DECENTRALISED PROCEDURE PUBLIC ASSESSMENT REPORT DICLOFENAC-RATIOPHARM 30 MG/G GEL DICLOFENAC ABZ 30 MG/G GEL DICLOFENAC SODIUM ...
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Decentralised Procedure
Public Assessment Report
Diclofenac-ratiopharm 30 mg/g Gel
Diclofenac AbZ 30 mg/g Gel
Diclofenac sodium
DE/H/5130+5138/001/DC
Applicant: Teva B.V.
Date: 23.05.2018
This module reflects the scientific discussion for the approval of Diclofenac-ratiopharm
30 mg/g Gel/ Diclofenac AbZ 30 mg/g Gel. The procedure was finalised on 21.02.2018.TABLE OF CONTENTS I. INTRODUCTION .................................................................................................................... 4 II. EXECUTIVE SUMMARY ...................................................................................................... 4 II.1 Problem statement .....................................................................................................................4 II.2 About the product......................................................................................................................4 II.3 General comments on the submitted dossier...........................................................................4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles ..4 III. SCIENTIFIC OVERVIEW AND DISCUSSION .................................................................. 5 III.1 Quality aspects ...........................................................................................................................5 III.2 Non-clinical aspects ...................................................................................................................6 III.3 Clinical aspects...........................................................................................................................6 IV. BENEFIT RISK ASSESSMENT ............................................................................................ 8 Diclofenac-ratiopharm 30 mg/g Gel/ Diclofenac AbZ 30 mg/g Gel, DE/H/5130+5138/001/DC Public AR 2/8
ADMINISTRATIVE INFORMATION
Proposed name of the medicinal Diclofenac-ratiopharm 30 mg/g Gel
product in the RMS: Diclofenac AbZ 30 mg/g Gel
Name of the drug substance (INN Diclofenac sodium
name):
Pharmaco-therapeutic group D11AX18
(ATC Code):
Pharmaceutical form(s) and Gel; 30 mg/g
strength(s):
Reference Number for the DE/H/5130+5138/001/DC
Decentralised Procedure:
Reference Member State: DE
Concerned Member States: ES, LU
Applicant (name and address): Teva B.V. (Teva Generics)
Swensweg 5
2031GA, Haarlem
Netherlands
Names and addresses of Balkanpharma - Troyan AD
manufacturers responsible for batch 1 Krayrechna Str.
release in the EEA: Troyan 5600
Bulgaria
Diclofenac-ratiopharm 30 mg/g Gel/ Diclofenac AbZ 30 mg/g Gel, DE/H/5130+5138/001/DC Public AR 3/8I. INTRODUCTION
Based on the review of the data on quality, safety and efficacy the application for Diclofenac-
ratiopharm 30 mg/g Gel / Diclofenac AbZ 30 mg/g Gel, in the treatment of actinic keratosis is
approved.
II. EXECUTIVE SUMMARY
II.1 Problem statement
N/A
II.2 About the product
Diclofenac sodium is a non-steroidal anti-inflammatory drug. The mechanism of action of diclofenac
in actinic keratosis is not known but may be related to the inhibition of the cycloxygenase pathway
leading to reduced prostaglandin E2 (PGE2) synthesis. Efficacy of the treatment has only been
demonstrated in placebo-controlled studies. Comparative studies with topical 5-fluorouracil have not
been conducted. The long term beneficial effects of diclofenac gel have not been proven.
Diclofenac gel has been shown to clear actinic keratosis (AK) lesions with maximum therapeutic
effect seen 30 days after cessation of drug therapy.
The proposed indication for diclofenac sodium 30 mg/g gel is the treatment of actinic keratosis.
In adults diclofenac sodium 30 mg/g gel is applied locally to the affected area twice daily. The amount
needed depends on the size of the affected area. Normally 0.5 grams of the gel (the size of a pea) is
used on a 5 cm x 5 cm lesion site. The maximum daily amount of 8 grams of gel allows simultaneous
treatment of up to 200 cm2 skin surface area.
The usual duration of treatment is from 60 to 90 days. Maximum effect has been observed with
treatment durations towards the upper end of this range. Complete healing of the lesion(s) or optimal
therapeutic effect may not be evident for up to 30 days after completion of therapy.
