Mutual Recognition and Decentralised Procedure

Transkript

1 Mutual Recognition and Decentralised Procedure Unternehmensstrategie Ablaufplanung Probleme Dr. Ulrich Granzer

2 Regulatorische Aspekte und Strategien Strategien für die Verfahrenswahl Dialogstrategien mit Behörden: Scientific Advice Auswahlkriterien des RMS und CMS Dossier und Sachverständigengutachten EU Zulassungsstrategien als Teil der globalen Entwicklung User Testing Environmental Risk Assessment Pharmacovigilanzsysteme

3 Kriterienkatalog für eine neue Substanz: Verfahrenswahl Bekanntheitsgrad der Indikation Je neuer desto zentraler immer zentral: HIV und virale Erkrankungen, Krebs, Diabetes, Neurodegenerative Erkrankungen (z.b. Alzheimer), Orphans, Biotechs Medizinische Schule in der EU Indikationsspezifische Unterschiede Länderspezifische Besonderheiten Paediatric Regulation KONSEQUENZ: NEUE SUBSTANZEN IMMER ZENTRAL

4 Das Finden des richtigen RMS Kriterien Flexibilität, wenn es schwierig wird Antizipation der europäischen Situation Bisherige Verfahren (Track Record) Rolle in Gremien (z.b. Efficacy WP, ICH) Verteidigung der Erstzulassung Anwalt der Firma kritisch-positive Zusammenarbeit mit der Firma

5 Das Finden des richtigen RMS weitere Kriterien Indikationsgebiet Spezialisierung von Behörden Expertenwissen in Behörden Assoziationen zwischen Behörden Medizinische Praxis in Europa Nord - Süd - Ost - West - Unterschiede Unterschiede zwischen Einzelländern

6 Weitere Punkte Concerned Member States Welche? Gibt es in einem Staat besondere Vorbehalte? Kann man von einer soliden Mehrheit der CMSs ausgehen? (Gefahr der Arbitration/Referrals) Ziel: Aufbau eines Kriterienkatalogs mit vordefinierter Gewichtung Vermeidung einer Bauchentscheidung

7 Kriterienkatalog Kriterium (Beispiele) Gewichtung (1 5) Lokaler Support 4 Opinionleader im Land 2 Medizinische Praxis 5 Dialogmöglichkeiten mit 5 Behörde Klinische Prüfungen im Land 2... Summe Land 1

8 Prinzipiell geeignete Produkte für die dezentralen Verfahren Früher: Neue Moleküle in bekannten Indikationen, die nicht im Brennpunkt einer Lobbying Gruppe stehen Jetzt: Neue Wirkmechanismen in bekannten Indikationen Generika

9 Paediatric development PIP and its implications for the choice of the procedure Regulation states Extension of the duration of the supplementary protection certificate For new medicines and for products covered by a patent or a Supplementary Protection Certificate (SPC), the six-month SPC extension will be granted if all the measures included in the agreed paediatric investigation plan are complied with, if relevant information on the results of studies is included in product information if the product is authorised in all Member States

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11 Behördendialog Welche Inhalte? Briefing Document, Präsentation, jeweils mit konkretem Ziel Wann, Wie oft? Vor Phase III Vor Einreichung Während des Verfahrens, wann immer ein konkreter Grund vorliegt Wer mit Wem? Experte mit Experte in moderiertem und gut vorbereitetem Gespräch

12 Ziele des Behördendialogs Vorstellung des Produktes Kennen lernen der Experten Erfahren, wo eventuelle Problemfelder liegen Aufbau eines Vertrauensverhältnisses zwischen pharmazeutischem Unternehmer und Behörde

13 How to obtain knowledge about authorities: Scientific Advice Questions regarding SciAdv When to go? Development plan How often? Topics? Topics to be avoided? How binding is a scientific advice? What happens if the advice from different authorities differs?

