJPJ5 is a Japanese post marketing surveillance (J -PMS) study which is required by the Pharmaceutical Affairs Law and must be conducted in accordance with GPSP, Japanese regulations. The design is multi-centre, open-labe!, non-control, multiple doses, non-interventional, prospective, observational study. Prior to the site initiation of this J -PMS, the contract for the surveillance must be concluded between NPKK and the medical institution. After the contract was concluded, the patient registration form and this investigation form are filled in for the patients planned to begin receiving treatment with this marketed drug. The patient registration form, with necessary entries and signature or seal, is immediately mailed to the Case Registration Center to complete the registration. The observation period is one-year. The investigators describe the safety and efficacy data into the CRFs as soon as completion of observation period and NPKK collects CRFs from the investigators. NPKK carries out the statistical analysis and prepare the interim report, and it is submitted to PMDA annually. Methods

Measurement

• Patient's background • Drugs used for the treatment of systemic type severe myasthenia gravis before the use

of this drug • Information on the use of this drug • Concomitant drugs • Concomitant therapies • Laboratory test • MG-ADL scale or ADL score


• Efficacy: physician rates the responses of each patient on a three-category scale: (1) effective, (2) in effective and (3) exacerbated.

• Discontinuation of the Drug • Adverse events

Objective(s)

To confirm the long-term safety and efficacy of Neoral® on Japanese Systemic myasthenia gravis patients under actual medical environment.

Study design The design is multi-centre, open-label, non-control, multiple doses, non-interventional, prospective, observational study.

Study population /Sample size A total of 122 patients suffering from myasthenia gravis participated in a Sandimmun Neoral Japanese PMS study (study code COLO400JJP15), of whom one was a 13-year old female pediatric patient who received a dose of Sandimmun Neoral of 3.77 mg/kg (average) for a period of 387 days.

Treatments Sandimmun Neoral

Outcomes/endpoints N/A

Statistical Methods Descriptive statistics were used to evaluate available data from normal medical practice.

Results

Recruitment/ Number analysed A total of 122 patients suffering from myasthenia gravis participated in a Sandimmun Neoral Japanese PMS study (study code COLO400JJP15).

Baseline data One was a 13-year old female pediatric patient who received a dose of Sandimmun Neoral of 3.77 mg/kg (average) for a period of 387 days.

Efficacy results None reported

Safety results


One ADR of hypertrichosis was reported in this pediatric patient. Of note, only in Japan Sandimmun Neoral is indicated for myasthenia gravis (in the case where the effect of steroids is insufficient or the administration is difficult because of adverse reactions in the treatment after thymectomy) based on literature reference and local experience. In EU and other countries myasthenia gravis is not approved indication of Sandimmun Neoral. Patients in the 15-17 years age range There was no patient in this age range.

3. Discussion on clinical aspects

In terms of efficacy, the results in overall 4 different indications (one representing off label use within the EU) observed in observational, mainly safety trials (with no formal CSR, or protocol) for the paediatric population is minimal. The safety in the paediatric population (including the age range 15-17 years) was not different compared to the elder subpopulations of each of the trials, and as labelled. V. INITIAL RAPPORTEUR’S OVERALL CONCLUSION AND

RECOMMENDATION Overall conclusion As an interim conclusion of the RMS it can be stated that in view of the methods of the 4 clinical trials assessed (plus further obstacles caused by the language of the CSRs) the RMS has not updated the preceding sections after having received CMS comments. However, based on the main message of both CMS comments received - i.e. the significantly different rejection rate in the paediatric compared to the adult lung transplant population (91.67% v. 58.33%) as reported in the synopsis of trial COLO400EJP08 – the RMS concludes that trials COLO400EJP06, COLO400D1401, and COLO400JJP15 do not affect B/R in granted paediatric indications and do not require regulatory action. As to trial COLO400EJP08 further clarifications by the MAH are required in order to draw a final overall conclusion as to the B/R in the indication (having a very general wording in the SmPC) prophylaxis of rejection after organ transplantation, concrete organ lung, in children, and as to potential regulatory actions required thereof. Recommendation Based on the data submitted, the MAH should provide clarifications as to lung transplant trial COLO400EJP08 as part of this worksharing procedure (see section VI “Request for Supplementary Information”) VI. INITIAL REQUEST FOR SUPPLEMENTARY INFORMATION The following CMSs comments have been received by RMS :

