CHMP ASSESSMENT REPORT FOR Elonva

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CHMP ASSESSMENT REPORT FOR Elonva

Transcript Of CHMP ASSESSMENT REPORT FOR Elonva

European Medicines Agency Evaluation of Medicines for Human Use
London, 19 November 2009 Doc.Ref.: EMA/CHMP/802299/2009
CHMP ASSESSMENT REPORT FOR Elonva
International Nonproprietary Name: corifollitropin alfa Procedure No. EMEA/H/C/1106
Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted.
7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 75 23 70 51
E-mail: [email protected] http://www.emea.europa.eu

TABLE OF CONTENTS

1. 1.1 1.2
2. 2.1. 2.2. 2.3. 2.4. 2.5. 2.6.

BACKGROUND INFORMATION ON THE PROCEDURE ........................................... 3 Submission of the dossier ........................................................................................................ 3 Steps taken for the assessment of the product.......................................................................... 3
SCIENTIFIC DISCUSSION................................................................................................. 5 Introduction.............................................................................................................................. 5 Quality aspects ......................................................................................................................... 7 Non-clinical aspects ............................................................................................................... 11 Clinical aspects ...................................................................................................................... 17 Pharmacovigilance................................................................................................................. 36 Overall conclusions, risk/benefit assessment and recommendation ...................................... 40

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1. BACKGROUND INFORMATION ON THE PROCEDURE

1.1 Submission of the dossier

The applicant N.V. Organon submitted on 04 December 2008 an application for Marketing Authorisation to the European Medicines Agency (EMEA) for Elonva, through the centralised procedure falling within the Article 3(1) and point 1 of Annex of Regulation (EC) No 726/2004.

The legal basis for this application refers to:

A - Centralised / Article 8(3) / New active substance.

Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application.

The applicant applied for the following indication: “Controlled Ovarian Stimulation (COS) for the development of multiple follicles and pregnancy in women participating in an Assisted Reproductive Technology (ART) program.”

Information on Paediatric requirements

Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMEA Decision P/131/2008 for the following condition:

• Hypogonadotrophic hypogonadism.

on the agreement of a paediatric investigation plan (PIP).

The PIP is not yet completed.

Scientific Advice:

The applicant received Scientific Advice from the CHMP on 27 January 2006. The Scientific Advice pertained to non-clinical and clinical aspects of the dossier.

Licensing status:

The product was not licensed in any country at the time of submission of the application.

The Rapporteur and Co-Rapporteur appointed by the CHMP and the evaluation teams were:

Rapporteur: Pieter de Graeff

Co-Rapporteur: Patrick Salmon

1.2 Steps taken for the assessment of the product

• The application was received by the EMEA on 04 December 2008. • The procedure started on 24 December 2008. • The Rapporteur's first Assessment Report was circulated to all CHMP members on 13 March
2009. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 19 March 2009. • During the meeting on 20-23 April 2009, the CHMP agreed on the consolidated List of Questions to be sent to the applicant. The final consolidated List of Questions was sent to the applicant on 23 April 2009. • The applicant submitted the responses to the CHMP consolidated List of Questions on 22 July 2009. • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Questions to all CHMP members on 4 September 2009.