14 Comparison EU/FDA FDA: Pre-IND Meeting End of phase II Meeting Pre-NDA/pre-BLA Meeting EU: Before start of clinical development Before phase III Before submission

15 EMA 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)

16 EMA 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

17 Briefing document including the Questions and Company's positions The questions are ordered and numbered sequentially to address specific scientific issues (order: quality/biotech/pre-clinical/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. Overall objectives: Get advice and learn whether a working relationship can easily be established

18 Die Verfahren

19 Verfahrensablauf Die Rolle des BfArM als Reference Member State Assessment Reports Klärungs- und Dialogphase Arbitration gewünscht oder gefürchtet? SPCs Der Entscheidungsfindungsprozeß Übersetzung Spezifische nationale Anforderungen

20 Mutual Recognition Procedure Application to first member state 210 days National evaluation and licencing process First Authorization: RMS 90 days Mutual Recognition Process Assessment report including SPC, PIL Applicant request on mutual recognition of first (reference) authorisation By day days 5 days Objections from CMSs clarification and dialogue / point of view of applicant (orally or writing) resolution of issues 20 Additional National Authorization(s)

21 Decentralized Procedure Application to all member states RMS to start review 70 days RMS evaluation of the dossier: Preliminary Assessment Report (PAR) PAR to CMSs and Applicant 30 days Day 105: Clock stop or positive close of procedure CMSs send comments to RMS and Applicant Consultation between RMS, CMS and Applicant (5 days) 3 6 months Preparation of response document by applicant Day 106: Submission of the response RMS updates PrAR to prepare draft AR (DAR) Day 120: Consensus? End of procedure 21 Day 120: No consensus? Follow on process

22 Mutual Recognition und dezentrales Verfahren - Unterschiede MR MA vorhanden Assessment Report durch RMS Gegenseitige Anerkennung innerhalb von 90 Tagen nach Start Basis: Assessment Report Dezentral Keine MA vorhanden Application an alle Staaten, in denen eine Zul. angestrebt wird RMS erstellt Draft Assessment Report innerhalb der ersten Phase des Verfahrens

23 Mutual Recognition und dezentrales Verfahren - Unterschiede MR Bei Problemen: Coordination Group 60 Tage zur Lösung Falls die Unstimmigkeiten nicht gelöst werden: CHMP Dezentral Bei Unstimmigkeiten: Coordination Group 60 Tage zur Lösung Falls die Unstimmigkeiten nicht gelöst werden: CHMP

24 Rücknahmen Rücknahme vs potentielle Arbitration Seriousness of risks to public health Label changes Einführung von Kontraindikationen Anzahl der CMSs, die serious risks beschreiben Diskussion second wave vs Augen zu und durch Strategie Wann? Bis direkt vor Erhalt des Draft Assessment Reports

25 BfArM als RMS Beratungsgespräch(e) vor Einreichung Festlegung einer für beide Seiten verbindlichen Zeitschiene Europäisches Assessment Mängelschreiben mit besonderer Berücksichtigung möglicher nationaler Besonderheiten Dialog bereits während der Phase I der Bearbeitung Hinweis auf gravierende Probleme

26 Assessment Reports Kritisch genug Eindeutige, positive Stellungnahme bei positiver Entscheidung Eingehen auf europäische Problemfelder Beispiel: QT Streckenveränderungen im EKG Antibiotikaproblematik in der EU Verschieden medizinische Schulen Unterstützung durch pharm. Unternehmer: kritische Overviews (nur die sind gute Overviews)

27 Assessment reports und SPC Unterstützung ( Justification ) der Schlüsselstellen der SPC 1. Indikation 2. Kontraindikationen 3. Vorsichtsmaßnahmen bei der Anwendung 4. Nebenwirkungen: CAVE US Data Sheet Alle anderen Punkte sind weniger bedeutsam

28 MRP

29 Tag 50 bis Tag 90 Serious risks to public health Die Fragen müssen zufriedenstellend beantwortet werden RMS als wichtigster Ansprechpartner Diskussion der Antwortentwürfe Kommentierung von Fragen der CMS s Direkter Dialog RMS und CMS(s) Austausch aller relevanten Informationen Kollegen in der Behörde als Partner

30 Tag Finale Finalisierung der SPC kann man mit der SPC das Produkt vermarkten? Konkurrenznachteile? Alle Entscheidungsträger in der Firma anwesend? Diskussion potentieller Entscheidung mit RMS Information von RMS über Entscheidung vor Info an CMS Verhandlungsführer in Firma mit ausreichend Erfahrung essentiell

31 Wenn alles gut gegangen ist Information über Abschluss des Verfahrens an CMS s und Antragsteller Übersetzung der SPC in alle Landessprachen Zeitpunkt der Übersetzung innerhalb der Firma Geschwindigkeit der Zulassungserteilung: abhängig von der Bereitstellung der Übersetzung und der PIL

