Up-Date IVD-R in Europe Dr. Jrg-M. Hollidt 15. November 2017 Table - - PowerPoint PPT Presentation

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Up-Date IVD-R in Europe Dr. Jrg-M. Hollidt 15. November 2017 Table - - PowerPoint PPT Presentation

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Up-Date IVD-R in Europe Dr. Jrg-M. Hollidt 15. November 2017 Table of Content in.vent`s Mission and Capabilities New Regulations in Europe (IVD-R) Principles and Pitfalls of sample Procurement Clinical studies in.vent is a

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Up-Date IVD-R in Europe

  • Dr. Jörg-M. Hollidt
  • 15. November 2017
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Table of Content

  • in.vent`s Mission and Capabilities
  • New Regulations in Europe (IVD-R)
  • Principles and Pitfalls of sample Procurement  Clinical studies
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in.vent is a member

  • f the

DiagnostikNet Berlin-Brandenburg

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targeted procurement

  • f

human biomaterials

The Mission

We are human

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  • 40+ highly qualified Employees
  • 1200 m2 office & lab, 1000 m2 storage + cold storage
  • Active since 2001 in the field of diagnostics
  • Partner of all diagnostic Stakeholders for the procurement of biologic

material of human origin

(e.g. standardization, innovations, research, development, production, controls, clinical studies, ...)
  • Excellent national and international reputation
  • in.vent clinical services (ICS)

in.vent

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  • Own study site in Hennigsdorf premises
  • Extensive co-operations
  • Sampling and shipping worldwide
  • Own protein-biochemistry laboratories
  • Extensive experience in processing, storage

and logistics of human biomaterial

  • range:
clinically defined samples  20 t prepared material
  • Disease state material in small volumes and bulks/units

in.vent

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certified according to:

DIN EN ISO 9001:2015 DIN EN ISO 13485:2012

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environment Regulatory affairs

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Quelle:

Relevance of the Diagnostic Industry in the EU

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Changing regulatory environment in the EU

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regulatory environment

  • current: IVD-directive (IVD-D 98/79/EC)

translated in national laws and regulations

  • new: IVD-regulation (IVD-R 2012 / 0267)

European law: valid for all memberstates

increased requirements clinical studies performance studies

IVD-R valid in Europe since 25.05.2017

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Old IVD Directive (IVD-D)

recitals: 35

  • n

5 pages definitions: 10

  • n

2 pages paragraphs: 24

  • n

17 pages annexe: 10

  • n

24 pages total: 47 pages

New IVD Regulation (IVD-R)

recitals: 101

  • n

37 pages definitions: 74

  • n

14 pages paragraphs: 113

  • n

229 pages annexe: 15

  • n

208 pages total: 476 pages

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time line

IVD-R effective in Europe since 25.05.2017 Transition period of 5 years (2022) plus: ‚warehouse clause‘ exemption of 3 years

(final date 2025)

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time line

Folien für die interne Verwendung bereitgestellt von der Autorin

IVD Regulation current situation IVD-R valid in Europe since 25.05.2017

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  • ld directive
annex II, list A Notified Body, QMS Audits, release of each lot individually by NB, DD HIV, Hepatitis, Bloodgrouptesting annex II, list B NB involved, technical documentation (TD) approved by NB, QMS Audit Rubella, PSA, Glucose (selftest) Products for self testing / home testing NB involved, approval of labelling, IFU pregnancy tests, hormone tests All other IVD No NB involved Clinical chemistry, cancer, CDx, genetic testing

IVD directive 98/79/EC

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Classification

Class D

high risk for the public high individual risk
  • HIV ½
  • Hepatitis C, B virus
  • HTLV I/II
  • Blood grouping ABO,
Rhesus, Kell, Kidd and Duffy
  • Chagas
  • Syphilis (screening of
blood donations)

Class C

moderate risk for the public high individual risk
  • Syphilis
  • Newborn screening
  • Prenatal screening
  • Cancer-Marker
  • CDx
  • Bloodglucosesystems
  • Home care products

Class B

no risk for the public moderate individual risk
  • Thyroid function
  • Fertility testing
  • Clinical chemistry
  • Autoimmune diseases

Class A

no risk for the public no individual risk
  • Wash buffer
  • Analysers
  • Sample vials
  • Culture media

intended use is of the essence

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Up-coming Regulation

Notified Body mandatory: 10-20% Notified Body NOT involved: 80-90% Notified Body mandatory : 80-90% Notified Body NOT involved: 10-20%

IVD directive 98 / 79 / EC IVD regulation 2012 / 0267

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Key challenges as manufacturer