II.3 General comments on the submitted dossier
This decentralised application concerns a generic version of diclofenac sodium 3% gel, under two
trade names. In this Assessment Report, the name diclofenac sodium 30 mg/g gel is used.
This is an application for a ‘generic’ medicinal product made in accordance with Article 10.3, a so
called ‘hybrid’ application, of Directive 2001/83/EC (as amended by Directive 2004/27/EC).
The application is for diclofenac sodium 30 mg/g gel, which is the generic version of the reference
product Solaraze 3% (30 mg/g, gel) by Almirall, S.A., registered since 01/09/2000.
According the concept paper on the development of a guideline on “quality and equivalence of topical
products (EMA/CHMP/QWP/558185/2014)”, the applicant has submitted in-vitro data comparing the
qualitative and quantitative composition, microstructure, physical properties, product performance,
and administration, to proof pharmaceutical equivalence of diclofenac sodium 30 mg/g gel with the
EU reference product. In addition, the applicant submitted a supportive therapeutic equivalence study
(efficacy and safety of test product in comparison to placebo) including the comparison of diclofenac
sodium 30 mg/g gel with the US reference product. The supportive clinical data support a conclusion
of therapeutic equivalence between the applied product and the EU reference product.
With Germany as the Reference Member State in this decentralised procedure, Teva B.V. is applying
for the Marketing Authorisations for diclofenac sodium 30 mg/g gel in ES and LU.
The applicant has sought scientific advice from the MHRA (1126; 23 March 2016) on the proposal of
abridged MAA of the developed product.
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical
principles
The RMS has been assured that acceptable standards of GMP are in place for these product types at all
sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer
authorisations issued by inspection services of the competent authorities as certification that
acceptable standards of GMP are in place at those sites.
Regarding the statement on GMP for the active substance a statement/declaration is provided from the
manufacturer(s) responsible for manufacture of the finished product and batch release situated in the
EU.
Diclofenac-ratiopharm 30 mg/g Gel/ Diclofenac AbZ 30 mg/g Gel, DE/H/5130+5138/001/DC Public AR 4/8III. SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 Quality aspects
Drug substance
The drug substance used for the manufacture of the drug product diclofenac sodium 3 % gel,
diclofenac sodium is monographed in the Ph. Eur. The quality of the substance is controlled in
compliance with the corresponding monograph of the Ph. Eur. The suitability of the monograph to test
the drug substance has been verified by EDQM respectively. The certificates of suitability have been
granted and copies of the current version of the certificates are provided. A declaration that no starting
materials derived from human or animal origin are used during the drug substance manufacturing
process is stated on the CEPs, respectively. A re-test period of 5 years is defined for the drug
substance if stored into a triple polyethylene bags placed in a HDPE drum.
Drug Product
Diclofenac sodium 3 % gel is a dermatological gel used for the treatment of actinic keratosis.
Objective of the drug product development was to prepare a generic formulation that has similar
qualitative and quantitative to the European originator product Solaraze 3 % gel, marketed in 1997 by
Hyal Sweden Ltd and taken over by Bioglan Laboratories Ltd in 2000. The applicant justifies this
decision claiming that the generic product is the same pharmaceutical form and the same route of
administration as the reference product Solaraze 3 % gel.
The ingredients and the manufacturing process of the drug are considered suitable to produce a
pharmaceutical product of the proposed quality.
All relevant quality characteristics of the drug product (release and shelf-life) are specified.
Specifications are justified and conform to ICH guidelines. The presence of elemental impurities
should be evaluated, according with ICH Q3D guideline. The description of the analytical methods
used to analyse the drug product are adequate, the validation results are plausible.
The manufacturing process has been schematic described as well as the in-process controls.
The quality of excipients complies with the requirements of the corresponding Ph. Eur. and USP/NF
monograph.
25 g, 50 g, 60 g, 90 g or 100 g gel are packed in aluminium membrane tubes closed with plastic (PP or
PE) screw caps. Compliance of the material used for the primary package with the relevant European
requirements is demonstrated by certificate of conformity.
In the light of the provided stability data, the proposed shelf-life of 15 months with protecting from
light is accepted.