32 Referral aus der Sicht des Betroffenen CPMP Meetings in wingdings

33 Referral Läuft wie ein zentrales Verfahren Dauert einige Monate Entscheidung immer für die ganze EU, aber gerichtet an die Mitgliedsstaaten Wo kein Zulassungsantrag aktiv ist, gibt es nach Arbitration keine Zulassung Kriterien für die Einleitung von Seiten des Antragstellers Geschwindigkeit: Repeat use oder Referral: Entscheidung vor Tag 120 dezentral, Auswahl der CMS im MR Verfahren Situation (Mehrheitsverhältnisse) im CHMP

34 Risiko: Referral Geschwindigkeit Definierte clock stops, Zeit bei der Kommission und dem Standing Committee Effizienz Bezug nur auf "serious risks" Keine neuen Probleme im Referral Verfahren Status: Das Verfahren ist übersichtlicher geworden, die Zeiten werden eingehalten, neue Probleme werden (meist) nicht aufgeworfen

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36 EU Risk Management Plan

37 Vier Hauptpunkte Risk detection Risk assessment Risk minimisation Risk communication

38 Gesetzestext ensuring that any request from the competent authorities for the provision of additional information necessary for the evaluation of the risks and benefits of a medicinal product is answered fully and promptly, including the provision of information regarding the volume of sales or prescriptions for themedicinal product concerned providing the competent authorities with any other information relevant to the evaluation of the risks and benefits of a medicinal product particularly information concerning postauthorisation safety studies.

39 EU Risk Management Plan (EU-RMP) The description of a risk management system should be submitted in the form of an EU-RMP. Part I A Safety Specification A Pharmacovigilance Plan Part II An evaluation of the need for risk minimisation activities and (only) if there is a need for additional (ie non- routine) risk minimisation activities A risk minimisation plan

40 Wann muß ein Plan erstellt werden? Zu jeder Zeit möglich Einreichung zur Zulassung Alle neuen Arzneimittel! Biosimilars Signifikante neue Darreichungsform/Indikation Während der ersten Vermarktungsphase Signal Wiedereinführung nach Marktrücknahme Spezielle Sicherheitsvorkehrungen Immer, wenn es von einer Behörde gefordert wird Beispiele: Referral/Arbitration

41 EU Risk Management Plan (EU-RMP) The description of a risk management system should be submitted in the form of an EU-RMP. Part I A Safety Specification A Pharmacovigilance Plan Part II An evaluation of the need for risk minimisation activities and (only) if there is a need for additional (ie non- routine) risk minimisation activities A risk minimisation plan

42 The risk minimisation plan should list the safety concerns for which risk minimisation activities are proposed

43 Risk Minimisation Plan: Aufgaben Definition der potentiellen Risiken Alle Indikationseinschränkungen Kontra - Indikationen Vorsichtsmaßnahmen bei der Anwendung Schwangerschaft Bedienen von Maschinen Nebenwirkungen Abhängigkeiten Wechselwirkungen Klasseneffekte

44 Wechselwirkungen Häufigster Grund für Rücknahmen Fast immer Cytochrom P 450

45 Umsetzung Risikokommunikation Arzt/Apotheker Werbematerial Außendienstmitarbeiterschulung Dear Dr Letter Patient Gebrauchsanweisung Schulungsmaterial für den Arzt zur Abgabe an den Patienten

46 Überwachung der Effekte der Umsetzung Umfragen zur Risikokommunikation Epidemiologische Studien (Beispiel GPRD/ HMO s) Anwendungsbeobachtungen Phase IV Studien Signaldetektion aus PMS

47 Auflagen und Committments Unterschied Auflage: Condition for Approval Committment: Freiwillige Verpflichtung, eine Leistung zu erbringen Häufig verwendetes Tool Oft Phase IV Studien Manchmal Patientenregister (z.b. bei Orphans)

48 Bedeutung für die Firma Ohne RMP keine Zulassung! Standard für Neuzulassungen in neuen Therapiegebieten und neuen Produktklassen Marketingtool oder Verkaufsverhinderer Vorlage der Werbematerialien bei lokaler Behörde Rechtzeitige Abstimmung Planung innerhalb der Firma Globale vs nationale Planung

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50 ERA Wird bei neuen Substanzen immer verlangt Soll die Zulassung nicht behindern Umweltbundesamt als Behörde im Hintergrund Abstufung je nach Eintragsmenge in die Umwelt Abhängigkeit vom geschätzten Umsatz

51 Erfahrung mit dem DCP Das Verfahren funktioniert, wenn es losgegangen ist RMS kann positiv und negativ sein Referral bei Divergenzen: Einzelbehörde kann Verfahren verlangen 60 (90) Tage Extra CMD kann diskutieren, nicht entscheiden Slots Timing für Slots Auswahl der Behörde aufgrund nicht vorhandener Kapazität Fragen an Dr Bachmann: Wie slottet es denn so? Lösungsmöglichkeiten???

