EUROPEAN MEDICINES AGENCY

SCIENCE MEDICINES HEALTH

EMA/6374/2018

EMA/PDCO Summary Report

on an application for a waiver

UPI number: 647139

Ranibizumab

Lucentis

Novartis Europharm Limited

EMEA-000527-PIPOS-17

 

30 Churchill Place e Canary Wharf e London E14 5EU e United Kingdom
Telephone. +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5510
Send a question via our website www.ema.europa.eu/contact An agency ofthe European Union

Application Summary

 

 

Active substance(s), class and mechanism of action: Ranibizumab (ATC code: SO1LA04) is a
recombinant humanized immunoglobulin G1 kappa isotype monoclonal antibody fragment targeted
against human vascular endothelial growth factor (VEGF) A. The binding of ranibizumab to VEGF-A
prevents the interaction of VEGF-A with its receptors, thus blocking VEGF’s effects on vascular
permeability, angiogenesis, and neovascularization. VEGF is over-expressed in ocular conditions that
result in ocular neovascularization and retinal edema and lead to vision loss. Differences in the
mechanism of action between children and adults are not expected.

Product name: Lucentis 10 mg/mL solution for injection

MAH / applicant: Novartis Europharma Limited, United Kingdom

Authorised indication(s): In the European Union, Lucentis is approved in adults for the treatment of:
s  neovascular (wet) age-related macular degeneration

e visual impairment due to choroidal neovascularization

® visual impairment due to diabetic macular edema

e visual impairment due to macular edema secondary to retinal vein occlusion (RVO) (branch RVO or
central RVO)

Planned indication(s) in adults: Treatment of moderately severe to severe nonproliferative diabetic
retinopathy (NPDR) and proliferative diabetic retinopathy (PDR)

Condition: Diabetic retinopathy (DR)

Proposed indication(s) in children: Not applicable - a full waiver is being requested
Potential benefit for children: Not applicable - a full waiver is being requested
Clinical development: Not applicable

Pharmaceutical form: Not applicable

Route of administration: Intravitreal injection

Non-clinical plans: Not applicable

Extrapolation: Not applicable

Waiver(s), deferrals: A full waiver for the condition of “diabetic retinopathy” in all subsets of the
pediatric population is requested. The grounds for the waiver are based upon a lack of significant
therapeutic benefit.

Overall, the prevalence of any severity of DR in children with diabetes was found to be between 0% and
20.3%. The prevalence of moderate to severe NPDR or PDR was found to be between 0% and 0.4%, at
most. Using the number of Western European children and young adults under 20 years of age who had
DM in 2016 (129,170 [GBD 2016)]), it is expected that the number of children with moderate to severe
NPDR or PDR is between 0 and 517, at most.

This number of 517 patients may need to be corrected for the following factors. First, it is based on data
representing patients of up to 20 years of age and not for children up to 18 years of age. Given the
strong influence of duration of DR on severity, older patients (18 to 20 years of age) may contribute to
this number. Second, it was not possible to limit the analysis to moderately severe to severe NPDR (Early
Treatment Diabetic Retinopathy Study Level 47 to 53), for which treatment would generally be

 

 

EMA/6374/2018 Page 2/46

considered. Finally, spontaneous regression of disease was reported in some patients and none of the
children included in a literature review conducted by Novartis received treatment for DR. This observation
may further limit the number of patients eligible for a study.

The prevalence of any severity of DR in the pediatric population is low, and the occurrence of moderately
severe to severe NPDR or PDR, corresponding to patients with DR eligible for treatment, is extremely low.
Thus, it is considered unfeasible in practice to conduct a study in a sufficient number of patients to allow
for a robust assessment of the risks and therapeutic benefits of ranibizumab as a treatment option for DR
in the pediatric population.

 

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Table of contents

Application Summary ........zuuuu020n0nnnnnunnnnnunnnnn nn nn nn nn nn nn nn nn nn nn nn nn nun nun nun nun nn n nun 2
Table of contents .......uunnnnnnnnnnnnnnnnnununnnnnunnnnnnnnnnnnnnnnnunnnnnnnununnnnnnnunnnnnnnunnnnnnnnn A
Abbreviations.........uuunununununanunununnnnnnnnnnnnnununununnnnnnnnnnnnnnnnnnnnnununununnnnnnnnnnnunnnnnn Ö

Part A- Administrative and product information .......z.zuuuunnunnnnnunnnnnunnnnnunn Z