Pharmaceutical equivalence
According concept paper on the development of a guideline on “quality and equivalence of topical
products (EMA/CHMP/QWP/558185/2014)”, pharmaceutical equivalence tests have been carried out
comparing quality data of diclofenac sodium 30 mg/g gel with the relevant reference medicinal
products, including qualitative and quantitative composition, microstructure, physical properties,
product performance, and administration. The tests were performed with the EU product “Solaraze 3%
gel” and also with the US product “Solaraze 3% gel”.
Diclofenac sodium 30 mg/g gel and the EU reference product “Solaraze 3% gel” are considered to be
pharmaceutically equivalent since:
• The pharmaceutical form is the same.
• The active substance content is the same.
• All the excipients used in both products are qualitatively same and quantitatively
similar.
• Quality characteristics are essentially the same. In particular, the applicant has
provided compared in-vitro diffusion studies showing that the diffusion profiles of the
generic and EU reference product are comparable. In addition, the submitted in-vitro
skin permeation study shows a similar cumulative permeation profile between
reference and EU reference product.
• Administration is the same.
In addition, the applicant submitted a supportive therapeutic equivalence study investigating the
efficacy and safety of Diclofenac sodium 30 mg/g gel in comparison with placebo and with the US
reference product (see Section III.3).
Diclofenac-ratiopharm 30 mg/g Gel/ Diclofenac AbZ 30 mg/g Gel, DE/H/5130+5138/001/DC Public AR 5/8III.2 Non-clinical aspects Pharmacology, Pharmacokinetics, Toxicology The general pharmacodynamic, pharmacokinetic and toxicological properties of diclofenac are well known. As diclofenac is a widely used, well-known active substance, no further non-clinical studies are required in this regard and the Applicant provides none. Overview based on literature review is, thus, appropriate in this respect. The submitted non-clinical overview on the general non-clinical pharmacology, pharmacokinetics and toxicology of diclofenac is considered adequate. Local tolerance of the medicinal product has not been evaluated in non-clinical studies. However, this is considered acceptable, since skin tolerance was evaluated in a clinical study (see Clinical Assessment). Environmental Risk Assessment (ERA) Since the medicinal product is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.3 Clinical aspects Pharmacokinetics The proposed product, diclofenac sodium 30 mg/g gel, is a locally applied product. As stated in the guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1), the conventional approach to determine bioequivalence based on systemic measurements of plasma concentration is not applicable for products that are intended for local use only without any significant systemic absorption. The applicant declared that the proposed product contains the same qualitative and similar quantitative composition as the EU reference product, Solaraze 3%, gel. According the concept paper on the development of a guideline on “quality and equivalence of topical products (EMA/CHMP/QWP/558185/2014)”, the applicant has submitted in-vitro data comparing the qualitative and quantitative composition, microstructure, physical properties, product performance, and administration, to proof pharmaceutical equivalence of diclofenac sodium 30 mg/g gel with the EU reference product. In addition, the applicant submitted a supportive therapeutic equivalence study (efficacy and safety of test product in comparison with placebo) including the comparison of diclofenac sodium 30 mg/g with the US reference product. Supportive data The applicant has conducted a randomized, double-blind, multiple-site, placebo-controlled, parallel design study comparing diclofenac sodium gel 3% (generic) to Solaraze (diclofenac sodium) Gel 3% in the treatment of actinic keratosis (Study 71204901). The US study 71204901 was a multi-center (31 centers) clinical trial conducted in 476 patients with actinic keratosis. The developed generic version of diclofenac sodium gel 3% was found to be therapeutically equivalent to Solaraze (diclofenac sodium) Gel 3% for the primary endpoint of 100% clearance of all the AK lesions within the treatment area at Study Day 90 (30 days after completion of 60 days of treatment). Both the Test and Reference products were also shown to be superior to placebo for the primary endpoint of 100% clearance of all AK lesions within the treatment area at Study Day 90 (30 days after completion of 60 days of treatment). Fisher’s exact analysis was performed for adverse events reported at least once in two or more treatment groups. There were two (2) statistical differences between the Test, Reference and Placebo groups in the occurrence of AEs. Fisher’s exact analysis of adverse events revealed that “Bronchitis” (p = 0.0258) and “Squamous Cell Carcinoma” (p = 0.0388) occurred at statistically significantly different rates between the three treatment groups. No further analysis was required for “Squamous Cell Carcinoma” (p = 0.0388) due to occurrence in the Placebo group only. Further analysis comparing the Test group to the Reference group demonstrated that there was no significant difference between the Test group and the Reference group in the occurrence of “Bronchitis” (p=1.0000). The descriptive analysis comparing the application site reactions for each treatment group using the Wilcoxon Rank Sum test showed no significant differences between the treatment groups. The type, incidence and severity of the adverse events reported during the study were consistent with the disease being treated and those anticipated based on the labelling of the reference product. Diclofenac-ratiopharm 30 mg/g Gel/ Diclofenac AbZ 30 mg/g Gel, DE/H/5130+5138/001/DC Public AR 6/8
The Applicant has confirmed that the US test product used in the supportive therapeutic equivalence
study 71204901 is identical to the EU test product. From the clinical point of view the presented study
data are accepted as supportive data.