52 Clinical Overview

53 Clinical Overview The overview will be the most crucial document for a successful submission. Thus, the main items and issues should be named as clearly as possible and a story should be told throughout the document

54 Overview - content Medical need for treatment Introduction and exec summary Indication sought Summary of the main clinical trials Brief discussion that the benefit risk ratio is positive

55 Efficacy PK/PD profile Efficacy overview Description of the population treated Rationale on the medical need and a clear description of the patients benefit of the treatment Critical description of the clinical trials Justification of duration of treatment

56 Safety Overview on the safety of the drug class Drug drug interactions seen as well as some information on in vitro and animal experiments Cytochrome P450 subclasses Most important reason for withdrawals in the last 20 years QT prolongation

57 Safety SAE s, AE s: Description and valuation Signals of substance specific issues Target organ toxicity from animal experiments Special patient populations Elderly Children Hepatic and renal impairment

58 Overall benefit/risk evaluation This is the chapter where the SPC has to be defended based on the items and issues discussed above The rationale for the indication should be given based on the objectives of the trials Phase III trials determine the indication Only what has been shown and proven will be approved Patient populations excluded may become contra-indications

59 Overall benefit/risk evaluation The dosing should be explained for all strengths The side effects should be listed from trials (and from the field post launch experience) Precautions and contra indications need to be explained and justified

60 Aim of the overview Explain and defend the SmPC and the US and Japanese Data Sheets All headlines and paras to be dealt with Clear opinion of the expert Final statement: Benefit risk evaluation leads to a positive conclusion the new drug should be approved

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62 From Potential Serious Risk to Public Health to a Decision of the European Commission - Industry Experiences Dr Ulrich Granzer Granzer Regulatory Consulting & Services Munich, Germany

63 European Marketing Authorisation Scope 63

64 MRP and DCP Scope 64

65 Scope of MRP/DCP: New active substances (if not mandatory for the centralised procedure) Generic medicinal products to authorised reference medicinal products Informed consent Well established use (WEU; bibliographic applications) line extensions to national authorisations known substances in new combination New indications/new pharmaceutical forms for known substances 65

66 Article 17 of Directive 2001/83/EC Applications for marketing authorizations in two or more Member States in respect of the same medicinal product shall be submitted in accordance with Articles 27 to Where a Member State notes that another marketing authorization application for the same medicinal product is being examined in another Member State, the Member State concerned shall decline to assess the application and shall advise the applicant that Articles 27 to 39 apply. 66

67 Article 18 of Directive 2001/83/EC Where a Member State is informed in accordance with Article 8(3)(1) that another Member State has authorized a medicinal product which is the subject of a marketing authorization application in the Member State concerned, it shall reject the application unless it was submitted in compliance with Articles 27 to

68 Mutual Recognition Procedure Application to first member state 210 days National evaluation and licencing process First Authorization: RMS 90 days Mutual Recognition Process Assessment report including SPC, PIL Applicant request on mutual recognition of first (reference) authorisation By day days 5 days Objections from CMSs clarification and dialogue / point of view of applicant (orally or writing) resolution of issues 68 Additional National Authorization(s)

69 Decentralised Procedure 69

70 Decentralized Procedure Application to all member states RMS to start review 70 days RMS evaluation of the dossier: Preliminary Assessment Report (PAR) PAR to CMSs and Applicant 30 days Day 105: Clock stop or positive close of procedure CMSs send comments to RMS and Applicant Consultation between RMS, CMS and Applicant (5 days) 3 6 months Preparation of response document by applicant Day 106: Submission of the response RMS updates PrAR to prepare draft AR (DAR) Day 120: Consensus? End of procedure 70 Day 120: No consensus? Follow on process

71 Decentralized Procedure Day 120: Follow on process 25 days Day 145: CMSs send (final) comments on draft AR CMSs prepare response to Draft Assessment Report 30 days CMSs send comments to RMS and Applicant Consultation between RMS, CMS and Applicant (5 days) Day 150: Consensus?: Yes? End of procedure 30 days NO? RMS prepares report on outstanding issues by Day 180 Day 180: CMD becomes involved 71 Day 195: Discussion at CMD /Break out session Procedure is forwarded to the Coordination group for the Mutual Recogntion and the Decentralized Procedure (CMD)

