1 Zulassung von biotechnologischen Arzneimitteln Forum März 2010 Dr. Stefan Blesse Granzer Regulatory Consulting & Services
2 ICH relevance and Guidelines Scientific Advice meeting EMEA Structure and content of key FDA Meetings EMEA pre-submission meeting request Das zentrale Zulassungsverfahren, die Rolle von BfArM, PEI Conditional approval, exceptional circumstances Toxicology testing of MAb s Biogenerics
3 ICH The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration.
4 ICH Purpose The purpose is to make recommendations on ways to achieve greater harmonisation in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines.
5 ICH Objective The objective of such harmonisation is a more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines whilst maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health
6 Stufen der Erstellung einer Guideline bei ICH... Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA.
7 Internationales Regelwerk für biotechnologische Arzneimittel ICH guidelines Prinzipiell eigene Guidelines für Biotech Produkte in den Bereichen CMC: Chemistry, Manufacture and Controls/ Chemie/Pharmazie Toxikologie Prinzipiell gleiche Entwicklungsbedingungen Klinik
8 Chemie/Pharmazie Quality of Biotechnological Products Q5A Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin Q5B Quality of Biotechnological Products : Analysis of the Expression Construct in Cells Used for Production of r-dna Derived Protein Products Q5C Quality of Biotechnological Products : Stability Testing of Biotechnological/Biological Products Q5D Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products Q5E Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process
9 Q5A: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin The tripartite harmonised ICH guideline was finalised (Step 4) in March This is concerned with testing and evaluation of the viral safety of biotechnology products derived from characterised cell lines of human or animal origin. The purpose is to provide a general framework for virus testing experiments for the evaluation of virus clearance and the design of viral tests and clearance evaluation studies.
10 Scope Viral safety of biotechnology products derived from characterised cell lines of human or animal origin (i.e., mammalian, avian, insect), not TSE! Viruses That Could Occur in the Master Cell Bank (MCB) Adventitious Viruses That Could Be Introduced during Production
11 To Do List Suggested Virus Tests for MCB Working Cell Bank (WCB)
12 Q5E: Comparability of Biotechnological /Biological Products Subject to Changes in Their Manufacturing Process The tripartite harmonised ICH guideline was finalised (Step 4) in November The objective of this document is to provide principles for assessing the comparability of biotechnological/biological products before and after changes are made in the manufacturing process for the drug substance or drug product.
13 Q5E: Therefore, this guideline is intended to assist in the collection of relevant technical information which serves as evidence that the manufacturing process changes will not have an adverse impact on the quality, safety and efficacy of the drug product. The document does not prescribe any particular analytical, nonclinical or clinical strategy.
14 S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals The tripartite harmonised ICH guideline was finalised (Step 4) in July This document covers the preclinical safety testing requirements for biotechnological products. It addresses the use of animal models of disease, determination of when genotoxicity assays and carcinogenicity studies should be performed, and the impact of antibody formation on duration of toxicology studies S6 preclin safety biotech sb.pdf
15 CHMP Alle Guidelines wurden übertragen Keine gravierenden Unterschiede zu ICH Regelwerk wird derzeit um biosimilars erweitert
16 FDA Alle Guidelines wurden übertragen Keine gravierenden Unterschiede zu ICH Regelwerk wird derzeit nicht um biosimilars erweitert Entwicklung: Senat hatte geplant, bis zum Herbst 2007 ein Regelwerk zu initiieren (zusammen mit der FDA)
17 Vorgehensweise Guidelines geben nur Anhaltspunkte keine Kochrezepte Konsequenzen: Aufstellung eines detaillierten Entwicklungsplans Genaue Charakterisierung des Wirkstoffes Bindungsverhältnisse Spezifität: humanspezifisch? Diskussion der Entwicklung mit FDA, EMEA, nationalen Behörden
18 Scientific Advice EMEA
19 EMEA Guidance Cover letter (1-3 pages) Name of company Contact Person details (Telephone; Fax; s) Description of the product Trade Name (if available) INN (if available) Company s code Pharmacological classification (ATC code if available) Eligibility for centralised procedure Type of request: SA or PA, Initial or Follow-Up Area of advice: Quality/Pre-Clinical/Clinical/Significant benefit (for protocol assistance)
20 EMEA Guidance Fee payment (for SA) Fee waiver/reduction (Protocol Assistance) Justification for request Intended Indication(s) to be supported by the development at time of MAA Mention of previous Scientific Advice received (National and/or EU Authorities, Other Relevant International Authorities) Detailed Table of Contents; containing full listing of annexes and references
21 Briefing document including the Questions and Company's positions The questions are ordered and numbered sequentially to address specific scientific issues (order: quality/biotech/preclinical/clinical issues/significant benefit). Each question is followed by a separate company s position including a justification(s) of the company strategy for each topic. The company s position should be summarised after each question in the briefing document.