Comment CMS:


We generally endorse the assessment report by the Rapporteur. However, we notice a somewhat surprisingly high rejection rate among the paediatric lung transplant recipients (91.67 % compared to 56.96 %). A question to the MAH regarding this could be considered. Comment CMS: The CMS endorses the RMS comments regarding the three studies: COLO400EJP06, COLO400D1401, COLO400JJP15. The CMS has the following additional comments on study COLO400EJP08: In this study, the rejection rate in the paediatric lung transplant population is significantly different from the adult population (91.67% v. 58.33%), and suggests a difference in a major efficacy outcome between the adult and paediatric populations. The MAH has not discussed this difference nor proposed any SmPC updates to include results of this paediatric study. In section 5.1, there are no results from clinical trial data included, and no information on solid organ transplantation apart from the statement “Successful solid organ and bone marrow transplantations have been performed in man using ciclosporin to prevent and treat rejection and GVHD”. There is no differentiation made between different types of solid organ transplantation. The CMS considers that the MAH should be asked to clarify these data and put them into context within the adult and paediatric Japanese and other countries’ lung transplantation programmes. The MAH should conclude whether efficacy in the paediatric population is indeed different from adults in this indication and, if needed, propose wording to be added under the paediatric population sub-heading of section 5.1.

Based on these comments, the RMS proposed the following LoQ: List of questions

1. As to synopsis (and CSR in Japanese language) of trial COLO400EJP08 the MAH is requested to clarify whether the following quotation (as of the synopsis) “Also, the percentage of patients in whom rejection occurred was 91.67% (11/12 patients) and showed no significant difference with 56.96% (45/79 patients) of patients aged 15 years and older (p=0.0255)” reflects an inadequate translation of the CSR. A p of 0.0255 characterizes a difference as statistically significant. A clarification is also requested to the kind of rejection reported (acute or chronic rejection reaction (bronchiolitis obliterans?), graft rejection?) and the populations (12 and 79) in this comparison resulting in a p of 0.0255.

2. The MAH is requested to submit an up-to-date and EU-wide harmonised SmPC of Sandimmun and/or Sandimmun Neoral in English language, if feasible. After clarification of the meaning of the results of trial COLO400EJP08 in terms of “rejection”, the MAH is invited to put these result into context within the adult and paediatric Japanese and other countries’ lung transplantation programmes. In addition, the MAH should conclude whether efficacy in the paediatric population is indeed different from adults in this indication and, if needed, propose wording to be added under the paediatric population sub-heading of section 5.1


VII. ASSESSMENT OF RESPONSE TO INITIAL QUESTIONS Question 1 As to synopsis (and CSR in Japanese language) of trial COLO400EJP08 the MAH is requested to clarify whether the following quotation (as of the synopsis) “Also, the percentage of patients in whom rejection occurred was 91.67% (11/12 patients) and showed no significant difference with 56.96% (45/79 patients) of patients aged 15 years and older (p=0.0255)” reflects an inadequate translation of the CSR. A p of 0.0255 characterizes a difference as statistically significant. A clarification is also requested to the kind of rejection reported (acute or chronic rejection reaction (bronchiolitis obliterans?), graft rejection?) and the populations (12 and 79) in this comparison resulting in a p of 0.0255 Response The Study synopsis was prepared from the clinical study report (CSR) of the trial COLO400EJP08, a Japanese Observational Surveillance Report, available in Japanese language. Novartis accepts that there was an error in the translation of the Study COLO400EJP08 synopsis in English (release date: 28-Jan-2015), which cascaded into the critical expert overview submitted in the context of Article 46 DE/W/089/pdWS/001. As noted by the Rapporteur, the text should be in line with the data and it should read as: “Also, the percentage of patients in whom rejection occurred was 91.67% (11/12 patients) and showed no a significant difference with 56.96% (45/79 patients) of patients aged 15 years and older (p=0.0255)” Novartis would like to clarify below the kind of rejection reported in the studied population (Table 1-1).