72 Decentralized Procedure Day 195: Discussion at CMD /Break out session Day 210: Mutual Approval? NO? Yes? End of procedure Grant of national licenses within 30 days Publication of Assessment report on the internet Referral to CMD

73 Decentralized Procedure Day 195: Discussion at CMD /Break out session Day 210: Mutual Approval? Yes? NO?: life becomes difficult! End of procedure Grant of national licenses within 30 days Referral to CMD Publication of Assessment report on the internet

74 Public Assessment report on the internet Information on the product Information on the reasons for apporval Justification of indications and other major sections of SPC (Summary of Product Characteristics) Description of dossier content: Preclinical and clinical Good source for competitors Deletion of commercially confidential information Definition may differ between applicant and authority

75 75 CMD(h)-Referral in DCP and MRP

76 CMD-Referral - Trigger: Disagreement between MS concerned by the application at the end of MRP (Day 90) or DCP (Day 210) based on potential serious risk to public health What does this mean? If all are positive: Case closed If all are negative but the applicant: CASE CLOSED One MS has to be positive to trigger a referral

77 60 Days CMD-Procedure (CMD-SOP) Day 0 Day 10 Day~20 Day 25 RMS starts procedure: Draft LoQ to MSs for comments final LoQ to the Applicant 1st CMD-Meeting: Discussion of case Response from Applicant on LoQ 10 days for preparation of response (day 11 day 20) No new information Usually no new arguments Improvement of statements if possible Cooperation with RMS, if RMS is positive Cooperation with CMS, if at least one CMS is positive 77

78 Day 35 Day 45 Day~50 Day 60 Updated AR of the RMS to CMD MSs position on response to LoQ Discussions at 2nd CMD-Meeting; Hearing of written comments close of procedure with two options: consensus or referral to CHMP

79 Withdrawal of Applications The applicant has the right to withdraw the application until the last day of the MRP or DCP. However, if the applicant has withdrawn the application from a MS because a potential serious risk to public health was raised by this MS, the application will be automatically forewarded for discussion to the CMD(h) A withdrawal will not help the applicant! 79

80 Referrals to CHMP in 2007 (21 Procedures) Product Reason for Referral to CHMP CHMP Vantas Safety & Efficacy positive Fentastad (5) Bioequivalence, SPC, Quality, Non-clinical Negative-RE Simvastatin Krka Bioequivalence negative Eformax Quality, Safety & Efficacy negative Bicaluplex 150 mg Safety & Efficacy of an indication positive Xeomin Safety & Efficacy positive Menitorix Safety & Efficacy positive Coxtral Efficacy negative Pulairmax Quality, Safety & Efficacy negative Oracea Safety & Efficacy positive Rapinyl Safety & Efficacy positive Alvesco Efficacy positive Atorvastatin (4) Bioequivalence withdrawn 80

81 The next round CHMP Referral

82 Referral under Article 29(4) of Council Directive 2001/83/EC, as amended

83 Why does it come to referrals, an example? Feedback from CHMP Summary of major issues resolved during the CMD(h) procedure between day 0 and day 60 Summary of the final coordination group discussion and remaining unresolved scientific issues Risk:benefit concerns In conclusion the overall risk:benefit for Interesting Product has not been sufficiently demonstrated by the submitted documentation and the RMS concludes that the product is not approvable Proposed list of questions To be addressed by applicant in the OE and in writing

84 The life example Start of Procedure 20 September 2007 Responses to LoQ: 03 December 2007 Restart of the procedure: 25 December 2007 Assessment Report: 09 January 2008 Comments from CHMP: 14 January 2008 Oral Explanation/Opinion: CHMP January 2008

85 The outcome The new Rapporteur and the Applicant convinced the CHMP to give a consensus vote, which was positive. The RMS eventually became positive as well The eventual Rapporteur played a key role in the entire procedure and was open for discussions with the company at any stage of the procedure starting already in the pre-cmd phase

86 Meaning for the applicant Eventual approval Repeat use procedure with member states not involved in the DCP should lead to approval without Objections as CHMP and EU Commission have been positive Time consuming compared to regular DCP

87 Overall Conclusion: Science has to be right All steps need a very thorough and detailed preparation The responses and, in particular, the OE need a lot of work Someone with the right experience needs to be part of the applicant s team: Experience in Oral Explanations Preparation of response documents Discussion and sometimes negotiations with regulatory authorities at any stage of procedure

88 THANK YOU

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