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Development ansd Evaluation of Medicinal Products Master Degree, 2012-2013

Nonclinical Guideline

Tuesday 23 October 2012 Claude Bernard University, Lyon – France

Laennec, Room 106

Rolf Bass, FFPM (Hon)

Apl. Prof. Pharmacol. and Toxicol., Charité, Univ. Hospital Berlin Visiting Prof. Pharmaceutical Medicine, Univ. Basel

NONCLINICAL GUIDELINE (S)

R. Baß 23-10-2012 2

3

Regulation

Guidelines

Decision

EU-Member States

to be transposed into national law

Addressed to whom? Effect?

all “persons” of the EU

directly binding - “breaks” national law

single “person(s)“ (MAH, EU-MS, .. )

interested “persons” (MAH, ...)

provision of guidance (“soft-law“)

directly binding - case by case

- “breaks” national law

Directive

Drug Regulation in the EU

MAH: Marketing Authorisation Holder

R. Baß 23-10-2012 3

Pharmaceutical Legislation •  The testing Council Directive 75/318/EEC

(20-05-1975 as amended) (now: moved to Dir 2001/83/EC: Annex) Introduction of „Standards and protocols“ for the performance of tests and trials: protection of public health and facilitation of „Free movement of goods“ within the EU

•  Adoption of „Uniform rules“ applicable to tests and trials and their assessment will provide same chances for all companies

R. Baß 23-10-2012 4

Pharmaceutical Legislation

•  Nota bene: The relevant EU Legislation is now set out in Directive 2001/83/EC as amended by Commission Directive 2003/63/EC, thus incorporating the updated ANNEX I (previously Annex I to Directive 75/318/EC) on the „Testing of medicinal products“ (as set forth in Art. 8(§)(i) of this Directive):

•  Q, S, E Standards and Protocols in respect of the testing of medicinal products for humans

R. Baß 23-10-2012 5

Pharmaceutical Legislation

•  Nota bene: Commission Dir 2003/63/EC sets the requirements (among others) for the CTD, GLP, and the „Non-clinical Details“ according to the agreed CTD Standards and Formats: •  Summaries (ex-Expert Reports): „Non-clinical

Overview“ •  Summaries of studies/data: „Tabulated Study

Reports“ •  Reports:

•  „slot your study here“ •  the test on xyz must show …, … the xyz test means …

R. Baß 23-10-2012 6

•  All current Regulatory Procedures evolved from national procedures and rely on involvement of

National Competent Authorities and their (internal and/or external) Experts

•  Regulatory handling, scientific assessment and regulatory decisions may be performed or handled by

the same or different (legal) entities (Authorities)

•  All Procedures remain under the responsibility of the sponsor / company, and under the control of the

Competent Authority

Regulatory Procedures

7

R. Baß 23-10-2012 7

•  Competent Authorities are: •  EMA (reg/scientific) plus Eur. Com. (reg decisions)

•  Competent Authorities of the Member States (scientific/reg) •  Each Member State has one or more such Authority

•  Decisions may need to be taken by the relevant Ministry of that Member State

•  e.g. BfArM and PEI for human medicines in Germany

•  They are competent to assess and decide


8

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9

EMA National Competent Authorities

•  EU - Network •  of European Experts

•  For the authorisation of medicinal products

•  For pharmacovigilance European Risk Management Strategy

•  For GXP and other quality related inspections and surveillance


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10

Federal Institute for Drugs and Medical Devices (BfArM) Kurt-Georg-Kiesinger-Allee 3 D-53175 Bonn Tel.: +49 (0)228 207-30

http://www.bfarm.de

Paul-Ehrlich-Institut (PEI)

Paul-Ehrlich-Strasse 51 – 59 D-63225 Langen Tel: +49-(0)6103 770 http://www.pei.de