Detailed description of the study population, adult and paediatric, is also provided as annex to this Response [Annex to Novartis’ Responses - Case list of COLO400EJP08]. For each patient enrolled in Study COLO400EJP08, the listing includes information on primary disease, age, sex, rejection type, onset of ADRs, survival rate. Following to their review, Novartis could not identify clear trends and reliable clinical evidence leading to a difference in efficacy in adults vs. paediatric patients treated with Sandimmun and/ or Sandimmun Neoral following lung transplantation (see Novartis’ response to Question 2). Assessment of Response From the RMS point of view it is unclear if there was an error in translation of the study which cascaded into the critical expert overview because it is still unclear what is meant by “Also, the percentage of patients in whom rejection occurred was 91.67% (11/12 patients) and showed no a significant difference with 56.96% (45/79 patients) of patients aged 15 years and older (p=0.0255)”.


Anywhere, a p of 0.0255 characterizes a difference as statistically significant from the RMS point of view. The MAH is requested to clarify the statistically significance. Question 2 The MAH is requested to submit an up-to-date and EU-wide harmonised SmPC of Sandimmun and/or Sandimmun Neoral in English language, if feasible. After clarification of the meaning of the results of trial COLO400EJP08 in terms of “rejection”, the MAH is invited to put these result into context within the adult and paediatric Japanese and other countries’ lung transplantation programmes. In addition, the MAH should conclude whether efficacy in the paediatric population is indeed different from adults in this indication and, if needed, propose wording to be added under the paediatric population sub-heading of section 5.1 Response On the basis of the Japanese paediatric results of [study COLO400EJP08] in lung transplantation, Novartis does not recommend changes to the current text in the Sandimmun and Sandimmun Neoral EU SmPCs and considers that the efficacy and safety information available in the approved product information adequately reflect all clinically relevant knowledge of the medicine available with the Company to date. [Study COLO400EJP08] is a Japanese post-marketing surveillance study (J-PMS), which was required by the Pharmaceutical Affairs law of Japan, and conducted in accordance to the Good PMS Practice (GPSP) (or Good Pharmacovigilance Practices). In this J-PMS study, drug use-results survey was conducted in lung transplantation, and available data were collected from normal medical practice over a reexamination period covering from 01-Sep-2003 to 19-June-2011. 92 patients were enrolled from 4 clinical sites in Japan and their observation period was of 10 years maximum. From these patients, 12 were pediatric patient, younger than 15-year old (age 10.7±3.0 years, range 6-15) and one patient was 15 years old with no efficacy data available. All children were treated off-label as Sandimmun and Sandimmun Neoral are not indicated in paediatric population for transplantation, including lung transplantation, in Japan and worldwide. The number of pediatric patients (13) involved in the clinical study COLO400EJP08 was limited in the surveillance and was too small to lead to statistical significance of the efficacy data in this population. Novartis’ evaluation of the study outcome could not be further supported by clinical evidence from other sources: there are currently no on-going lung transplantation programmes within Novartis and no global clinical studies were conducted in lung transplantation in paediatric patients in Japan or worldwide. Lung transplantation is a treatment option in the advanced stage lung disease (Benoist T.M. and Benden C (2019)). Most paediatric patients enrolled in the study COLO400EJP08 presented with significant confounders (e.g. the surgical approach is likely more challenging, effects of immunosuppression in the developing immune system of a child and psychosocial aspects, particularly in adolescents, have to be taken into consideration), which would make it difficult to determine whether the higher rejection rate observed in children in this study is linked to the medical treatment with Sandimmun / Sandimmun Neoral. In conclusion, [study COLO400EJP08] included only 13 paediatric patients exclusively from Japan and its efficacy results in children vs adults were inconclusive as they could not be confirmed by other Novartis clinical data. Novartis is of the opinion that the experience gained with study COLO400EJP08 does not provide any relevant information that could benefit to the