22 Annexes include Background information (Product Profile, Inv. Brochure) Information relating to the questions (e.g. relevant study protocols or draft study protocol or study outlines) Bibliographical data (references) Content of previous scientific advice received (national EU Authorities, other rel. Int. authorities, eg FDA) Relevant guidelines (other than CHMP Guidance documents), e.g. ICH, FDA
23 The new Advice Procedure with EMEA Aims: Reduced time frame (40/70 days instead of 70/100d) Broader and more general advice for specific types of medicinal products or treatments, in collaboration with the relevant Working Parties Emphasis on products intended for the new mandatory centralised procedure, i.e. acquired immune deficiency syndrome, cancer, neurodegenerative disorders, diabetes and, as of 20 May 2008, auto-immune diseases and other immune dysfunctions and viral diseases Emphasis on emerging therapies and new therapies
24 The new Advice Procedure with EMEA Emphasis on safety aspects of scientific advice, including review of pharmacovigilance plans SA requests on acceptability of the development programme for future conditional approval SA requests on the design of trials to assess safety and efficacy in a new indication expected to bring significant clinical benefit compared to existing therapies, for the purpose of extending the data protection of one year as defined in Article 14(11) SA requests for medicinal products intended to be marketed exclusively outside the Community, in the context of WHO collaboration as defined in Article 58(2).
25 Areas for scientific advice Quality (!) Preclinical section: Relevant species Duration of tox testing Clinical Indication vs. study objectives Endpoints Inclusion and Exclusion criteria
26 Who should attend? Company: Experts Observer Moderator Not: CEO, Final decision makers
27 Structure and content of key FDA Meetings
28 Meeting with the FDA Nothing required Highly recommended Three different types: A; B; C
29 Timelines for the different meetings
30 Type A Immediate need - stalled drug development program (i.e., a critical path) Generally reserved for dispute resolution, to discuss clinical holds, and special protocol assessment Scheduled with 30 days of FDA receipt of a written request Company may not want to have such a meeting!!!!!!!!!!!!!!!
31 Type B Pre-IND Certain end of Phase 1 End of Phase 2/pre-Phase 3 Pre-NDA/BLA FDA generally grants one each of the Type B for each potential application (i.e., NDA, BLA). Scheduled within 60 days of the FDA receipt of the written request
32 Type C Do not pertain to the development/review of NDA Policy meeting, meeting on a special item of global importance, like discussion on surrogate endpoints Not related to advertising/promotional labeling launch activities and materials Scheduled within 75 days of request
33 Pre-IND meeting Primary focus on pre-clinical and clinical data to support proposed initial IND trial Preliminary overview of proposed drug development program May be equivalent to EOP1 or EOP2 meeting for drugs already studied in foreign countries or under other INDs Goal: Avoid clinical hold on initial IND
34 End of phase II meeting Most important meeting between FDA and sponsor during drug development Review of pre-clinical, clinical, and CMC data from Phase 1 and 2 studies Review proposed pivotal trials and overall drug development program Focus on proposed claims for labeling Goal: FDA agreement to Phase 3 program
35 Pre-NDA (pre-submission) meeting Ideally 6 to 12 months before planned NDA submission Uncover major, unresolved problems Preliminary review of data from Phase 3 studies Primary focus on format and content of NDA Discussion of plan for electronic submission Goals: Avoid refusal to file and prepare for efficient review of NDA
36 Special Protocol Assessment Reauthorization of PDUFA 1997 (PDUFA II) Provision for special protocol assessment & agreement Evaluate within 45 days certain protocols / issues to assess adequacy per scientific / regulatory requirements