Competent Authorities in Germany

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11

Marketing Authorisation (MA) in the EU

Centralised Procedure

Mutual Recognition Procedure, and

Decentralised Procedure

One

Pan- European MA

MA in more than one EU- Member State

MA in just one EU- Member State

National procedure


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12

Marketing Authorisation Time Table

Day 1

Clock stop

Day 120

Clock start

• Day 121

•  Commission triggers Decision Making Process – for EU-MA

•  National approval by Member States

Day 210 EU /

National Approval

in 210 days

• Questions Answers Responses


Applicant submits Dossier

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13

Centralised Procedure: Mandatory •  biotechnological medicinal products, … •  orphan medicinal products •  new active substances for which the therapeutic indication is the

treatment of: –  diabetes –  cancer –  acquired immune deficiency syndrome (HIV) –  neurodegenerative disorder (Alzheimer, …) –  auto-immune diseases and other immune dysfunctions –  viral diseases –  other extensions to be approved by the Council upon proposal from

the EC

Regulatory Procedures: Scope

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Centralised Procedure: Optional •  (any) new active substance •  innovative medicinal products •  Products in the interest of patients at Community level

–  Pandemic –  Generic medicinal products of nationally authorised reference

medicinal products –  OTC medicinal products –  …

•  generic medicinal products of reference medicinal products authorised by the CP

Any other product / substance •  Decentralised, Mutual Recognition, National, Herbal


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15

Clock Stop

Post Authorisation

0 121 120 210 330 : DAY

Scheme of Centralised Procedure

Phase 1 Phase 2 Clock Stop

Hearing Opinion

180

Decision Decision making phase

Pre Submission

Mandatory Scope ? Optional Scope ?

• Scientific Advice • Pre-Submission queries and meetings • Submission of the application • Appointment of Rappoprteurs • Validation of the Dossier

Scientific Assessment by Rapporteur and Co-Rapporteur - Discussion with CHMP

• Overview (and Conclusions on Benefit/Risk – Issues to be addressed) • Quality • Non-Clinical • Clinical

Marketing Authorisation valid throughout the EU/EEA

Fulfillment of Obligations and PhV RMS

•  Accelerated assessment procedure? •  Conditional marketing authorisation? •  Compassionate use? •  Cooperation with WHO ? •  PIP ?

GXP I n s p ec t i o s to be p e r f o r m e d? CHMP Peer Review

R. Baß 23-10-2012 15

•  new active substances (unless mandatory for the centralised procedure)

•  generic medicinal products to national (and centrally ?) authorised “Reference Medicinal Products” (not applicable for biotechnological medicinal products)

•  Informed consent

•  Well established use (WEU) (bibliographic applications)

•  Line extensions to national authorisations

•  Known substances in new combination

•  Homeopathics

•  Traditional herbal medicinal products


16

MRP/DCP: National Marketing Authorisation

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17

Mutual Recognition Procedure (MRP) and Decentralised Procedure (DCP) are methods of work sharing between the MS

•  They constitute mandatory Procedures to obtain national MAs in MS’s of the EEA for the same medicinal product:


•  Same qualitative and quantitative active ingredient

•  There may be the differences in excipients provided that there is no impact on safety and efficacy

•  Same pharmaceutical form, but …

•  Link between companies

•  all license holders

•  all legal entities •  (Commission Communication July 1998)

If

and and

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1. Mutual Recognition Procedure (MRP) where the medicinal product has already received in a MS a MA at the time of application

and/or

2. Decentralised Procedure (DCP) where the medicinal product has not received in a MS a MA at the time of application

Regulatory Procedures: Applicability

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19

Discussion between all MS

90 days

MA RMS

MA RMS

MA CMS

MA CMS

MA CMS

MA CMS

MA RMS

MA CMS

MA CMS

1. MRP 2. DCP RMS

CMSs RMS Applicant Dossier Dossier

CMSs AR, SPC, PL, label

90 days

Final SPC, PL, label

Draft AR, SPC, PL,

label

Final AR, SPC, PL,

label Final AR

Proposal for changes (CMSs)

Dossier

120 days

+


R. Baß 23-10-2012 19

20

Regulatory Procedures: Guidelines European Union basic legislation in the pharmaceutical sector:

“Rules Governing Medicinal Products in the EU”: EUDRALEX

Volume 1 Community legislation Volume 2 The Notice to Applicants NTA

Volume 2A – Procedures for Marketing Authorisation

Volume 2B – Presentation & content of the application dossier

Volume 2C – Regulatory Guidelines (see EMA-website)

Volume 3 Guidelines – Quality, Safety, Efficacy (see EMA-website)

Volume 4 Guide to Good Manufacturing Practice for Medicinal Products Volume 5- 8 Veterinary issues (mirror image of human medicines) Volume 9 Pharmacovigilance (9A-human; 9B-veterinary) - NOW REPLACED

Volume 10 Good Clinical Practice

R. Baß 23-10-2012 20

•  EMA website: http://ema.europa.eu •  Human medicines

•  Human guidelines

•  General guidance: Guideline Procedure, Regulatory Affairs Guidelines

•  CHMP Guidelines: Position Papers, scientific Guidelines, e.g. Safety

•  Q, S, E Guidelines are valid for all Procedures

Guidelines

21

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CHMP Working Parties To provide recommendations to the CHMP in

the form of : •  Guidelines / Notes for Guidance •  Points to consider •  Position statements •  Public statements

on specific matters related to the quality, efficacy and safety, etc. of medicinal products

To be adopted by the CHMP

22

Guidelines

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CHMP Working Party: SWP

23

Guidelines

• Problem and /or topic arises: task attributed to SWP • Problem Statement: provided to CHMP • Position Paper: adopted by CHMP (published) • Draft guideline: Rapporteur system: SWP • Provisional adoption: CHMP (published for comments) • Hearing with Interested Parties: SWP • Revision of draft Guideline: SWP • Adoption of Guideline: CHMP • Publication: EMA: announcing implementation date, e.g.:

• CHMP/SWP/1042/99: Repeated dose toxicity

• ICH Guidelines may enter at any stage, e.g.: • CHMP/ICH/174/95: Genotoxicity: Standard battery for testing

R. Baß 23-10-2012 23

Work plan for the Safety Working Party

Product related issues

Expected contribution in scientific advice

Expected contribution in protocol assistance

Expected contribution in product assessment

Expected contribution in post-authorisation issues

Requests from other working parties, and committees such as CHMP, CAT and HMPC on product related issues.

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CHMP guidelines and related documents Note for guidance on photosafety testing (CPMP/SWP/398/01) Action: The guideline will be developed as ICH topic S10 Comments: Concept Paper for the revision of the guideline adopted by the CHMP in 2Q 2008. Q&A adopted by CHMP in June 2010 Reflection paper on the impact of 3Rs on pharmaceutical testing Action: To be considered in 2011 Reflection/Position paper on available validated biomarkers Action: To be considered in 2011 Comments: Intended to be updated regularly to provide a comprehensive list of validated bimarkers

R. Baß 23-10-2012 25

CHMP guidelines and related documents The Safety Working Party shall contribute to multidisciplinary guidelines under development, at the request of the CHMP or other working parties, which are identified after adoption of this work plan. •  Guideline on the quality, preclinical and clinical aspects of medicinal products

containing genetically modified cells (EMEA/GTWP/58311/2007)

•  Revision of the note for guidance on quality, preclinical and clinical aspects of gene transfer medicinal products (CPMP/BWP/3088/99)

•  Guideline on quality, non-clinical and clinical aspects of live recombinant viral vectored vaccines (EMEA/CHMP/VWP/141697/2009)

•  Guideline on DNA vaccines

•  Guideline on the application of the risk-based approach for advanced therapy medicinal products

R. Baß 23-10-2012 26

CHMP guidelines and related documents •  Reflection paper on the non-clinical and clinical aspects of cell-

based products containing stem cells

•  Reflection paper on quality, nonclinical and clinical aspects specific to autologous chondrocyte medicinal products

•  Guideline on similar biological medicinal products containing monoclonal antibodies

•  Guideline on similar biological product containing recombinant interferon beta

•  Guideline on similar biological medicinal products containing recombinant follicle stimulation hormone