Patients and Health Care Professionals in Europe and/or worldwide. There were also no wording changes proposed for the [Japanese product information]. Assessment of Response The statement of the MAH “All children were treated off-label as Sandimmun and Sandimmun Neoral are not indicated in paediatric population for transplantation, including lung transplantation, in Japan and worldwide.” cannot be accepted by the RMS. At least in Germany Sandimmun and Sandimmun Neoral are labelled in paediatric populations (see e.g. SmPC under section 4.3 and 4.4 in German language): Section 4.3 “Kinder und Jugendliche In klinische Studien waren auch Kinder ab einem Alter von 1 Jahr eingeschlossen. In einigen Studien benötigten und vertrugen Kinder und Jugendliche höhere Dosen von Ciclosporin pro kg Körpergewicht als die bei Erwachsenen eingesetzten. Eine Anwendung von Sandimmun bei Kindern außerhalb der Transplantationsindikationen mit Ausnahme des nephrotischen Syndroms kann nicht empfohlen werden (siehe Abschnitt 4.4).“ Section 4.4 „Anwendung bei Kindern in anderen Indikationen als Transplantationen Abgesehen von der Behandlung von nephrotischem Syndrom liegen keine entsprechenden Erfahrungen mit Sandimmun bei Kindern vor. Eine Anwendung bei Kindern unter 16 Jahren außerhalb der Transplantationsindikationen mit Ausnahme des nephrotischen Syndroms kann daher nicht empfohlen werden.“ The MAH is still requested to conclude whether efficacy in the paediatric population is indeed different from adults in this indication and further requested to propose wording to be added under the paediatric population sub-heading of section 5.1. VIII. RAPPORTEUR’S DAY 90 OVERALL CONCLUSION AND

RECOMMENDATION Overall conclusion

The questions were not satisfactorily answered by the MAH. Recommendation

The MAH is requested to provide clarifications (see section VII “Assessment of response to questions”). IX. ASSESSMENT OF APPLICANT’S DAY 90 RESPONSE Question 1 From the RMS point of view it is unclear if there was an error in translation of the study which cascaded into the critical expert overview because it is still unclear what is meant by “Also, the percentage of patients in whom rejection occurred was 91.67% (11/12 patients) and showed no significant difference with 56.96% (45/79 patients) of patients aged 15 years and older (p=0.0255)”.


Anywhere, a p of 0.0255 characterizes a difference as statistically significant from the RMS point of view. The MAH is requested to clarify the statistically significance. Response Novartis acknowledges the assessor’s comment and would like to clarify that Novartis is aligned with the RMS opinion that a p-value of 0.0255 characterizes a difference as statistically significant. In our response to the RSI submitted on 25 June 2019, the corrected text had a ‘strikethrough’ on the word ‘no’ to show the change that Novartis accepted (re-provided below): “Also, the percentage of patients in whom rejection occurred was 91.67% (11/12 patients) and showed no a significant difference with 56.96% (45/79 patients) of patients aged 15 years and older (p=0.0255)” As provided in the earlier response to the RSI there was an error in the translation of the Study COLO400EJP08 synopsis in English (release date: 28-Jan-2015) from the Japanese synopsis. As noted by the Rapporteur, the text should be in line with the data and it should read as: “Also, the percentage of patients in whom rejection occurred was 91.67% (11/12 patients) and showed a significant difference with 56.96% (45/79 patients) of patients aged 15 years and older (p=0.0255)”. Assessment of Response The typographical error was acknowledged and is accepted. Question 2 The statement of the MAH “All children were treated off-label as Sandimmun and Sandimmun Neoral are not indicated in paediatric population for transplantation, including lung transplantation, in Japan and worldwide.” cannot be accepted by the RMS. At least in Germany Sandimmun and Sandimmun Neoral are labelled in paediatric populations (see e.g. SmPC under section 4.3 and 4.4 in German language): Section 4.3 “Kinder und Jugendliche In klinische Studien waren auch Kinder ab einem Alter von 1 Jahr eingeschlossen. In einigen Studien benötigten und vertrugen Kinder und Jugendliche höhere Dosen von Ciclosporin pro kg Körpergewicht als die bei Erwachsenen eingesetzten. Eine Anwendung von Sandimmun bei Kindern außerhalb der Transplantationsindikationen mit Ausnahme des nephrotischen Syndroms kann nicht empfohlen werden (siehe Abschnitt 4.4).“ Section 4.4 „Anwendung bei Kindern in anderen Indikationen als Transplantationen Abgesehen von der Behandlung von nephrotischem Syndrom liegen keine entsprechenden Erfahrungen mit Sandimmun bei Kindern vor. Eine Anwendung bei Kindern unter 16 Jahren auserhalb der Transplantationsindikationen mit Ausnahme des nephrotischen Syndroms kann daher nicht empfohlen werden.“


