Regulatory experiences and future mechanisms to accelerate product development and approval in the EU

Transcription

1 Regulatory experiences and future mechanisms to accelerate product development and approval in the EU Dr. Ilona Reischl BASG/AGES Austrian Agency for Health and Food Safety GmbH

2 Disclaimer EMA: The views expressed in this presentation are my personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. BASG/AGES: The views expressed in this presentation are my personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the Austrian Competent Authority. 2

3 Current Frameworks in Europe Clinical Trials Market Access Marketing Authorization Named patient use Approval under exceptional circumstances Compassionate use Conditional approval Regular MA 3

4 Clinical Trials Regulation A binding legislative act that must be applied in its entirety across the EU in its exact wording. Directive A legislative act that sets out a goal that all EU countries must achieve, but it is up to the individual countries to decide how. During the integration into national law adaptation to existing legislation might be necessary. Clinical trials used to be governed by a directive (Dir/2001/20/EC) and in the future will be governed by a regulation to ensure harmonization 4

5 Public Access to documents "Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Document access: Doc /1; ; (COD)&l=en Guidance on posting and publication of result-related information on clinical trials in relation to the implementation of Article 57(2) of Regulation (EC) No 726/2004 and Article 41(2) of Regulation (EC) No 1901/2006 (October 2012) EudraLex Vol. 10; Chapter V: Additional Information 5

6 Draft Clinical Trial Regulation The Goals Harmonised authorisation dossier (EudraLex, Vol. 10) Single portal for submission managed by EMA Reporting MS proposed by applicant; involvement of intended MSs Clear, binding (maximal) timelines Distinction between cooperative and intrinsic national/local aspects `Qualified opt-out for a MS Organizational setup and internal competences MS responsibility Swift procedure to extend a CT to additional MSs Coordination/advisory forum managed and chaired by the Commission 6

7 Article 14: 2 nd wave Arbitrary example 2 nd wave EU-portal RMS Part I Opt-out EU-portal EU-portal Part II Part II Opt-out EU-portal Applicant cms Part II Part II Part II Approval Part II Part II Part II Flags from 7

8 Article 11 Limitation to part I Arbitrary example EU-portal RMS Part I EU-portal Part II within 2 y Approval Applicant cms Flags from 8

9 Assessment Part I 9

10 Named patient use Art. 5 Dir/2001/83/EC A Member State may, in accordance with legislation in force and to fulfil special needs, exclude from the provisions of Dir/2001/83/EC medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorized health care professional and for use by his individual patients on his direct personal responsibility 10

11 Compassionate Use Art. 83 REG 2004/726 Exemption from Art. 6 of Dir/2001/83/EC: Member States may make a medicinal product for human use (eligible for centralized licensure) available for compassionate use Definition: Making a product available to a group of patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who cannot be treated satisfactorily by an authorized medicinal product. The product must either be the subject of a MAA or undergoing clinical trials. Member State shall notify the Agency on approvals, CHMP may adopt opinions Applicants need to give patients access to the new medicinal product during the period between authorization and placing on the market 11

12 EU Central Marketing Authorization MA under exceptional circumstances Conditional MA Regular MA Comprehensive data Cannot be provided Rare indication Scientific knowledge Ethical issues Annual review Early evidence for positive Benefit/risk Annual review until completion Comprehensive data on benefit/risk Review after 5y 12

13 Licensure under exceptional circumstances Article 14 (8) of the Regulation (EC) No 276/2004, and Part II of Annex I of Directive 2001/83/EC, as amended Criteria: Inability to provide comprehensive data on the efficacy and safety under normal conditions of use, because: the intended indication is encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, or in the present state of scientific knowledge, comprehensive information cannot be provided, or it would be contrary to generally accepted principles of medical ethics to collect such information 13