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• The Rapporteurs circulated the updated Joint Assessment Report on the applicant’s responses to all CHMP members on 17 September 2009.
• The final GCP integrated inspection report of the inspection carried out at one investigator site in South Korea (06-10/04/09), one investigator site in Taiwan (13-17/04/09) and at the sponsor site in the Netherlands (11-14/05/09) was issued on 22 September.
• During the CHMP meeting on 21-24 September 2009, the CHMP agreed on a List of Outstanding Issues to be addressed in writing or in an oral explanation by the applicant.
• The applicant submitted the responses to the CHMP list of outstanding issues on 15 October 2009.
• The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Outstanding Issues to all CHMP members on 2 November 2009.
• The Rapporteurs circulated the updated Joint Assessment Report on the applicant’s responses to all CHMP members on 13 November 2009.
• During the meeting on 16-19 November 2009, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a Marketing Authorisation to Elonva on 19 November 2009. The applicant provided the letter of undertaking on the follow-up measures to be fulfilled post-authorisation on 18 November 2009.
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2. SCIENTIFIC DISCUSSION
2.1. Introduction
This is an application for a biotech medicinal product containing corifollitropin alfa in the frame of the centralised procedure submitted in accordance with Article 3(1) and point 1 of Annex of Regulation (EC) No 726/2004 and with Article 8(3) of Directive 2001/83/EC, as amended (i.e. a complete and independent application with administrative, quality, pre-clinical and clinical data). The medicinal product Elonva contains the active substance corifollitropin alfa (also called Org 36268), a new glycoprotein, which belongs to the pharmaceutical class of the gonadotropins. corifollitropin alfa is a new glycoprotein produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology, using chemically defined cell culture medium without the addition of antibiotics, human or animal derived proteins (protein-free) or any other components of human or animal origin. By adding the carboxy-terminal peptide of the β-subunit of hCG to the β-chain of human FSH (Figure 1), the elimination half-life of Elonva was almost 2-fold increased compared to recFSH (33 hours, range 27-41 hours). Figure 1: Schematic representation of the design of Elonva (adapted from Thesis of Beckers N.G.M., Follicular and Luteal Phase Aspects of Ovarian Stimulation for In Vitro Fertilization, 2006, Erasmus University, Rotterdam, The Netherlands).
FSH is available on the European market in combination with LH (hMG = human menopausal gonadotropin) and in purified forms derived from human menopausal urine or as recombinant peptide produced by cultured cells.1,2 The currently approved recombinant follicle stimulating hormones (FSH) in Europe are Puregon (follitropin beta) and Gonal-F (follitropin alfa), which have additional indications besides the indication“Controlled Ovarian Stimulation in medically assisted reproduction programs”. Please refer to the EPAR for these products for more detailed information. Corifollitropin alfa is proposed for ART programs only.
1 Nugent D, Vandekerckhove P, Hughes E, et al. Gonadotrophin therapy for ovulation induction in subfertility associated with polycystic ovary syndrome. Cochrane Database Syst Rev 2000;(4):CD000410. 2 Bayram N, van Wely M, van Der Veen F. Recombinant FSH versus urinary gonadotrophins or recombinant FSH for ovulation induction in subfertility associated with polycystic ovary syndrome. Cochrane Database Syst Rev 2001 ;(2):CD002121.
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Due to its prolonged duration of FSH activity, a single subcutaneous injection of the recommended dose of corifollitropin alfa may replace the first seven injections of any daily (rec)FSH preparation in a COS treatment cycle.
Secretion of gonadotropins (LH and FSH) is controlled by GnRH (gonadotropin releasing hormone) produced in the hypothalamus. FSH, like LH, is synthesized and secreted by the anterior pituitary gland. FSH is essential for normal female gamete growth and maturation, and normal gonadal steroid production. In the first protocols used in assisted reproduction techniques (ART; standard “long” protocol), a GnRH agonist was used to suppress the hypothalamic-pituitary ovarian axis for controlled ovarian stimulation and additionally to prevent a premature LH surge. When desensibilisation has been achieved, controlled ovarian stimulation with gonadotropins (FSH alone or FSH + LH) is started, while the use of the GnRH agonist is continued until the time when hCG will be administered. Another option for ovarian stimulation in ART is the use of a GnRH antagonist. In contrast to the long-acting agonists that first stimulate and later inhibit pituitary gonadotropin secretion by desensitizing gonadotrophs to GnRH via receptor down-regulation, the antagonists block the GnRH receptor in a dose-dependent competitive fashion and have no flare effect; gonadotropin suppression is almost immediate.
Corifollitropin alfa is recommended for use in a GnRH-antagonist protocol. As stimulation starts in the early follicular phase of the natural cycle, the duration of stimulation is shorter and less FSH is used as compared to the standard ART protocol with a GnRH agonist. A schematic presentation of the dosing schedule is given in Figure 2:
Figure 2. Corifollitropin alfa /GnRH antagonist treatment regimen, as used in the pivotal Phase III studies 38819 and 107012
Note: The duration of FSH treatment and the day of hCG administration were dependent on the follicular response as assessed by ultrasonography.
The proposed therapeutic indication of corifollitropin alfa was “Controlled Ovarian Stimulation (COS) for the development of multiple follicles and pregnancy in women participating in an Assisted Reproductive Technology (ART) program.”
The approved indication is: “Controlled Ovarian Stimulation (COS) in combination with a GnRH antagonist for the development of multiple follicles in women participating in an Assisted Reproductive Technology (ART) program”
Treatment with corifollitropin alfa should be initiated under the supervision of a physician experienced in the treatment of fertility problems. Corifollitropin alfa is supplied in pre-filled syringes as a solution for injection (0.5 ml), either containing 100 μg or 150 μg of corifollitropin alfa. In women with a body weight ≤ 60 kilograms a single dose of 100 micrograms should be administered. In women with a body weight > 60 kilograms a single dose of 150 micrograms should be administered. The recommended doses of corifollitropin
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alfa have only been established in a treatment regimen with a GnRH antagonist. For further information on the stimulation scheme please refer to section 4.2 of the SPC.
Paediatric aspects
With respect to the granted indication (COS) a waiver in all subsets of the paediatric population was granted on the grounds that clinical studies in COS cannot be expected to be of significant therapeutic benefit to or fulfil a therapeutic need of the paediatric population.
Nevertheless for the indication “Treatment of hypogonadotrophic hypogonadism” studies within a paediatric subset will be performed.