  • New system of classification (§ 39)
  • New conformity compliance procedure (§ 40)
  • CDx
  • Verification of TD for class C and D
  • Clinical evidence (§ 47)
  • Surveilance, vigilance in the market (chapter VII, § 58-64)
  • UDI System (§ 22)
  • ‚qualified person‘ in place
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  • Product Verification and Validation Including:
  • Information on analytical performance characteristics
  • Information on clinical performance and clinical evidence
  • performance evaluation report:
  • reports on the scientific validity
  • the analytical performance
  • the clinical performance
  • Documents shall be included and/or fully referenced
  • Stability
  • Software verification and validation
  • Additional information in specific cases, e.g.:
– Specific requirements for sterile devices (conditions for manufacturing, bioburden testing, pyrogen testing etc. – devices placed on the market with a measuring function (accuracy)

Requirements as per Annex II

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  • Analytical validation: Consistency of the test in being able

to measure the specific biomarker

  • Clinical validation: Consistency and accuracy of the test in

predicting the clinical target or outcome claimed

  • Clinical utility: Test should improve the benefit or risk of an

associated drug in the selected and non-selected groups Health Claim

Diagnostic Development

Drucker E, Krapfenbauer K, Pitfalls and limitations in translation from biomarker discovery to clinical utility in predictive and personalised medicine. EPMA J. 2013 Feb 25;4(1):7.
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  • Portfolio analysis
  • Classification
  • Clustering
  • Prioritize / view on rentability
  • Establishing / adopting of QMS
  • Gap analysis of TD
  • Performance studies
  • Riskmanagement
  • Usability
  • Software / life-cycle / documentation
  • Analysis of the supply chain / Q-Agreements
  • Planing of Market-surveillance

Lay-out of a transition-plan

Early contact with NB

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  • Risk management Plan
  • Interdisciplinary team in place
  • R&D
  • Clinical
  • Production
  • QM/QA/QC
  • Product management
  • RM defined throughout the life span of the product
  • RM anaylsis and infrastucture
  • Definition of a risk acceptance matrix
  • Commitment to risk reducing activities
  • Reduce risk by Design

Compliance Check TD Chapter 5

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  • § 57 IVD-R / Annex XII part A
  • Left-overs / studies w/o risk for the donor
  • No authorization needed
  • Consent necessary
  • Ethical aspects according to national regulations
  • Data protection
  • § 58-64 IVD-R / Annex XIII part A & Annex XIV
  • potential risk for the patient
(e.g. interventional clinical studies, CDx, complex sampling)
  • Design similar to Rx studies
  • Scientific and ethical approval
  • written informed consent
  • Ethical commitee / IRB mandatory
  • Aproval necessary

Performace evaluation and studies

Mandatory! Exceptions only in well funded situations with sufficient clinical data

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samples principles and pitfalls

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Value chain of In-vitro-Diagnostics

Identification Validation Evaluation Development Production Standardization (technical) Clinical Definition Analytical Definition Volume Quantity
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Plasma, Sera,

Tissue, Organs, Swabs/Smears Sputum, Faeces,

CSF, Lavage, Synovia,

Sweat, Urine

Diversity of Material

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Biomarker identification,

Standardisation,

proficiency testing, internal QC, perfomance testing, pre-analytics,

controls, market surveillance,

clinical studies

Diversity of usage

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  • Small number of samples
  • Lack of history information of the samples
  • Case and control specimens which are not matched with age / sex
  • Slow progression of a disease: requiring high numbers of well-stratified

patients

  • Urgent need for novel therapeutics that have a positive

impact on morbidity and mortality

Pitfalls in analytical methods I

Issaq HJ, Waybright TJ, Veenstra TD. Cancer biomarker discovery: opportunities and pitfalls in analytical methods. Electrophoresis. 2011;32(9):967–975.
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  • Samples with a complex matrix such as serum, plasma, urine or tissue

from patients / controls

  • Limited metabolomic / proteomic coverage
  • Lack of sensitive / specific prognostic biomarkers for disease progression /

regression screening

  • Need to follow clear SOPs for sample selection, collection,

storage, handling, analysis and data interpretation

Pitfalls in analytical methods II

Issaq HJ, Waybright TJ, Veenstra TD. Cancer biomarker discovery: opportunities and pitfalls in analytical methods. Electrophoresis. 2011;32(9):967–975.
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  • Increase of plasma catecholamine concentration by 50 to 100%

due to stress reactions before venipuncture.  Butterfly cannula, sampling 30 min after venipuncture

Example

Plasma Catecholamines

31

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Patient´s preparation

donor position

horizontal to upright

haemo concentration increase in concentration of all blood components not under going ultrafiltration increase around 5-15 % ( plus circadian) Upright to horizontal haemo dilution decrease in concentration of all blood components not under going ultrafiltration decrease around 5-15 % ( plus circadian) „recovery“ of the patient under hospitalisation
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The Quality is remembered long after the price is forgotten

Sir Henry Royce

Co-Founder of Rolls-Royce Motor Cars

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Thank you.

C o n t a c t

  • Dr. Jörg-M. Hollidt
jm.hollidt@inventdiagnostica.de T +49 (0) 3302 551 99 11 in.vent Diagnostica GmbH
  • Neuendorfstr. 17  16761 Hennigsdorf
www.inventdiagnostica.de