The MAH is still requested to conclude whether efficacy in the paediatric population is indeed different from adults in this indication and further requested to propose wording to be added under the paediatric population sub-heading of section 5.1. Response Novartis acknowledges the assessor’s comments and accepts that as per the Study COLO400EJP08, the percentage of patients in whom rejection occurred showed a statistically significant difference between patients aged below 15 years and the patients aged 15 years and older (p=0.0255). The reason for this statistically significant difference observed in paediatric patients was considered to be the presence of various confounders (type of transplanted lung, type of surgery, age at the time of transplantation, family relationship, age and sex of a donor etc). Hence, the efficacy results in children vs adults from the study COLO400EJP08, which included only 13 paediatric patients exclusively from Japan, are considered inconclusive and cannot be generalized to the overall paediatric transplant population. In the context of Article 46, Novartis accepts to propose wording to be added under the paediatric population sub-heading of section 5.1, as below: ‘A post-marketing surveillance study conducted in 92 lung transplant Japanese patients (including 13 paediatric patients) has shown a statistically significant difference in rejections that occurred in patients less than 15 years old, when compared to patients aged 15 years and older. However, these results are considered inconclusive and cannot be generalized to the overall paediatric transplant population.’ Assessment of Response The MAH provided a clarification on the statistically significance of the difference observed in the translation of the subgroup analysis (by age). An argument that age at the time of transplantation is, or is not, a confounding factor of such an analysis is difficult to follow. According to the RMS it is the factor by which patients were sub-grouped. The RMS acknowledges that the MAH accepts to propose wording. The proposed wording, however, is not acceptable for the RMS. Relevant information is missing in the proposal (the size of the observed difference, the frequency of rejections, and the clinical relevance of the term “rejection” in the translation). Currently the RMS is concluding, based on the response of the MAH, that the meaning of “rejection” has to be clarified prior to decide on the clinical relevance of the term, and the usage of results in terms of a rather unclear (origin: Japanese) term “rejection” in a SmPC intended for the market of the EU. The MAH is invited to provide clarifications as to the meaning of the term, or endpoint, “rejection” (both in its Japanese original meaning, and after its English translation) used to describe results of lung transplantation trial COLO400EJP08, provided that these “rejections” are actually clinically relevant (hyper-acute, acute, cellular, chronic) rejections (of graft tissue), and the statistically significant difference reported in a subgroup analysis has any meaning for paediatric recipients of a lung transplantation. X. RAPPORTEUR’S OVERALL CONCLUSION AND



Based on the data submitted, the MAH may provide clarifications as to the meaning of the term, or endpoint, “rejection” (both in its Japanese original meaning, and after its English translation) used to describe results of lung transplantation trial COLO400EJP08. The SmPC proposal made by the MAH (see above) is not recommended to be implemented in SmPCs used within the EU. The last sentence is not accepted at all since the MAH currently considers age (at transplantation) as a confounding factor of a subgroup analysis by age. Whether the statistically significant result of this analysis, thus, is “inconclusive”, is accordingly entirely unclear to the RMS. The first sentence of the SmPC proposal seems to be informative but the most relevant information, i.e. the frequency of the rejections and the clinically relevance of those events, is missing in this statement. The frequency of those “rejections” is numerically very high in both subgroups (91.67% (11/12 patients) vs. 56.96% (45/79 patients)) but currently considered clinically not relevant by the RMS since the meaning of the term “rejection” in the Japanese original documents is unclear to the RMS. The reported survival rates (supposedly in both meanings i) patient and ii) graft survival) in the same subgroups are high (91.67% (11/12 patients) vs. 86.08% (68/79 patients)), actually numerically higher in the younger age group. XI. SUPPLEMENTARY INFORMATION The following CMSs comments have been received by RMS :

Comment CMS: SE agrees with the RMS’s conclusion that the proposed amendment to SmPC section 5.1 should be further discussed. Study COLO400EJP08 on ciclosporin in lung transplantation indicates a higher rate of rejections in the paediatric compared to the adult population. According to the AR, the MAH argues that this is not verified by other paediatric lung transplant populations treated with ciclosporin. SE finds that any amendment to section 5.1 regarding the rejection rate in the paediatric lung transplant population should be based on all available data in this population, which is not considered possible without a cumulative review of data from this subpopulation in clinical studies as well as post-marketing. This is not considered feasible within this procedure. Thus, if a wording in 5.1 is considered appropriate, assessment of all available data on the risk of lung graft rejection in children compared to adults should be performed. In such case, the MAH needs to submit a cumulative review in a separate procedure, i.e. a type II variation.