14 Licensure under exceptional circumstances Obligations may include the following: the applicant shall complete an identified programme of studies within a time period specified by the competent authority, the results of which shall form the basis of a reassessment of the benefit/risk profile the medicinal product in question may be supplied on medical prescription only and may in certain cases be administered only under strict medical supervision, possibly in a hospital and in the case of a radio-pharmaceutical, by an authorized person the package leaflet and any medical information shall draw the attention of the medical practitioner to the fact that the particulars available concerning the medicinal product in question are as yet inadequate in certain specified respects 14

15 Approvals exceptional circumstances EMA Homepage products, 14 orphan Medicine Active Substance MAH Authorisation Orphan Replagal agalsidase alfa Shire Human Genetic Therapies AB 2001 no Aldurazyme laronidase Genzyme Europe B.V no Ventavis iloprost Bayer Schering Pharma AG 2003 no Xagrid anagrelide Shire Pharmaceutical Contracts Limited 2004 yes Prialt ziconotide Eisai Ltd yes ATryn antithrombin alfa GTC Biotherapeutics UK Limited 2006 no Evoltra Clofarabine Genzyme Europe B.V yes Naglazyme Galsulfase BioMarin Europe Ltd yes Atriance nelarabine Glaxo Group Limited 2007 yes Elaprase idursulfase Shire Human Genetic Therapies AB 2007 yes Increlex mecasermin Ipsen Pharma 2007 yes Yondelis trabectedin Pharma Mar S.A yes Ceplene histamine dihydrochloride Meda AB 2008 yes Ilaris canakinumab Novartis Europharm Ltd 2009 no Adjupanrix split influenza virus, inactivated, containing antigen: A/VietNam/1194/2004 (H5N1) like strain used (NIBRG-14) GlaxoSmithKline Biologicals S.A no Firdapse amifampridine BioMarin Europe Ltd 2009 yes influenza virus surface antigens, inactivated: A/Viet Nam/1194/2004 Novartis Vaccines and Diagnostics S.r.l. Foclivia 2009 no (H5N1) Pandemic Influenza Vaccine H5N1 Baxter whole virion inactivated containing antigen of pandemic strain: A/Vietnam/1203/2004(H5N1) 7.5micrograms per0.5ml dose Baxter AG 2009 no Vedrop tocofersolan Orphan Europe S.A.R.L no Pumarix pandemic influenza vaccine (H5N1) (split virion, inactivated, GlaxoSmithKline Biologicals S.A. adjuvanted) 2011 no Vyndaqel tafamidis Pfizer Ltd yes Glybera alipogene tiparvovec uniqure biopharma B.V yes Defitelio defibrotide Gentium SpA 2013 yes Lojuxta lomitapide Aegerion Pharmaceuticals 2013 no Orphacol cholic acid Laboratoires CTRS 2013 yes 15

16 Conditional Marketing Authorization Marketing authorisation on the basis of less complete data than is normally the case and subject to specific conditions and obligations.. when the patient population in a disease is small and comprehensive clinical trials are not feasible or where the medicinal product aims at the treatment, the prevention or the medical diagnosis of seriously debilitating or life threatening disease May be granted provided that the benefit/risk profile is positive Pharmacovigilance legislation provides additional tools for the conduct of post-authorization safety and efficacy studies Once the specific obligations are fulfilled and the missing data are provided, it is possible to convert the conditional marketing authorization into a normal marketing authorization. ec.europa.eu/health/files/latest_news/ _personalised_medicine_en.pdf 16

17 Conditional Approvals EMA Homepage products, 5 orphan Medicine Active Substance MAH Authorisation Orphan Diacomit stiripentol Biocodex 2007 yes Vectibix panitumumab Amgen Europe B.V no Tyverb lapatinib Glaxo Group Limited 2008 no Arzerra ofatumumab Glaxo Group Ltd 2010 yes Fampyra fampridine Biogen Idec Ltd no Votubia everolimus Novartis Europharm Ltd yes Adcetris brentuximab vedotin Takeda Pharma A/S 2012 yes Caprelsa vandetanib AstraZeneca AB 2012 no Pixuvri pixantrone dimaleate CTI Life Sciences Ltd no Xalkori crizotinib Pfizer Ltd no Bosulif bosutinib (as monohydrate) Pfizer Ltd 2013 yes Erivedge vismodegib Roche Registration Ltd 2013 no 17