2.2. Quality aspects

Introduction

The drug substance corifollitropin alfa is a glycoprotein consisting of two non-covalently linked subunits: an alfa subunit and a beta subunit corresponding to that of human FSH extended with a Cterminal peptide (CTP) corresponding to the beta subunit of hCG.

Corifollitropin alfa is derived from a Chinese Hamster Ovary cell line (CHO-K1) and a two-tiered cell banking system of Master Cell Bank (MCB) and Working Cell Bank (WCB) was developed by the applicant.

Corifollitropin alfa is produced using a chemically-defined cell culture medium without the addition of antibiotics, proteins or any other components of human or animal origin. The fermentation process consists of pre-culture and culture steps followed by cell free clarification. Two production scales are proposed.

Purification from the cell culture harvest is performed in an 11-step process comprising a series of chromatography steps, ultrafiltration/diafiltration steps, steps to inactivate and remove potential viral contaminants and a microfiltration step.

The drug product manufacturing process includes thawing of the drug substance, formulation with the excipients and mixing, sterile filtration and fill-finish.

Elonva is presented as a solution for subcutaneous injection in a pre-filled syringe for single use. Two dosage forms have been developed: 100 μg and 150 μg.

Drug Substance

Nomenclature INN Name: Compendial Name: USAN/JAN: Laboratory Code Name: CAS Registry Number: Other Names:

corifollitropin alfa not applicable corifollitropin alfa Org 36286 195962-23-3 Follicle-stimulating hormone (human alfa-subunit reduced) complex with follicle-stimulating hormone (human beta-subunit reduced) fusion protein with 118-145 chorionic gonadotropin (human beta subunit)