37 Procedure Sponsor sends written request Purpose: Reach agreement on design/trial size Binding for sponsor and FDA after trial start Exemptions: With written agreement of sponsor & FDA If Director/FDA Reviewing division determines a substantial scientific issue essential for determination of safety or effectiveness of trial was identified after testing began. Timing: Usually response within 45 d after submission
38 Meetings with the FDA Who is responsible: Homepage Contact CSO (Consumer Safety Officer) or Project coordinator for a certain area Discuss information needs for the proposed meeting Prepare briefing book in accordance with guidance docs Discuss all deviations with CSO
39 Responsibilities of applicant Prepare agenda for meeting Briefing Book (all relevant infos, structure of briefing book in accordance with IND/CTD) Define participants from company and FDA as well
40 Internal procedures? Preparation of development plan CMC Preclinical Clinical Development Plan Outline of clinical trials Plan including timelines CCDS: Company Core Data Sheet TPP: Target Product Profile TPP Draft Template FDA.pdf Regulatory Plan
41 Why? Company has to show that own internal planning process intact and plan available (competence of company) Authority wants plan beforehand Company always in driver s seat
42 What s next? Define responsibilities within company One person finally and eventually responsible Timelines are defined A GANTT chart is available
43 Preparation of briefing One message defined Questions to be defined Clear questions No open questions Determination of company positions
44 Wrong questions Does the FDA have additional thoughts on how to show superiority of our product against the competitor Can you think of further tox testing? Should we do other work in analytics supporting our data?
45 Good questions We deem our clinical program appropriate to show xyz. Does the agency agree? As discussed in the briefing book the animal model leads to a clear proof of principle for our new drug candidate. Do you agree?
46 What next? Rehearse, then rehearse, and then rehearse Devils Advocate
47 Finally Submit meeting request only after the draft of the briefing book is already in good shape
48 EMEA Presubmission meeting request
49 Pre-submission Meeting - Content Structure of file Format of file: CTD vs ectd Specific requests: Accelerated approval Conditional approval Approval under exceptional circumstances Information to be provided to EMEA presubmission meeting form.doc
50 EU - Zulassungen
51 Zulassungen im zentralen Verfahren Alle Neuentwicklungen
52 Warum zentrales Verfahren? Neuheit Seit Aufkommen von biotechnologischen AM erst wenige Jahre vergangen Ressourcen Spezialwissen erforderlich Volksgesundheit Gefahrenabschätzung der neuen Technologien
53 VERORDNUNG (EG) Nr. 726/2004 Die Erfahrung, die seit dem Erlass der Richtlinie 87/22/EWG des Rates vom 22. Dezember 1986 zur Angleichung der einzelstaatlichen Maßnahmen betreffend das Inverkehrbringen technologisch hochwertiger Arzneimittel, insbesondere aus der Biotechnologie, gewonnen wurde, hat gezeigt, dass ein zwingendes zentralisiertes Verfahren für die Genehmigung von technologisch hochwertigen Arzneimitteln, insbesondere aus der Biotechnologie, eingerichtet werden muss, damit das hohe Niveau der wissenschaftlichen Beurteilung dieser Arzneimittel in der Europäischen Union aufrechterhalten wird und das Vertrauen der Patienten und der medizinischen Fachkräfte in diese Beurteilung erhalten bleibt.
54 726/2004 Besonders wichtig ist dies im Zusammenhang mit dem Entstehen neuer Therapien wie der Gentherapie und damit verbundener Zelltherapien und der xenogenen somatischen Therapie. Dieses Vorgehen sollte insbesondere zur Gewährleistung des reibungslosen Funktionierens des Binnenmarktes im Arzneimittelsektor beibehalten werden
55 Arzneimittel, die mit Hilfe eines der folgenden biotechnologischen Verfahren hergestellt werden Technologie der rekombinierten DNS; kontrollierte Expression in Prokaryonten und Eukaryonten, einschließlich transformierter Säugetierzellen, von Genen, die für biologisch aktive Proteine kodieren Verfahren auf der Basis von Hybridomen und monoklonalen Antikörpern.