18 Licensure Recommendation for EMA scientific advice or protocol assistance for orphan medicinal products Parallel scientific advice with FDA Parallel scientific advice with HTA (Health Technology Assessment) Specifically about the justification for applying for a MA under exceptional circumstances - on the inability to provide comprehensive data Recommendation for a pre-submission meeting Regulatory Scientific advice and protocol assistance 18

19 EMA Roadmap to continue to review the model for regulation of medicines in the EU, particularly with regard to: the development of medicines the benefit/risk balance the point of decision-making for authorization post-authorization follow-up the growing importance of health technology assessment bodies specific considerations relating to herbal medicines a possible reconsideration of the extent to which legislation governing veterinary medicines is tailored to the specific requirements of this sector 19

20 EMA Roadmap to 2015 The Agency's focus in the area of facilitating access to medicines will be on activities designed to reduce the productivity gap that currently exists in the development of medicines. Activities in this area will include investigating the underlying reasons for the productivity gap, encouraging the use of scientific advice during the development process, and promoting early interaction between regulators and sponsors. The Agency will also explore how regulatory pathways can best align market access of new medicines with the growing knowledge over time of benefits and risks 20

21 Implementation EMA Roadmap 21

22 EU HTA Network Members: National authorities or bodies responsible for HTA designated by the participating Member States Strategic multiannual work programme and evaluation instrument on the implementation of such programme Working groups to examine specific questions on the basis of terms of reference defined by the HTA Network On request of the Commission, EMA may participate in meetings of the HTA Network and its working groups HTA Network may invite European and international organizations to attend meetings as observers 22

23 References Adaptive Licensing: a useful approach for drug licensing in the EU? H-G. Eichler, EMA, London, March Appropriate evidence for adaptive marketing authorization J-P. de Jong, D.E. Grobbee, B. Flamion, S.R. Forda and H.G.M. Leufkens Nat. Rev. Drug Discovery Vol 12, 2013, p 647 The risks of risk aversion in drug regulation H-G. Eichler, B. Bloechl-Daum, D. Brasseur, A. Breckenridge, H. Leufkens, J. Raine, T. Salmonson, C.K. Schneider and G. Rasi Nat. Rev. Drug Discovery Vol 12, 2013, p

24 Thank you for your attention! 24

25 Exceptional circumstances Defitelio severe veno-occlusive disease (VOD) in patients undergoing haematopoietic stem-cell transplantation (O) patient registry for further data on long-term safety, health outcomes, and use in practice. Healthcare professionals to be provided with information on how to enter patients in the registry Lojuxta homozygous familial hypercholesterolaemia a long-term study for further data on safety and effectiveness, including side effects on the liver, stomach, gut, and cardiovascular system. Data on pregnancies in women taking the medicine, and on healthcare professionals compliance with the recommendations to screen and monitor patients before and during treatment Orphacol genetic deficiency of liver enzymes (O) database of patients treated with Orphacol to monitor the safety and effectiveness of the treatment. Results submitted to CHMP at regular, specified intervals 25

26 Conditions (EPAR) Bosulif Philadelphia-chromosome positive chronic myeloid leukaemia (CML)(O) the company that markets Bosulif will carry out and submit the results of a larger study with Bosulif in patients with Ph+ CML previously treated with one or more tyrosine kinase inhibitors and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options Erivedge - basal cell carcinoma the company that markets Erivedge will provide the results of a large safety study in patients with locally advanced or metastatic disease. It will also provide updated results on Erivedge s effectiveness and safety from the main study 26