•  Evaluation of pandemic lesson learnt

R. Baß 23-10-2012 27

CHMP SWP guidelines for revision

•  Points to consider on the non-clinical assessment of the carcinogenic

potential of insulin analogues (CPMP/372/01) •  Action: Possible revision in 2011 •  Comments: The guideline will be updated when ICH S6 is finalised

•  Note for guidance on non-clinical tolerance testing of medicinal products (CPMP/SWP/2145/00)

•  Environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00)

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CHMP SWP guidelines for revision

•  Replacement of animal studies by in vitro models (CPMP/SWP/

728/95)

•  Guideline on excipients in the label and package leaflet of medicinal products for human use (CPMP/463/00)

•  Note for guidance on pre-clinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95)

•  Guideline on the investigation of drug interactions (CPMP/EWP/560/95/Rev. 1)

R. Baß 23-10-2012 29

CHMP/ICH Guidelines and activities The Safety Working Party shall contribute to applicable ICH guidelines under development that are identified after adoption of this work plan. •  ICH S2 R1: Guidance on genotoxicity testing and data interpretation for

pharmaceuticals intended for human use

•  ICH S6: Preclinical safety evaluation of biotechnology-derived pharmaceuticals

•  ICH M3R2: Guidance on the non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals

•  ICH S10: Guidance on photosafety testing

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CHMP/ICH Guidelines and activities •  ICH Q3D: Guidance on heavy metal impurities

•  ICH M7: Guidance on genotoxic impurities

•  ICH Topic M6: General principles to address viral shedding of gene therapy vector

•  ICH E14: The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs

•  ICH SX: Non-clinical testing of vaccines

•  ICH Brainstorm session on reproduction toxicity

R. Baß 23-10-2012 31

EU Regulatory Activities •  Requests from other scientific committees and working parties

and the HMPC on guidelinerelated issues.

•  Medical devices and ancillary medicinal products: data requirements for “Notified body consultations”

•  Requests from the European Commission, EDQM and Member States on pharmacotoxicological issues

•  Animal Welfare – EU initiatives in the 3Rs (EPAA, ECVAM)

•  Assessor’s training (tbc)

•  Workshop (tbc)

R. Baß 23-10-2012 32

Activities with external parties •  Drug regulatory authorities outside the EU

- Liaison with FDA and other agencies.

•  Meeting with interested parties e.g. learned societies, public health stake holders (public health professionals, patients’ organisations), pharmaceutical industry representatives upon request. - Meetings with the EFPIA Safety Ad Hoc Group. - ILSI HESI - Expansion of the collaboration on the following topics: hepatotoxicity, toxicogenomics, carcinogenicity studies, developmental toxicity (juvenile), cardiac safety, in vitro genotoxicity, environmental risk assessment and association of adjuvants and autoimmunity.

•  Critical Path Initiative (US) •  Innovative Medicines Initiative (imi) (Europe)

R. Baß 23-10-2012 33

INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL

REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE

ICH ?

R. Baß 23-10-2012 34

1960, 1970 >>

Rapid increase in laws, regulation and guidelines for reporting and evaluation the data on quality, safety and efficacy of new medicinal products.

History (1)

R. Baß 23-10-2012 35

The detailed technical requirements had diverged over time to such extent that industry found it necessary to duplicate many time-consuming and expensive test procedures, in order to be able to market new products internationally.

History (2)

R. Baß 23-10-2012 36

•  Harmonisation of regulatory requirements was pioneered by the European Community in the 1980ies

•  Europe demonstrated that harmonisation was feasible.

History (3)

R. Baß 23-10-2012 37

•  Birthday April 1990, at a meeting hosted by EFPIA in Brussels

•  Representatives of the regulatory agencies and industry associations of Europe, Japan and the USA met and agreed

•  ICH Steering Committee was established

History (4)

R. Baß 23-10-2012 38

1 week to month Up to 3 months 3 months and longer

INTERNATIONAL GUIDELINES FOR THE DURATION OF ANIMAL TOXICITY STUDIES - 1986

0

5

10

15

20

Proposed human exposure

Ani

mal

exp

osur

e (m

onth

s)