56 Europäische Union Mehr als 40 Zulassungsbehörden EMEA Nationale Behörden Scientific advice prinzipiell zentral und/oder national
57 Deutschland Paul Ehrlich Institut Bundesinstitut für Arzneimittel und Medizinprodukte
58 PEI Mono- und polyklonale Antikörper Tumorimpfstoffe, Zellbank, Medien Klassische Impfstoffe Gentransfer- Arzneimittel Somatische Zelltherapeutika Xenogene Zelltherapeutika
59 BfArM Alle anderen! Chemisch modifizierte Moleküle Peptide Proteine Nukleinsäurederivate Aber: Es gibt Grenzbereiche, wo man fragen sollte
60 The Centralised Procedure Articles 6 14 of Regulation 726/2004
61 Evaluation timetable for Centralized Procedure at EMEA Nomination of Rapporteur and Co-Rapporteur Dossier Submission Day 1 Start of procedure Day 80 Receipt of assessment reports (AR) (primary conclusions by Rapporteur, Co-Rapporteur) Day CHMP discusses/amends draft questions Day 120 CHMP adopts list of questions for sponsor Clock stops Day 121 Clock re-starts after submission of responses
62 Evaluation timetable for Centralized Procedure at EMEA Day 150 Joint AR (Rapporteur + Co-Rapp) to EMEA Day 180 CHMP assessment report final no issues - test vote - List of outstanding issues Day 181 Oral explanation (with up to 60 additional days clarification process) Day 210 CHMP adopts final opinion
63 Final steps in CP & Commissions Decision Procedure Application to EMEA 210 days CHMP Opinion 45 days 60 days 15 days Applicant; Request for re-examination Deatiled grounds Final CHMP Opinion 15 days Applicant: No request for re-examination Draft of Commission Decision 15 days Transmission of the opinion with Annexes to Commission, MS and applicant 15 days Referral to Agency new Rapporteur 22 days Important new questions of a scientific or technical nature Standing Committee YES 15 days Applicant NO Communication to the Council: Commission may defer the decision for 1 month Abbreviation: MS = Member State Final Commission Decision = Approval Council may take a divergent decision
64 Special schemes in Regulation (EC) 276/2004 Conditional Marketing Authorisation Article 14 (7) Regulation 726/2004, and Regulation EC No 507/2006 EMEA Draft Guidance EMEA/509951/2006 Exceptional Circumstances: Article 14 (8) of Regulation (EC) No 276/2004 Relevant documentation for applications in exceptional circumstances are laid down in Part II of Annex I of Directive 2001/83/EC, as amended. 64 Guideline EMEA/357981/2005 Accelerated Assessment Article 14 (9) of Regulation (EC) No 726/2004 Guideline EMEA/419127/2005
65 Conditional Approval Regulation 726/2004, Article 14, 7 authorisation may be granted subject to certain specific obligations to be renewed annually by the Agency The provisions for granting such authorisation shall be laid down in a Commission Regulation adopted in accordance with the procedure referred to in Article 87(2) and this Commission Regulation is: EC 507/
66 EC 507/2006 : Conditional Approval Scope (Art 2) serious debilitating or life-threatening emergency threats orphan drugs Conditions (Art 4), all to be met positive benefit/risk evaluation likely that comprehensive data can be provided unmet medical need (no satisfactory method, major therapeutic advantage) benefit of immediate availability outweighs the risk inherent in the fact that additional data are still required CMC + preclinical data available as usual Eligible for accelerated assessment
67 EC 507/2006 : Conditional Approval OBLIGATIONS and PROVISIONS (507/2006 Art 5) 1. the MAH holder shall be required to complete ongoing studies or to conduct new studies 2. the collection of pharmacovigilance data: RMP! 3. timeframe for completion shall be clearly specified in the conditional marketing authorization 67
68 EC 507/2006 : Conditional Approval Wheras: It should also be made clear that applications containing requests for conditional marketing authorisations may be the subject of an accelerated assessment procedure in accordance with Article 14(9) of Regulation (EC) No 726/
