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