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Description of the drug substance
The drug substance corifollitropin alfa is a glycoprotein consisting of two non-covalently linked subunits: an alfa subunit of 92 amino acids which is common to different glycoprotein hormones (FSH, LH, TSH, hCG) and a beta subunit corresponding to that of human FSH (111 amino acids) extended with CTP of the beta subunit of hCG (28 amino acids). The alfa and beta subunits each contain two N-linked glycosylation sites and disulphide bonds (five and six, respectively). The CTP part contains six O-linked glycosylation sites. The apparent molecular mass of corifollitropin alfa is 47 kDa.
• Manufacture
All manufacturing steps, Quality Control testing and release of the drug substance are performed at N.V. Organon, Oss, The Netherlands. This site is EU-GMP compliant and a valid manufacturing authorisation was provided.
Development genetics
The cell line producing corifollitropin alfa was generated by transfection of Chinese Hamster Ovary cells (CHO-K1) with an expression plasmid comprising DNA sequences which encode the alfa chain and the extended beta subunit, yielding CHO.FSH.CTP13 after cloning and sub-cloning steps. The CHO.FSH.CTP13 cell line was gradually adapted to grow in protein-free and animal component free culture medium. The adapted clone CHO.FSH.CTP13.PF.5 (“Research” cell line) was thus generated and used for the preparation of a MCB and WCB.
Cell bank system
A two-tiered cell banking system of MCB and WCB has been developed and maintained in accordance to cGMP and ICH guidelines.
Seed cells corresponding to the high-producing clone CHO.FSH.CTP13.PF.5 were thawed, resuspended and cultured in a protein-free and animal component free culture medium, leading to the establishment of the MCB and WCB. Procedures followed for the preparation of MCB and WCB were appropriately described. An extensive range of tests has been performed for their characterisation, in accordance with ICH guidelines, including identity, viability, genetic stability and viral safety.
Fermentation process
Pre-culture is initiated from a single WCB vial and subsequent expansion in a culturing container, seed bioreactor and production bioreactor, successively. A production bioreactor is then inoculated. Following the production phase, the bioreactor is harvested using cross-flow filtration or dead end filtration in order to remove cells from the cell culture supernatant. The resulting cell culture filtrate is then further purified.
Purification process
Purification of the cell free culture supernatant is performed by chromatographic, concentration/diafiltration and virus removal/inactivation steps.
Manufacturing process development and process validation
Throughout development, changes have been introduced in the drug substance manufacturing process, including the protein free cell line, formulation and manufacturing scale.
A comprehensive process manufacturing history was provided, showing the different changes introduced, and the corresponding batches involved, as well as the use of these batches.
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An extensive comparability exercise was conducted between the non protein-free process and the commercial protein-free process. Comparability studies were also conducted to support the scale-up of the fermentation process.
The corifollitropin alfa manufacturing process was validated using data from both process scales with respect to consistency, robustness performance and quality attributes. It was demonstrated that the process consistently maintains process parameters within specified ranges and meets acceptance criteria for performance indicators. Overall, process validation was considered satisfactory.
Characterisation
A) Elucidation of structure and other characteristics:
The elucidation of the structure of corifollitropin alfa was mainly based on complete amino acid sequence analysis, peptide mapping and analysis of the post-translational modifications (glycosylation and disulfide bridges). The amino acid sequence matches exactly the prediction based on the DNA nucleotide sequence and was further confirmed by the results for the amino acid composition and the N-terminal sequence. Nterminal heterogeneity was shown comparable to that of recombinant FSH (follitropin beta).
The N-linked glycan structures were determined to be bi-, tri- and tetra-antennary oligosaccharides with sialic heterogeneity, as expected for the FSH part. The O-linked glycan structures were determined to be mono- and bi-antennary oligosaccharides with sialic heterogeneity, as expected for the hCG part.
Five disulfide bridges in the alfa subunit and three of the beta subunit were determined, whereas three other disulfide bridges were inferred from the crystal structures of hCG and FSH. No other posttranslational modifications are present.
Conformational analysis of corifollitropin alfa confirmed structural resemblance to gonadotropins.
B) Impurities:
Potential process-related impurities include cell substrate derived impurities (host cell proteins, host cell DNA), microbiological contaminants, column leachables, residual solvents and additives (antifoaming agent).
Potential product-related substances and impurities include deamidation products, oxidation products free subunits, oligomers (aggregation of two or more heterodimers), N-terminal residue loss.
• Specification
The drug substance release specifications, which include tests for identity, purity and impurities, potency, quantity and general attributes, are acceptable and well justified.
• Stability
The design of the stability program, including the testing intervals and temperature storage conditions, are in accordance with current ICH guidelines. The tests chosen are a subset of tests from the release specifications selected for stability-indicating properties. The stability data provided were within the specifications and support the proposed shelf life and the proposed storage conditions for the drug substance.
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Drug Product
• Pharmaceutical Development
Elonva is presented as a solution for subcutaneous injection in a pre-filled syringe (type I hydrolytic glass) for single use. Each syringe contains 100 μg or 150 μg of corifollitropin alfa formulated with sodium citrate, sucrose, polysorbate 20, methionine, sodium hydroxide, hydrochloric acid and water for injections. These excipients are commonly used in formulating protein pharmaceuticals. The syringe is assembled into an automatic safety system to prevent needle stick injuries after use and is packed together with a sterile injection needle. Each pre-filled syringe contains 0.5 ml solution for injection.
Throughout drug product development changes have been introduced, including a new formulation and primary container. The new formulation, corresponding to the commercial formulation, was used for Phase I, the Phase II dose finding study and all Phase III studies.
• Adventitious Agents
No human-/animal-derived raw materials were used in the preparation of the MCB or WCB and in the manufacture of the drug substance and drug product. Only cells prior to the Research cell line were cultivated with foetal calf serum (FCS) sourced from USA, Canada and Australia. Data were provided to support the use of FCS. MCB, WCB and host cell lines were tested for bovine viruses and no contamination was detected. Safety concerning TSE is considered sufficiently assured. Control of potential contamination by other non-viral adventitious agents (mycoplasma, bioburden, endotoxins) was considered adequate.
Extensive virus screening was conducted. The MCB, WCB, post-production cells and bulk harvest were found to be free from infectious adventitious viral contamination. However, as expected for CHO cells, the transmission electron microscopy investigation showed minimal evidence of virus-like particles. The purification process of corifollitropin alfa includes several steps for inactivation/removal of viruses. Viral safety has been sufficiently demonstrated. To further confirm the robustness of the process, the applicant will undertake post-approval studies.
• Manufacture of the product
The drug product is manufactured at Vetter Pharma-Fertigung, GmbH & Co. KG, Ravensburg, Germany. Assembly with the safety device and secondary packaging of the drug product is carried out at Organon (Ireland) Ltd., Swords, Ireland. Quality control testing and batch release are performed at Organon (Ireland) Ltd., Swords, Ireland or NV Organon, Oss, The Netherlands.
The frozen purified drug substance is thawed, formulated with the different excipients, sterile filtered and aseptically filled into sterile glass syringes which are then closed with a plunger and a tip cap.
Process validation was performed and provided a documented, thorough understanding of the ability of the manufacturing process to consistently and reliably meet predetermined product specifications and quality attributes.
• Product specifications
Appropriate specifications have been developed. The drug product specifications contain tests for identity, impurities, potency, quantity and general attributes.
• Stability of the Product
Real-time and accelerated stability studies were initiated in accordance with ICH guidelines and per protocol to monitor the time-temperature stability of cGMP lots of drug product. On the basis of the
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