Comment CMS: We agree with the RMS conclusion that further discussion is warranted on the proposed amendment to the text in SmPC section 5.1. There is insufficient information in this procedure to draw meaningful conclusions; the wider context of paediatric versus adult lung transplantation has not been fully discussed, and the meaning of the term ‘rejection’ has not been clarified. It is of potential clinical importance to understand whether there is a difference in rejection rates between paediatric and adult lung transplant recipients based on the use of ciclosporin. However, given the small number of paediatric patients in study COLO400EJP08 and the number of potential confounders it is not feasible to reach a conclusion during this work-sharing procedure. We therefore support the SE comments that proposed changes to section 5.1 should only be considered after a


cumulative review of all post-marketing and clinical studies involving paediatric and adult lung transplantation, and that this is outside the scope of this work-sharing procedure. The CMS proposes the MAH reviews the totality of evidence for ciclosporin efficacy in paediatric lung transplantation and submits a type II variation with proposed wording to update SmPC section 5.1 within 60 days of the conclusion of this work-sharing procedure.

XII. ASSESSMENT OF APPLICANT’S DAY 120 RESPONSE Rapporteur’s Comment Based on the data submitted, the MAH may provide clarifications as to the meaning of the term, or endpoint, “rejection” (both in its Japanese original meaning, and after its English translation) used to describe results of lung transplantation trial COLO400EJP08. The SmPC proposal made by the MAH (see above) is not recommended to be implemented in SmPCs used within the EU. The last sentence is not accepted at all since the MAH currently considers age (at transplantation) as a confounding factor of a subgroup analysis by age. Whether the statistically significant result of this analysis, thus, is “inconclusive”, is accordingly entirely unclear to the RMS. The first sentence of the SmPC proposal seems to be informative but the most relevant information, i.e. the frequency of the rejections and the clinically relevance of those events, is missing in this statement. The frequency of those “rejections” is numerically very high in both subgroups (91.67% (11/12 patients) vs. 56.96% (45/79 patients)) but currently considered clinically not relevant by the RMS since the meaning of the term “rejection” in the Japanese original documents is unclear to the RMS. The reported survival rates (supposedly in both meanings i) patient and ii) graft survival) in the same subgroups are high (91.67% (11/12 patients) vs. 86.08% (68/79 patients)), actually numerically higher in the younger age group. Response Novartis acknowledges the assessor’s comments on the submitted responses to the D90 pAR and would like to further clarify in more detail on the reported lung transplantation rejections that occurred in pediatric patients below 15 years of age (n=12). Firstly, Novartis would like to clarify on the number of pediatric patient’s assessed for the efficacy and safety in this study (JP08). In responses to the queries raised in the D90 pAR, submitted on 13 September 2019, Novartis mentioned 13 pediatric patients, based on the EU age classification (<18 years of age). However, since in Japan, the pediatric population is defined by age <15 years, the JP08 CSR was generated based on this age classification and has only 12 pediatric patients. Therefore, safety and efficacy were assessed in 91 patients including 12 pediatric patients aged <15 years and 79 patients aged >15 years. For your further information, patient #0079 was aged above 15 years and below 18 years of age and was added as the 13th patient in individual patient narratives provided in the attached [Annex 1]. All the described rejections in the study, in patients below 15 years of age (n=11), were diagnosed based on the clinical diagnosis and subsequent chest x-ray only. Notably, an invasive diagnostic lung transplant biopsy was not performed in any of these pediatric patients to obtain the histopathological findings to confirm the assumed clinical diagnosis of solid organ rejection. As per study protocol ‘acute rejections’ were observed in 8 of these pediatric patients while ‘chronic rejection’ was reported in only 1 pediatric patient. Both, acute and chronic rejections, were reported coincidently in 2 pediatric patients. Since none of these pediatric patients underwent invasive diagnostic lung transplant biopsy, none of the reported rejections were classified as proven. Hence, the clinical relevance of these reported lung rejections was finally


