Mutual Recognition and Decentralised Procedure

UnternehmensstrategieAblaufplanung

Probleme

Dr. Ulrich Granzerwww.granzer.biz

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

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

Das Finden des „richtigen“ RMSKriterien

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

Das Finden des „richtigen“ RMSweitere Kriterien

Indikationsgebiet– Spezialisierung von Behörden

– Expertenwissen in Behörden

– Assoziationen zwischen Behörden

– Medizinische Praxis in Europa• Nord - Süd - Ost - West - Unterschiede

• Unterschiede zwischen Einzelländern

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“

Kriterienkatalog

Kriterium (Beispiele) Gewichtung (1 – 5)

Lokaler Support 4

Opinionleader im Land 2

Medizinische Praxis 5

Dialogmöglichkeiten mit Behörde

5

Klinische Prüfungen im Land 2

...

Summe Land 1

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

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

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

Ziele des Behördendialogs

Vorstellung des Produktes

Kennen lernen der Experten

Erfahren, wo eventuelle Problemfelder liegen

Aufbau eines Vertrauensverhältnisses zwischen pharmazeutischem Unternehmer und Behörde

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?

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

EMA Guidance Cover letter (1-3 pages)

Name of company Contact Person details (Telephone; Fax; E-mails) 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)

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

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

Die Verfahren

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

Application to first member state

Assessment reportincluding SPC, PIL

First Authorization: RMS

210 days

Applicant request on mutual recognition of first(reference) authorisation

Mutual Recognition Process

Objections from CMSsBy day 50

clarification and dialogue / point ofview of applicant (orally or writing)

resolution of issues

Additional National Authorization(s)

35 days

National evaluation and licencing process

Mutual Recognition Procedure

90 days

5 days

21

Application to all member statesRMS to start review

CMSs send comments to RMS and Applicant Consultation between RMS, CMS and Applicant (5 days)

PAR to CMSs and Applicant

70 days

Day 105: Clock stop orpositive close of procedure

RMS updates PrAR to prepare draft AR (DAR)

Day 106: Submission of the response

RMS evaluation of the dossier: Preliminary Assessment Report(PAR)

Decentralized Procedure

30 days

Preparation of response document by applicant3 – 6 months

Day 120: Consensus?End of procedure

Day 120: No consensus?Follow on process

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

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

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

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

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)

Assessment reports und SPC

Unterstützung („Justification“) der Schlüsselstellen der SPC1. Indikation

2. Kontraindikationen

3. Vorsichtsmaßnahmen bei der Anwendung

4. Nebenwirkungen: CAVE US Data Sheet

Alle anderen Punkte sind weniger bedeutsam

MRP

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

Tag 85 - 89

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

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

Referral aus der Sicht des Betroffenen

CPMP Meetings in wingdings

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

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

EU Risk Management Plan

Vier Hauptpunkte

Risk detection

Risk assessment

Risk minimisation

Risk communication

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 post-authorisation safety studies.

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

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

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

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

Risk Minimisation Plan: Aufgaben

Definition der potentiellen Risiken– Alle Indikationseinschränkungen

• Kontra - Indikationen

• Vorsichtsmaßnahmen bei der Anwendung

• Schwangerschaft

• Bedienen von Maschinen

– Nebenwirkungen– Abhängigkeiten– Wechselwirkungen– Klasseneffekte

Wechselwirkungen

Häufigster Grund für Rücknahmen

Fast immer Cytochrom P 450

Umsetzung

Risikokommunikation– Arzt/Apotheker

• Werbematerial

• Außendienstmitarbeiterschulung

• Dear Dr Letter

– Patient• Gebrauchsanweisung

• Schulungsmaterial für den Arzt zur Abgabe an den Patienten

Überwachung der Effekte der Umsetzung

Umfragen zur Risikokommunikation

Epidemiologische Studien (Beispiel GPRD/ HMO‘s)

Anwendungsbeobachtungen

Phase IV Studien

Signaldetektion aus PMS

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)

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

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

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???

Clinical Overview

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

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

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

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

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

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

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

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

From Potential Serious Risk to Public Health to a Decision of the European Commission - Industry Experiences

Dr Ulrich GranzerGranzer Regulatory Consulting & Services

Munich, Germany

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European Marketing Authorisation

Scope

64

MRP and DCP

Scope

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

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Article 17 of Directive 2001/83/EC

“1. ...

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 39.

2. 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.”

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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 39.”

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Application to first member state

Assessment reportincluding SPC, PIL

First Authorization: RMS

210 days

Applicant request on mutual recognition of first(reference) authorisation

Mutual Recognition Process

Objections from CMSsBy day 50

clarification and dialogue / point ofview of applicant (orally or writing)

resolution of issues

Additional National Authorization(s)

35 days

National evaluation and licencing process

Mutual Recognition Procedure

90 days

5 days

Decentralised Procedure

69

70

Application to all member statesRMS to start review

CMSs send comments to RMS and Applicant Consultation between RMS, CMS and Applicant (5 days)

PAR to CMSs and Applicant

70 days

Day 105: Clock stop orpositive close of procedure

RMS updates PrAR to prepare draft AR (DAR)

Day 106: Submission of the response

RMS evaluation of the dossier: Preliminary Assessment Report(PAR)

Decentralized Procedure

30 days

Preparation of response document by applicant3 – 6 months

Day 120: Consensus?End of procedure

Day 120: No consensus?Follow on process

71

Day 120: Follow on process

CMSs send comments to RMS and Applicant Consultation between RMS, CMS and Applicant (5 days)

Day 145: CMSs send (final) comments on draft AR

25 days

Day 150: Consensus?:

Procedure is forwarded to the Coordination group for the Mutual Recogntionand the Decentralized Procedure (CMD)

Day 180: CMD becomes involved

CMSs prepare response to Draft Assessment Report

Decentralized Procedure

30 days

RMS prepares report on outstanding issues by Day 18030 days

Day 195: Discussion at CMD/Break out session

End of procedureYes?

NO?

Day 195: Discussion at CMD/Break out session

Day 210: Mutual Approval?

Referral to CMD

Decentralized Procedure

End of procedureGrant of national licenses within 30 days

Yes?NO?

Publication ofAssessment report on the internet

Day 195: Discussion at CMD/Break out session

Day 210: Mutual Approval?

Referral to CMD

Decentralized Procedure

End of procedureGrant of national licenses within 30 days

Yes?

NO?: life becomes difficult!

Publication ofAssessment report on the internet

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

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CMD(h)-Referral in DCP and MRP

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

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Day 0 RMS starts procedure: Draft LoQ to MSs for comments

Day 10 final LoQ to the Applicant

Day~20 1st CMD-Meeting: Discussion of case

Day 25 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

60 Days CMD-Procedure (CMD-SOP)

Day 35 Updated AR of the RMS to CMD

Day 45 MSs position on response to LoQ

Day~50 Discussions at 2nd CMD-Meeting; Hearing of written comments

Day 60 close of procedure with two options:

consensus or referral to CHMP

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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!

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Referrals to CHMP in 2007 (21 Procedures)

Product Reason for Referral to CHMP CHMPVantas 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

The next round

CHMP Referral

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

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

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

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

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

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

THANK YOU