Accordingly, the clinical data from the therapeutic equivalence study (efficacy and safety of test
product in comparison to placebo) is considered supportive clinical (in vivo) data which taken together
support a conclusion of therapeutic equivalence between the applied product and the EU reference
product.
Legal Status
Medicinal product is subject to prescription only.
User Testing
The Applicant has not provided a full user testing report. However, a bridging report has been
presented. A bridging is considered acceptable due to the below mentioned grounds:
According to the guidance “Consultation with Target Patient Groups - Meeting the Requirements of
Article 59(3) without the Need for a Full Test – Recommendations for Bridging, CMDh/100/2007 Rev
1 April 2009”, a successful user test on one “parent” PL can be used to support a justification for not
testing a similar leaflet (“daughter” PL). A bridging report will not include the original data submitted
in respect of the “parent” PL, but the user consultation for the “parent” should have been submitted in
another application and the leaflet approved prior to the approval of the “daughter” PL. The “parent”
PL Solaraze 3% Gel was authorised via procedure numbers as approved under UK/H/0226/002/E02.
Furthermore, the design and layout issues have been addressed in the bridging report.
Summary Pharmacovigilance system
The Applicant has submitted a signed Summary of the Applicant's and/or Proposed Future MAH's
Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies
with the new legal requirements as set out in the Commission Implementing Regulation and as
detailed in the GVP module, the RMS considers the Summary acceptable.
Risk Management Plan
The applicant submitted a RMP.
The Safety specification was amended as proposed by the RMS:
Summary of safety concerns
Important identified risks • Hypersensitivity reactions including urticaria, asthma,
angioedema
• Photosensitivity reactions
Important potential risks • Systemic adverse drug reactions (gastrointestinal,
haemorrhagic, cardiovascular, renal and hepatic)
due to use on large areas/over prolonged period
• Use during third trimester of pregnancy
Missing information • Safety in pregnancy and breastfeeding
No additional pharmacovigilance activities and no additional risk minimisation activities are proposed
by the applicant. This is acceptable.
Periodic Safety Update Report (PSUR)
The marketing authorisation holder shall submit periodic safety update reports for this product in
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.
Diclofenac-ratiopharm 30 mg/g Gel/ Diclofenac AbZ 30 mg/g Gel, DE/H/5130+5138/001/DC Public AR 7/8IV. BENEFIT RISK ASSESSMENT Diclofenac sodium 30 mg/g gel and the EU reference product “Solaraze 3% gel” are considered to be pharmaceutically equivalent. In addition, the applicant submitted a supportive therapeutic equivalence study showing therapeutic equivalence of Diclofenac sodium 30 mg/g gel compared to the US reference product “Solaraze 3% gel” for the primary endpoint of 100% clearance of all the AK lesions within the treatment area at Study Day 90 (30 days after completion of 60 days of treatment). Both the Test and Reference products were also shown to be superior to placebo for the primary endpoint. Thus, from the clinical point of view, the benefit-risk-balance for Diclofenac sodium 30 mg/g gel is considered to be positive. The application is approved. For intermediate amendments see current product information. Diclofenac-ratiopharm 30 mg/g Gel/ Diclofenac AbZ 30 mg/g Gel, DE/H/5130+5138/001/DC Public AR 8/8
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