considered inconclusive and cannot be generalized to the overall pediatric lung transplant population. Accordingly, Novartis is of the opinion that the experience gained with study COLO400EJP08 does not provide any additional information that could be of further benefit to the Patients and Health Care Professionals in Europe or elsewhere. Due to absence of clinical relevance of the data obtained, Novartis considers that an update to the EU SmPC is not warranted. Assessment of Response The MAH provided clarification on the reported number of lung transplantation rejections that occurred in pediatric patients below 15 years of age. The number of pediatric patient’s assessed for the efficacy and safety in this study (JP08), mentioned 13 pediatric patients, were based on the EU age classification (<18 years of age). In Japan, the pediatric population is defined by age <15 years, the JP08 CSR was generated based on this age classification and has only 12 pediatric patients. Therefore, safety and efficacy were assessed in 91 patients including 12 pediatric patients aged <15 years and 79 patients aged >15 years. Further, the MAH clarified that all the described rejections in the study, i.e. in patients below 15 years of age (n=11), were diagnosed based on the clinical diagnosis and subsequent chest x-ray only. No confirmatively invasive diagnostic lung transplant biopsy was performed in any of these pediatric patients. ‘Acute rejections’ were observed in 8 of these pediatric patients while ‘chronic rejection’ was reported in only 1 pediatric patient. Both, acute and chronic rejections, were reported coincidently in 2 pediatric patients. However, since none of these pediatric patients underwent invasive diagnostic lung transplant biopsy, none of the reported rejections were classified as proven. Therefore, the MAH decided that the clinical relevance of these reported lung rejections was finally considered inconclusive. The MAH is further of the opinion that the experience gained with study COLO400EJP08 does not provide any additional information that could be of further benefit to the Patients and Health Care Professionals in Europe or elsewhere. Due to absence of clinical relevance of the data obtained, the MAH considers that an update to the EU SmPC is not warranted. This is in principle acceptable. Nevertheless, a cumulative review of all post-marketing and clinical studies involving paediatric and adult lung transplantation shall be conducted by the MAH. The MAH is requested to review the totality of evidence for ciclosporin efficacy in paediatric lung transplantation and to submit a type II variation with proposed wording to update SmPC section 5.1 within 60 days of the conclusion of this work-sharing procedure. XIII. FINAL RAPPORTEUR’S OVERALL CONCLUSION AND


Based on the response submitted by the MAH, not to update SmPC is acceptable. However, a cumulative review of all post-marketing and clinical studies involving paediatric and adult lung transplantation shall be conducted by the MAH. If the comparison of the data requires an amendment of the wording in 5.1 of the SmPC, the review and the assessment of these data shall be submitted within a type II procedure by the MAH.


XIV. UPDATED FINAL RAPPORTEUR’S OVERALL CONCLUSION AND RECOMMENDATION

The MAH has taken the recommendation of the RMS into account. Accordingly,

• a literature review on randomized controlled clinical trials, • a systematic review of 3 of these trials (a Penninga et al 2013 to assess the benefit

including 3 studies (Zuckermann et al 2003, Hachem et al 2007 and Treede et al 2012; included also in the literature review of the MAH), and

• available information on use of ciclosporin in adult and pediatric lung transplant patients from a postmarketing surveillance (COLO400EJP08 discussed within this AR)

• as well as considerations on an observational study monitoring C0, and blood collecting for analysis of C2 retrospectively (Iversen et al 2009; MAH sponsored).

have been submitted. Appendix 1 of this submission provides an overview on this information as follows:


Based on the evidence in pediatric patients available, the MAH concludes that the review outcome does not provide any additional information that could be of further benefit to the patients and health care professionals in Europe or elsewhere and hence, considers that an update to the EU SmPC is not warranted. The RMS appreciate the submission of responses (sequence 0029), and continues to shares the overall conclusion of the MAH.

public assessment report for paediatric studies submitted ... · sandimmun/sandimmun neoral...

Documents