A.1. Details of the medicinal product and overview of the application......zuussrsuennnennnnnnn nun 7
A.1.1. Details of the medicinal product .......z2su000nnenonan onen nun nun nn nnn nn nun nn nn nun nenn nun nn nennen nenn 7
A.1.2. Authorised use ..urensnennnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nun nnnnnnnnnnnnnnnnnnnnnn nenn 8
A.1.3. Applicant’s proposals ......sssusnnnnnnnnnunnunnnnnnnnunnunnnnnnnnunnunnunnnnnnnnennennnnnnn nun nen nun nennen 8
A.1.4. Discussion of proposed condition(s) (scope of application) ..........zzu2ssn0nnnnnnnnn nun nun 10
A.2. Regulatory information on completed clinical trials related to the condition and to the
development for the paediatric population ..........zuussuunennnnnnnnnnnnnnnnnnnnnnnnnnnnnn nun nn nn nn nn nn 11
A.3. Regulatory status of the product .....ureuennnnennnnnnnnnnnennnnnnnnnnnnnn nenn nennen nenn nennen nennen 11
A.3.1. Marketing authorisation status inside the European Union ........zu2zsu2u@n0nnnnnnnnn nun nun 11
A.3.2. Marketing authorisation status outside the European Union...........uursusnansanennennnnnn 12
A.3.3. Refusal / withdrawal / restriction of a marketing or extension authorisation or
application (inside or outside EEA) ........zz2su2sn0nnnnnnnnnn nun nun nun nan nun nun nun nun nn nun nun nun nn nun nun nun 12
A.4. Advice from a regulatory authority ......z2su2ss20n0nnnnnnnnnn nun nun n nn nun nun nun nun ann nn nun nun un nun namen 12

Part B- Overall development of the medicinal product ......-uunzunnannonnannannn LA
B.1. Discussion on similarities and differences in the condition between populations and

pharmacological rationale .........zuunsuunnnnnnnnnnnnnnnnnnannn nun nn nnn nenn nun nenn nn nnnen nun nnn nenn nenn nennen 15
B.1.1. Similarities and differences in the condition between populations ..........u.uuuennnen nn 15
B.1.2 Pharmacological rationale.......uussennsennnnnnnnnennnnnnnnnnnnnnnnnnnnnnnnnnnnunnnnnn nenn nennen nennen 27
B.2. Current methods of diagnosis, prevention or treatment in paediatric populations ....... 29
B.3. Significant therapeutic benefit and/or fulfilment of therapeutic needs .........z.2z222@00 000 30

Part C- Applications for product-specific waiverS ...uuununnannonnunnannannannannannn 32

C.1. Overview of the waiver request.........uusussnnennennennnnnun nam nen nun nun nun nun nn nun nun nnn nennen nennen 32
C.2. Justification for a product-specific waiver .....u2u22su00nnnnnnn nn nun nun nun nun nn nun n nun nun nn nun Hann nun 32
C.2.1. Applications based on a likely lack of safety or efficacy in part or all of paediatric

Population ....urserserenennnnnnnnnnnnnennnnnnnnnnnnnnnnn nun nnennnen nennen nenn nennen nennen nennen nennen nennen 32
C.2.2. Applications based on the disease or condition not occurring in the specified paediatric
SUbDSEt ....2ensannnnnnnnunnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nun nun nnnnnnnnnnnn nun nun nun nnnnn nun nnnnnnnnnnnnnunn nun n nun nun 33
C.2.3. Applications based on lack of significant therapeutic benefit .......z222s2@nnn0nnnonnn nn nn nn 33

Part D- Proposed paediatric investigation plan .......uuzunuannunnunnunnunnunnunnunnn DO
Part E - Request for deferrals BEEBEBEEEEEEEEEEEEEEEEEEEEEEEEEEEEEENEEEEEE EN EN EENEEHEEHEEH EHE EEH EHE HBHBHBHHENEN 36

Part F - ÄAnneXES ...ununnnununnnnnununnnnnununnnn nun En nn nn nn nn nn 37

F.1. Initial references.......u20s4200020nnnnnnnnnnnnn nun nn nn nn nn nn nn nun nun nun nun nun nnnnnunn nun nun nunn nun nun nun 37
Annexes related to the administrative documentation ..............uusu@s0nunnannnnnannnnnnnnnnnnnnn nen 37
ÄnnexeS...uusunununeneennnnnnnnnnnnnnnnnnnnnnnnnnnennnnnnnnnnnnnnnnnnnnnnnnn nenn nun nun nenn nun nenn nnnn une nun nun nen 37
References ..........u@@@0snnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnunnnnnnnnnnnnnnnnnnunnnnunnenen 37

Paediatric Committee discussion at Day 30. .uuunnnnnnnnnnnnnnnnnnnnnnnnunnnnnnnnnnnnnnnnn 41
On 12 March the applicant submitted the following supplementary information: ........s2.22.: 42

