Assessment report - European Medicines Agency

1 7 Westferry Circus Canary Wharf London E14 4HB United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416 E-mail Website An Agency of the European Union European Medicines Agency , 2011. Reproduction is authorised provided the source is acknowledged. 21 July2011 EMA/CHMP/424438/2011 Committee for Medicinal Products for Human Use (CHMP) Assessment report Plenadren International nonproprietary name: hydrocortisone Procedure No. EMEA/H/C/2185 Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Assessment report EMA/CHMP/424438/2011 Page 2/69 Table of contents 1 .. 3 Background information on the .. 3 Submission of the .. 4 Steps taken for the Assessment of the product2.

2 6 Scientific .. 6 .. 7 Quality .. 7 .. 7 Active .. 8 Finished Medicinal .. 9 Discussion on chemical, and pharmaceutical .. 10 Conclusions on the chemical, pharmaceutical and biological .. 10 Non- Clinical .. 10 .. 11 .. 14 .. 17 .. 20 Ecotoxicity/environmental risk .. 20 Discussion on Non-clinical .. 22 Conclusion on the non-clinical .. 23 Clinical .. 23 .. 24 .. 30 .. 30 Discussion on clinical .. 32 Conclusions on clinical .. 32 Clinical .. 48 Discussion on clinical .. 50 Conclusions on clinical .. 51 Clinical .. 58 Discussion on clinical .. 59 Conclusions on clinical .. 59 Consultation of Scientific Advisory Group (SAG) .. 61 .. 64 User consultation3 .. 64 Benefit-Risk Balance4.

3 68 Recommendation Assessment report EMA/CHMP/424438/2011 Page 3/69 1 Background information on the procedure Submission of the dossier The applicant DuoCort Pharma AB submitted on 06 May 2010 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Plenadren , through the centralised procedure under Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 23 October 2008. The application concerns a hybrid medicinal product as defined in Article 10(3)(b) of Directive 2001/83/EC and refers to a reference product for which a Marketing Authorisation is or has been granted in a Member State on the basis of a complete dossier in accordance with Article 8(3) of Directive 2001/83/EC, as amended.

4 Plenadren was designated as an orphan medicinal product EU/3/06/372 on 22 May 2006 in the following indication: treatment of adrenal insufficiency. The calculated prevalence of this condition was per 10,000 EEA population. Following the CHMP positive opinion on this marketing authorisation, the Committee for Orphan Medicinal Products (COMP) reviewed the designation of Plenadren as an orphan medicinal product in the approved indication. The outcome of the COMP review can be found on the Agency 's website: Medicine/Human Medicines /Rare disease designations. The Applicant applied for the following indication: Treatment of adrenal insufficiency in adults. The legal basis for this application refers to Article 10(3) of Directive 2001/83/EC hybrid application.

5 The application submitted is composed of administrative information, complete quality data, a clinical study comparing PK and safety with the reference medicinal product Hydrocortone and non-clinical and other clinical data based on the Applicant s own tests and studies and/or bibliographic literature substituting/supporting certain tests or studies. The chosen reference product is: Medicinal product which is or has been authorised in accordance with Community provisions in accordance with Community provisions in force for not less than 6/10 years in the EEA: Product name, strength, pharmaceutical form: Hydrocortone, 10mg, 20 mg, tablets Marketing authorisation holder: Merck Sharp & Dohme Ltd Date of authorisation: 23-02-1989 Marketing authorisation granted by: Member State (EEA) : UK - National procedure - Marketing authorisation number: PL 0025/5053, PL 0025/5054 Medicinal product authorised in the Community/Members State where the application is made or European reference medicinal product: Product name, strength, pharmaceutical form.

6 Hydrocortone, 10mg, 20 mg, tablets Marketing authorisation holder: Merck Sharp & Dohme Ltd Date of authorisation: 23-02-1989 Marketing authorisation granted by: UK - National procedure - Marketing authorisation number: PL 0025/5053, PL 0025/5054 Medicinal product which is or has been authorised in accordance with Community provisions in force and to which bioequivalence has been demonstrated by appropriate bioavailability studies: Product name, strength, pharmaceutical form: Hydrocortone, 10mg, 20 mg, tablets Marketing authorisation holder: Merck Sharp & Dohme Ltd Date of authorisation: 23-02-1989 Assessment report EMA/CHMP/424438/2011 Page 4/69 Marketing authorisation granted by: UK - National procedure - Marketing authorisation number: PL 0025/5053, PL 0025/5054 Bioavailability study number(s): 2006-0007084-89 Information on Paediatric requirements Not applicable.

7 Information relating to Orphan Market Exclusivity Similarity Not applicable. Market Exclusivity Not applicable. Scientific Advice The Applicant received protocol assistance from the CHMP on 21 September 2006 and 22 March 2007. The Scientific Advice pertained to clinical aspects of the dossier. Furthermore, National scientific advice pertained to clinical aspects of the dossier was provided by Sweden on 30 May 2005. Licensing status The product was not licensed in any country at the time of submission of the application. Steps taken for the Assessment of the product The Rapporteur and Co-Rapporteur appointed by the CHMP were: Rapporteur: Tomas Salmonson Co-Rapporteur: Robert James Hemmings The application was received by the EMA on 06 May 2010.

8 The procedure started on 23 June 2010. The Rapporteur's first Assessment report was circulated to all CHMP members on 10 September 2010. The Co-Rapporteur's first Assessment report was circulated to all CHMP members on 10 September 2010. During the meeting on 21 October 2010, 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 22 October 2010. The applicant submitted the responses to the CHMP consolidated List of Questions on 10 February 2011. The Rapporteur circulated the Assessment report on the applicant s responses to the List of Questions to all CHMP members on 28 March 2011. During the CHMP meeting on 14 April 2011, the CHMP agreed on a list of outstanding issues to be addressed in writing and by the applicant.

9 The Rapporteur circulated the Assessment report on the applicant s responses to the list of outstanding issues to all CHMP members on 07 June 2011. The SAG meeting of experts on 15 June 2011, convened to address questions raised by the CHMP. During the CHMP meeting on 21 June 2011, the CHMP agreed on a list of outstanding issues to be addressed in writing and in an oral explanation by the applicant. The Rapporteur circulated the Assessment report on the applicant s responses to the list of outstanding issues to all CHMP members on 08 July 2011. Assessment report EMA/CHMP/424438/2011 Page 5/69 During the CHMP meeting on 19 July 2011, outstanding issues were addressed by the applicant during an oral explanation before the CHMP.

10 During the meeting on 20 July 2011, 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 Plenadren. Assessment report EMA/CHMP/424438/2011 Page 6/69 2 Scientific discussion Introduction Plenadren modified-release tablets contain the active pharmaceutical ingredient (API) hydrocortisone, the most commonly prescribed API in glucocorticoid replacement therapy. Endogenous glucocorticoids are produced in the cortex of the adrenal gland with the main glucocorticoid in man being cortisol. Patients with adrenal insufficiency (AI) therefore lack endogenously produced cortisol. Adrenal insufficiency may be primary, as a result of a disease in the adrenal cortex, or secondary (central) due to an underlying hypothalamic-pituitary disorder.