EC

Japan

Canada

USA

From: R. Walker, DIA Symposium, Tokyo, October 1990 R. Baß 23-10-2012 39

•  Topics selected for harmonisation would be divided into Quality, Safety and Efficacy

•  Six-party Expert Working Groups (EWGs) for each topic

•  EWGs meet in the same week as the Steering Committee and report on their progress

Early meetings

R. Baß 23-10-2012 40

INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION

OF PHARMACEUTICALS FOR HUMAN USE

ICH 1 - Brussels, November 1991 ICH 2 - Orlando, October 1993 ICH 3 - Yokohama, November 1995 ICH 4 - Brussels, July 1997

ICH 5 - San Diego, November 2000

ICH 6 - Osaka, November 2003

International Conference on Harmonisation

R. Baß 23-10-2012 41

Improving Regulatory Success of the nonclinical parts of the CTD

§  CTD as facilitator or setting the stage and requirements ?

§  CTD setting straight your mind or compiling the „Dossier“ ?

§  CTD compilation as a last-minute exercise or slotting in reports as they come (and continuously assessing the „new situation“) ?

R. Baß 23-10-2012

International Conference on Harmonisation

42

•  Remove the need to duplicate studies – Avoid repetition of clinical studies – Reduce animal usage – Make research more economical

•  Harmonise application of requirements – Definitions – Presentation of documentation

•  Bring new medicines to the market sooner

Targets of harmonisation

R. Baß 23-10-2012 43

•  New types of medicinal product Proposals for guidelines to cover new products resulting from advances in technology and techniques for producing medicines (e.g., products arising from gene therapy and other developments in biotechnological and genomic research);

•  Lack of harmonisation in current technical requirements Proposals for further harmonsisation of existing requirements (e.g., as a result of work on the Common Technical Document);

•  Transition to technically improved testing procedures Proposals for action to facilitate the replacement of currently established testing procedures to more efficient and economical methods where these provide equal or better assurance to the safety and/or quality of new drug products.

Proposals for harmonisation (1)

R. Baß 23-10-2012 44

Proposals for harmonisation (2)

•  Review of an existing ICH Guideline Proposals for significant changes to the technical aspects of an ICH Guideline or proposals for a major addition to the guideline.

•  Maintenance of an existing ICH Guideline Proposals for relatively minor modification, updating clarification or review of ICH agreements to take account of either problems with implementation, new information or new scientific knowledge.

R. Baß 23-10-2012 45

•  Trade Associations EFPIA European Federation of Pharmaceutical Industries and Associations JPMA Japanese Pharmaceutical Manufacturers Association PhRMA Pharmaceutical Research and Manufacturers Association (USA)

•  Regulatory Authorities European Union: Commission and appropriate 'Parties'

(CHMP, QWP, BQWP, EWP, SWP, PhVWP) Japan Ministry of Health and Welfare and appropriate expert support

(MHLW, NIHS, Universities) USA Food and Drug Administration and appropriate expert support

(regulatory communication, efficacy, safety, quality - review staff, expert leads - CDER/CBER chief officers)

•  Oberservers Canada, EFTA, WHO

•  “Umbrella” Organisation, ICH Secretariat IFPMA: International Federation of Pharmaceutical Manufacturers Associations

Organisation: Parties to ICH

R. Baß 23-10-2012 46

Technical Discussions in EWG

STEP 1: DEVELOPMENT OF CONSENSUS

1

EWP = Expert Working Group R. Baß 23-10-2012 47

STEP 2: CONSENSUS TEXT RELEASED

FOR CONSULTATION


Consensus Achieved

1

2

R. Baß 23-10-2012 48

STEP 3: CONSULTATION OUTSIDE ICH


Consensus Achieved

Formal Consultation

1

2

3

R. Baß 23-10-2012 49

STEP 4: ICH GUIDELINE FINALIZED


Consensus Achieved

Formal Consultation

Finalized Text

1

2

3

4

R. Baß 23-10-2012 50

THE FIVE ICH STEPS


Consensus Achieved

Formal Consultation

Finalized Text

Implementation

1

2

3

4

5

R. Baß 23-10-2012 51

ICH No.