 

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Paediatric Committee discussion — conclusions at Day 60......unzununnnunnunnanen 46

 

EMA/6374/2018 Page 5/46

Abbreviations

 

Abbreviation

Definition

 

 

 

 

 

 

AMD age-related macular degeneration
Cmax maximum concentration levels
CNV choroidal neovascularization
DCCT Diabetes Control and Complications Trial
DM diabetes mellitus
DME diabetic macular edema
DR diabetic retinopathy
DRCR.net Diabetic Research Clinical Research network
ETDRS Early Treatment Diabetic Retinopathy Study
GBD Global Burden of Disease Collaborative Network
IQR interquartile range
NICE National Institute for Health and Care Excellence
NPDR nonproliferative diabetic retinopathy
PDR proliferative diabetic retinopathy
PRP panretinal photocoagulation
ROP retinopathy of prematurity
RVO retinal vein occlusion
UK United Kingdom
US United States
VEGF vascular endothelial growth factor
EMA/6374/2018 Page 6/46

Part A- Administrative and product information

On 14 December 2017 the applicant submitted to the European Medicines Agency an application for a
waiver.

 

 
   
 

Paediatric Co-ordinator

    
      

Rapporteur Karl-Heinz Huemer

Peer Reviewer Sylvie Benchetrit

 

 

Name Qutcome of evaluation of
conflict of interest

 

 

 

 

External Expert(s) <No experts were involved <Level 1>
by the PDCO.> <Level 2>
<Level 3>
Pre-submission meeting No
Start ofthe procedure Dayıi 23 January 2018
First discussion by the PDCO and request Day 30 23 February 2018

for supplementary information by

 

Adoption of the PDCO Opinion Day 60 23 March 2018

 

 

 

 

A.1. Details of the medicinal product and overview of the application

A.1.1. Details of the medicinal product

 

 

Applicant Novartis Europharm Limited

Active substance(s) Ranibizumab

INN Ranibizumab (Recommended)

Invented name Lucentis

Type of product Bio(techno)logical / Recombinant DNA derived product /
Monoclonal antibody

ATC code SO1LA04

Therapeutic area(s) Ophthalmology

 

 

 

 

 

EMA/6374/2018 Page 7/46

A.1.2. Authorised use

 

 

Condition(s)

Pharmaceutical formulation(s) authorised

Strength(s) authorised
Route(s) of administration authorised

Indication(s) authorised

 

Adults:

Treatment of neovascular (wet) age-related macular
degeneration (AMD)

Treatment of visual impairment due to choroidal
neovascularisation (CNV)

Treatment of visual impairment due to diabetic macular
oedema (DME)

Treatment of visual impairment due to macular oedema
secondary to retinal vein occlusion (branch RVO or central
RVO)

Children:
The product is not authorised in children

Solution for injection / Solution for injection in pre-filled
syringe

10 mg/ml
Intravitreal use
Adults:

The treatment of neovascular (wet) age-related macular
degeneration (AMD)

The treatment of visual impairment due to choroidal
neovascularisation (CNV)

The treatment of visual impairment due to diabetic macular
oedema (DME)

The treatment of visual impairment due to macular oedema
secondary to retinal vein occlusion (branch RVO or central
RVO)

Children: N/A

 

A.1.3. Applicant’s proposals

 

 

Condition(s)

Pharmaceutical formulation(s) proposed

Strength(s) proposed
Route(s) of administration proposed

Indication(s) proposed

 

Diabetic retinopathy (DR)

Solution for injection in cartridge, Solution for
injection/infusion

Not specified
Intravitreal use
Adults:

Treatment of moderately severe to severe non-proliferative
diabetic retinopahty (NPDR), and proliferative diabetic
retinopathy (PDR)

 

 

EMA/6374/2018

Page 8/46

Children: N/A; a full product specific waiver is requested

PIP indication proposed N/A; a full product specific waiver is requested

 

 

 

 

Comment:

Paediatric Co-ordinator:

The applicant has three agreed waivers for the conditions

«e Treatment of neovascular (wet) age-related macular degeneration (AMD)
e Treatment of visual impairment due to choroidal neovascularisation (CNV)
e Treatment of visual impairment due to diabetic macular oedema (DME)

e Treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch
RVO or central RVO)

On the grounds of lack of significant therapeutic benefit as clinical studies(s) are not feasible.

There is one agreed PIP (EMEA-000527-PIPO4-13) for the condition “Treatment of retinopathy of
prematurity” with a scheduled PIP completion date of December 2018.

