Zulassung von biotechnologischen Arzneimitteln

Forum März 2010

Dr. Stefan BlesseGranzer Regulatory Consulting & Services

ICH relevance and GuidelinesScientific Advice meeting EMEAStructure and content of key FDA MeetingsEMEA pre-submission meeting requestDas zentrale Zulassungsverfahren, die Rolle von BfArM, PEIConditional approval, exceptional circumstancesToxicology testing of MAb´sBiogenerics

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.

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.

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

Stufen der Erstellung einer Guideline bei ICH

... Guideline has been developed by the appropriateICH Expert Working Group and has been subject toconsultation by the regulatory parties, inaccordance with the ICH Process. At Step 4 of theProcess the final draft is recommended for adoptionto the regulatory bodies of the European Union,Japan and USA.

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

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

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 1997. 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.

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

To Do List

Suggested Virus Tests for – MCB

– Working Cell Bank (WCB)

Q5E:

Comparability of Biotechnological /Biological Products Subject to Changes in Their Manufacturing Process

The tripartite harmonised ICH guideline was finalised (Step 4) in November 2004. 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.

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.

S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

The tripartite harmonised ICH guideline was finalised (Step 4) in July 1997. This document covers the pre-clinical 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

CHMP

Alle Guidelines wurden übertragen

Keine gravierenden Unterschiede zu ICH

Regelwerk wird derzeit um biosimilars erweitert

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)

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

Scientific Advice EMEA

EMEA 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)

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

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.

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

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

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).

Areas for scientific advice

Quality (!)

Preclinical section: – Relevant species

– Duration of tox testing

Clinical– Indication vs. study objectives

– Endpoints

– Inclusion and Exclusion criteria

Who should attend?

Company:– Experts

– Observer

– Moderator

– Not: CEO, Final decision makers

Structure and content of key FDA Meetings

Meeting with the FDA

Nothing required

Highly recommended

Three different types: A; B; C

Timelines for the different meetings

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!!!!!!!!!!!!!!!

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

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

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

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

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

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

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

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

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

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

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

What‘s next?

Define responsibilities within company– One person finally and eventually responsible

– Timelines are defined

– A GANTT chart is available

Preparation of briefing

One message defined

Questions to be defined– Clear questions

– No open questions

– Determination of company positions

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?

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?

What next?

Rehearse, then rehearse, and then…rehearse

Devils Advocate

Finally

Submit meeting request only after the draft of the briefing book is already in good shape

EMEA Presubmission meeting request

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

EU - Zulassungen

Zulassungen im zentralen Verfahren

Alle Neuentwicklungen

Warum zentrales Verfahren?

Neuheit– Seit Aufkommen von biotechnologischen AM erst wenige

Jahre vergangen

Ressourcen– Spezialwissen erforderlich

Volksgesundheit– Gefahrenabschätzung der neuen Technologien

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.

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

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.

Europäische Union

Mehr als 40 Zulassungsbehörden

EMEA

Nationale Behörden

Scientific advice prinzipiell zentral und/oder national

Deutschland

Paul Ehrlich Institut

Bundesinstitut für Arzneimittel und Medizinprodukte

PEI

Mono- und polyklonale Antikörper

Tumorimpfstoffe, Zellbank, Medien

„Klassische“ Impfstoffe

Gentransfer- Arzneimittel

Somatische Zelltherapeutika

Xenogene Zelltherapeutika

BfArM

Alle anderen!– Chemisch modifizierte Moleküle

– Peptide

– Proteine

– Nukleinsäurederivate

Aber: Es gibt Grenzbereiche, wo man fragen sollte

The Centralised ProcedureArticles 6 – 14 of Regulation 726/2004

Nomination of Rapporteurand Co-Rapporteur

Start of procedureReceipt of assessment reports (AR)(primary conclusions by Rapporteur,Co-Rapporteur)

CHMP discusses/amends draft questions

Day 80

Day 100 - 119

Dossier Submission

Evaluation timetable for Centralized Procedure at EMEA

Day 120

CHMP adopts list of questions for sponsor – Clock stops

Clock re-starts after submission of responsesDay 121

Day 1

CHMP assessment report final

Day 210

Oral explanation(with up to 60 additional days clarification process)

CHMP adopts final opinion

Day 180

Day 150 Joint AR (Rapporteur + Co-Rapp) to EMEA

Day 181

Evaluation timetable for Centralized Procedure at EMEA

no issues- test vote -

List of outstanding issues

Application to EMEA

Applicant; Requestfor re-examination

210 days

Deatiled grounds

Abbreviation:MS = Member State

Final CHMP Opinion

Final steps in CP & Commissions Decision Procedure

45 days

60 days

Important new questions of ascientific or technical nature

Applicant: No requestfor re-examination

CHMP Opinion

Draft of Commission Decision

15 days

Transmission of the opinion with Annexesto Commission, MS and applicant

15 days

Standing Committee Applicant

15 days

Referral to Agency new Rapporteur

YES

Final Commission Decision = Approval

NO

Communication to the Council: Commission may defer the decision for 1 month

Council may take adivergent decision

22 days

15 days

15 days

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Conditional Marketing Authorisation– Article 14 (7) Regulation 726/2004, and Regulation EC No 507/2006

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/reg_2006_507/reg_2006_507_en.pdf

– EMEA Draft Guidance EMEA/509951/2006 http://www.emea.europa.eu/pdfs/human/regaffair/50995106en.pdf

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.– Guideline EMEA/357981/2005 http://www.emea.europa.eu/pdfs/human/euleg/35798105en.pdf

Accelerated Assessment

– Article 14 (9) of Regulation (EC) No 726/2004– Guideline EMEA/419127/2005 http://www.emea.europa.eu/pdfs/human/euleg/41912705en.pdf

Special schemes in Regulation (EC) 276/2004

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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 507/2006

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 usualEligible for accelerated assessment

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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

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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 726/2004.

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EC 507/2006 : Conditional Approval

Valid for 1 year

Renewable, to be switched to a regular MA

E.g. Sutent (PFIZER), Velcade (JANNSSEN)

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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

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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

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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

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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

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Conditional vs. MA under Exceptional Circumstances

Reg. (EC) 726/2004, Art. 14 and Dir. 2001/83/EC, Annex IReg. (EC) 507/2006

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Special Schemes

all products non-orphan drugs orphan drugs

total 150 112 (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. 2005 – Oct. 2009)

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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 …”

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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.”

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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”

Centralized Procedure: Reg. 726/2004, Art. 6 – 14

Centralised Procedure

Accelerated Procedure

Day 1

Start of procedure

Day 1

Clock stop Day 120

Clock start Day 121 Day 210

CHMP opionion in 210 days

Commission Decicion Making Process EU-Marketing Authorisation

„accellerated“ may be withdrawn by CHMP on day 120

CHMP opionion in 150 days

Clock stop Day 120

Clock start Day 121

Approvalreal day 150, no clock stop

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 !

Thank you