Title CPMP Doc. No. Step

S1A The Need for Carcinogenicity Studies of Pharmaceuticals

CPMP/ICH/140/95 Step 5

S1B Carcinogenicity: Testing for Carcinogenicity of Pharmaceuticals


S1C (R2)

Carcinogenicity: Dose selection for carcinogenicity studies of pharmaceuticals

EMEA/CHMP/ICH/383/95

Step 5

Guidelines - Safety

R. Baß 23-10-2012 52

ICH No.


S2A Genotoxicity: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals


S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals


S2 (R1)

Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use

CHMP/ICH/126642/08

Step 5

Guidelines - Safety (cont.)

R. Baß 23-10-2012 53

ICH No.


S3A Toxicokinetics: A Guidance for Assessing Systemic Exposure in Toxicology Studies


S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies


S4A Duration of Chronic Toxicity Testing in Animals (Rodent and non Rodent Toxicity Testing)


S5 (R2) Reproductive Toxicology: Detection of Toxicity to Reproduction for Medicinal Products + Male Fertility


S6 (R1) Preclinical Safety Evaluation of Biotechnology-Derived Products



R. Baß 23-10-2012 54


ICH No. Title CPMP Doc. No. Step S7A Safety Pharmacology Studies for

Human Pharmaceuticals CPMP/ICH/539/00 Step 5

S7B Non-Clinical Studies for Assessing Risk of Repolarisation – Associated Ventricular Tachyarrhythmia for Human Pharmaceuticals


S8 Immunotoxicology Studies EMEA/CHMP/ 167235/2004-ICH

Step 5

S9 Nonclinical Development of Oncology Pharmaceuticals

CHMP/ICH/646197/08

Step 5

S 10 Photosafety Step 0

R. Baß 23-10-2012 55

Guidelines - Multidisciplinary

ICH No.


M3 (M) Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (Modification)


M3 (R2)

Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals

Step 5

M7 Genotoxic Impurities Step 0

R. Baß 23-10-2012 56

Other Guidelines - Safety •  CPMP/QWP/1719/00 rec on safety requirements added 2008 •  CHMP/SWP/28367/07 first in-human trials •  CPMP/SWP/91850/06 Environmental risk assessment •  CPMP/SWP/799/95 „mixed applications“ •  CHMP/SWP/258498/05 Fixed combinations •  CPMP/SWP/1094/04 Evaluation of control samples •  CPMP/3097/02 Comparability – biotech proteins •  CPMP/QWP/159/01 Use of ethylene oxide •  CPMP/465/95 Vaccines •  3CC29A Chiral active substances •  CHMP/SWP/199726/04 Antisense oligodeoxynucleotide •  CPMP/818/97 Phenolphthalein ca. potential •  CPMP/SWP/2592/02 Rev 1 genetically modified animal models for ca. testing •  CPMP/SWP/372/01 Human insulin analogues ca. testing •  CHMP/203927/08 RA Repro/Lactation: from data to labelling •  CHMP/SWP/169215/05 Juvenile animals – paed. indications •  CHMP/SWP/2600/01 Human insulin analogues repro. Testing •  CPMP/SWP/2145/00 Local tolerance •  CHMP/SWP/150115/06 Drug-nduced hepatotxicity •  CHMP/SWP/94227/04 Dependence potential •  CPMP/SWP/398/01 Photosafety testing •  CPMP/2278/00 Addicition/dependence/withdrawal – SSRIs

R. Baß 23-10-2012 57

•  Improved Regulatory Cooperation – atmosphere of mutual confidence and trust

•  Globalisation of EU standards – GCP – Periodic Safety Updates Reports – Genotoxicity – Impurities

•  Scientific perspective – ICH Guidelines are robust – greater scientific value

Advantages (1)

R. Baß 23-10-2012 58

•  Trade effects – Increase of market penetration of EU companies in

other regions – Potential trade conflicts have been avoided

because of enhanced co-operation •  Political perspectives

– Active participation of the EU – Investment in the EU, such as pharmaceutical

research and development •  Reduction of duplication and resources

– Reduced duplication of testing – Reduced number of animals

Advantages (2)