The company has conducted two studies in choroidal neovascularization (CNV) and macular oedema (ME)
in the adult population. These studies have been open for inclusion of adolescent patients (aged 12-17
years inclusive) in a separate open label arm. The CHMP assessment report Procedure No.
EMEA/H/C/000715/11/0061 states:

“The open label adolescent arm, as part of a Ph3 trial in ME in adults, including 3 patients was recently
finalised (EMA/H/C/715/P46 070). The three patients did not report any related AEs, but the number of
patients is too limited to draw any conclusions with regards to potential differences in the AE profile
between the paediatric and the adult population. However, in adolescent patients, the eye is fully
developed (essentially developed at the age of 2-3 years). This is also, in contrast to the elderly and
fragile population with age-related macular degeneration, to that with diabetes of retinal vein occlusion, a
population without any specific risk factors. No additional concerns, compared with the adult population,
are thus raised.”

The PDCO during the PIP/waiver procedure EMEA-000527-PIPO3-13 PDCO concluded that “a formal
centralised prospective registry should be established to collect all available data on compassionate/off-
label use in the paediatric population, capturing the age of patient, indication, dose administered and
outcome”, ideally not limited to the (to be) licensed indication.” This issue has been discussed by the
PRAC during the extension of indication variation procedure EMEA/H/C/000715/11/0061: The PRAC
concluded not to request a registry to monitor off label use in children, but included the following
requirements:

1. For spontaneously reported AEs in children, the MAH should implement targeted questionnaires in
order to go back to the reporter to gain as much information as possible about the event as well as
the patient; including age of child, condition being treated, dose regimen used, and any efficacy data
if available etc. The results from these should be reported in the PSURs. The MAH is asked to
comment, and to update the RMP accordingly.

2. The MAH should provide a cumulative summary regarding their knowledge of off label use in children,
including in which disease conditions it was used. Furthermore, the MAH should discuss the possibility

 

 

 

EMA/6374/2018 Page 9/46

to undertake a drug utilisation study, with the aim to learn more about the use of Lucentis in children
and adolescents, including condition treated, age groups, and dose regimens used.

3. Ifthere are ongoing studies / registries, and if they would include also children, such data should
continuousiy be compiled and reported in the PSURs.

Rapporteur:

The paediatric coordinator presents a comprehensive overview of previous discussions of use of
ranibizumab in paediatric populations. This is fully supported.

As mentioned many of the conditions planned by the MAH are indeed very rare or not occurring in
children. Consequently they have received waivers from PDCO for the conditions treatment of AMD, CNV,
DME and BRVO/CRVO. In the indication ROP a PIP was agreed and is running. Additional discussions on
possible collection of data in paediatric patients were discussed and agreed with PRAC. For this PIP
procedure (diabetic retinopathy) there is some overlap with the already discussed DME indication which
was waived.

Peer Reviewer:

The comments of the coordinator on the previous numerous assessments with the EMA/PDCO are fully
supported.

The discussion of the waiver requests were discussed among other that adolescents could be included in
the adult studies, when similar pathophysiology is expected (ie MINERVA study).

In particular, diabetic retinopathy disease (age of onset, epidemiology) was discussed in relation to the
agreed full waiver requested for the condition of “treatment of visual impairment due to diabetic macular
oedema” (e.g. DME as a complication of diabetic retinopathy).

However, several discussions at the EMA (ie PDCO/HMP/PRAC) have highlighted the necessity of long-
term recollection and analysis of all possible paediatric data with ranibizumab, due to the MoA (Anti-
vascular Endothelial Growth Factor). In September 2016, the EMA CHMP/PRAC joint report
(EMEA/H/C/000715/11/0061, EMA/H/C/715/P46 072) in CNV follow-up 12 months of MINERVA study, it
was stated “although very limited, the efficacy and safety outcomes in the 5 adolescent patients that
were included in the study are promising as well as reassuring although too limited to allow any
conclusions”.

The applicant could provide an update of the overall measures requested by the PRAC, as detailed above
by the coordinator.

Indeed, a major concern is the potential off-label use in all the waivered conditions granted (3 already,
one under request), due to “lack of significant benefit”, while potentially some adolescents / children
could receive the treatment. Due to the fact that these populations (except those preterms in the
retinopathy of prematurity PIP ongoing) are not included in any indication with ranibizumab, the
requirement for careful monitoring in event more requested to the Applicant by the PDCO, to be clarified.

 

A.1.4. Discussion of proposed condition(s) (scope of application)

 

 

Comment:
Paediatric Co-ordinator:

The condition treatment of diabetic retinopathy has been previously agreed by the PDCO.

 

 

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