69 EC 507/2006 : Conditional Approval Valid for 1 year Renewable, to be switched to a regular MA E.g. Sutent (PFIZER), Velcade (JANNSSEN) 69
70 Exceptional Circumstances Regulation 726/2004, Article 14 (8) applicable when, in respect of particular therapeutic indications, the applicant can show that he is unable to provide comprehensive data on the efficacy and safety under normal conditions of use 70
71 Exceptional Circumstances Authorization must be based on one of the following grounds (set in Annex I to Directive 2001/83/EC): Rarity of disease (e.g. orphans) If it would be contrary to generally accepted principles of medical ethics to collect such information (e.g. pandemics, war, terrorist attacks) e.g. develop vaccine against anthrax This kind of MAH will not lead to a full MA- Dossier Annual re-assessment of these conditions is foreseen 71
72 Exceptional Circumstances OBLIGATIONS: applicant shall complete studies within a time period specified results of which shall form the basis of a reassessment of the benefit / risk administered only under strict medical supervision the package leaflet and any medical information shall draw the attention of the medical practitioner 72
73 Conditional Approval & Exceptional Circumstances Conclusion: the formal requirements of the RMP may increase the chances to make use of the conditions offered by conditional or exceptional approval RMP crucial Always further studies Likely: higher PSUR reporting frequency 73
74 Conditional vs. MA under Exceptional Circumstances Reg. (EC) 507/2006 Reg. (EC) 726/2004, Art. 14 and Dir. 2001/83/EC, Annex I 74
75 Special Schemes all products non-orphan drugs orphan drugs total (74.7*) 38 (25.3*) normal 132 (88.0*)# 106 (94.6 %)# 26 (68.4 %) accelerated 2 (1.3 %) 1 (0.9 %) 1 (2.6 %) exceptional 9 (6.0 %) 1 (0.9 %) 8 (21.1 %) conditional 8 (5.3 %) 5 (4.6 %) 3 (7.9 %) * of all products # due to the fact that Isentres conditional + accelerated Survey by Granzer Regulatory Consulting & Services, Dr. M. Dormeyer (CHMP press releases and EPARs Sept Oct. 2009) 75
76 Accelerated Assessment Regulation 726/2004 whereas (33): In order to meet, in particular, the legitimate expectations of patients and to take account of the increasingly rapid progress of science and therapies, accelerated assessment procedures should be set up, reserved for medicinal products of major therapeutic interest, and procedures for obtaining temporary authorisations subject to certain annually reviewable conditions 76
77 Accelerated Assessment Regulation 726/2004, Article 14 (9) When an application is submitted which are of major interest from the point of view of public health and in particular from the viewpoint of therapeutic innovation, the applicant may request an accelerated assessment procedure. The request shall be duly substantiated. If the Committee for Medicinal Products for Human Use accepts the request, the time-limit laid down in Article 6(3) first subparagraph, shall be reduced to 150 days. 77
78 Accelerated assessment Regulation 726/2004, Article 14 (9): When an application is submitted of major interest of public health and from the viewpoint of therapeutic innovation the applicant may request an accelerated assessment procedure 78
79 Centralized Procedure: Reg. 726/2004, Art Centralised Procedure Day 1 Clock stop Day 120 Clock start Day 121 Day 210 CHMP opionion in 210 days Start of procedure Clock start Day 121 Commission Decicion Making Process EU-Marketing Authorisation Day 1 Clock stop Day 120 Approval real day 150, no clock stop CHMP opionion in 150 days Accelerated Procedure accellerated may be withdrawn by CHMP on day 120
80 Biogenerics Per Definition not possible Guidance for certain substances/substance classes (epo, cancer/kidney) gcsf, heparin... for efficacy extrapolation Is biosimilarity possible or may biosimilars to be better than the originators? Reference products from the US not allowed for legal reasons even though this provokes unnecessary clinical studies Route of administration may change!
81 Thank you