R. Baß 23-10-2012 59

Animal Use for Toxicological Studies

From: C. E. Lumley and H. van Cauteren, 1997

Before ICH1 After ICH4 Single dose toxicity (2 routes) 2 Rodent

1 Non-rodent 200-300 16-32 50-100

0 Repeated-dose sub-chronic 1st duration ( eg 1 month)

Rodent Non-rodent

2nd duration ( eg 3 months) Rodent Non-rodent

Recovery Rodent Non-rodent

80 24

160 32

200 40

*160 32

0 0 0

40 Repeated-dose chronic 1 st duration ( eg 6 or 9 months)

Rodent Non-rodent

2nd duration ( eg 12 months) Rodent Non-rodent

160 32

160 32

160 32

0 0

Reproduction Segment I rat eg Japanese style eg US/EU style

Segment II rat eg Japanese style eg US/EU style

Segment II rabbit Segment III rat

192 96

96+48 96 60 96

192 0 0

96 60 96

Carcinogenicity 1st species ( eg rat) 2nd species ( eg mouse) Medium or short-term study

400-500 500 400-500

500 160

TOTAL 2720-2936 1478-1583 *Excludes offspring and dose-range finding studies

Advantages (3)

0

R. Baß 23-10-2012 60

•  Non-ICH Countries • Legitimacy of ICH ICH representing countries: 15% of the world population, and 90% of the pharmaceutical worldwide sale • Legitimacy of WHO To establish global standards has been embodied in WHO‘s constitution adopted in 1946

Disadvantages(1)

R. Baß 23-10-2012 61

• Resources –  ~ 20 European regulatory experts to be out of their

offices (for two periods of one week every year)

–  > 20 European regulatory experts involved in background preparatory and consulting work (for many periods, every year)

Disadvantages (2)

R. Baß 23-10-2012 62

•  Relative US dominance – FDA tends to play a dominant role – Language advantage

•  Approach taken by Japanese – Some topics with little EU interest

•  Implementation problems – Delay in the other regions, in some cases for

legal reasons – additional explanations, e.g. repeated dose

testing in non-rodents in US

Disadvantages (3)

R. Baß 23-10-2012 63

•  Global co-operation

•  Co-operation between regulators

•  Topics which can be legally implemented

•  Continuation of maintenance process

•  New technologies

•  Implementation and monitoring of the CTD

Future (1)

R. Baß 23-10-2012 64

New technologies / Topics •  Pharmacovigilance •  Gene therapy •  Cell therapy •  Pharmacogenomics

– Need of additional experts? – Need of brainstorming meetings?

•  Need of other documents, like 'points to consider'?

Future (2)

R. Baß 23-10-2012 65

Internet

ICH guidelines www.ich.org IFPMA www.ifpma.org EMEA www.ema.europa.eu EU www.pharmacos.eudra.org FDA www.fda.gov MHLW www.mhlw.go.jp EFPIA www.efpia.org JPMA www.jpma.or.jp PhRMA www.phrma.org

R. Baß 23-10-2012 66

Place and Value of the CTD

R. Baß 23-10-2012

Arriving at relevant statements

Readability, interpretation Problems within and beyond Non-clinical

Reports created and presented according to Guidelines and GLP Data as reported

Administrative Non-scientific Highest level of abstraction: SmPC, PIL, Labelling

Non-clinical narrative, summaries, tables and interpretation

67

Module 1

Regional Administrative

Information 1.0

Nonclinical Overview

2.4

Nonclinical Summary

2.6

Clinical Overview

2.5

Clinical Summary

2.7

Quality Overall

Summary 2.3

Module 3 Quality

3.0

Module 4 Nonclinical

Study Reports

4.0

Module 5 Clinical Study

Reports 5.0

Not part of CTD

CTD Module 2

ICH Common Technical Document

CTD Table of Contents 2.1

CTD Introduction 2.2

R. Baß 23-10-2012 68

THANK YOU

R. Baß 23-10-2012 69

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