WHO Prequalification of Diagnostics Regulatory

Transcription

1 WHO Prequalification of Diagnostics Regulatory Dr Lembit Rägo Head, Regulation of Medicines and other Health Technologies Essential Medicines and Health Products

2 Essential Medicines and Health Products Organigram EMP Essential Medicines and Health Products Dir. Kees de Joncheere Policy, Access & Use PAU Coord. Gilles Forte Regulation of Medicines & other Health Technologies RHT Head, Lembit Rägo Public Health, Innovation & Intellectual Property PHI Coord. Mirza Zafar Technologies Standards & Norms TSN Coord. David Wood Regulatory Systems Strengthening RSS Coord. Nora Dellepiane Prequalification Team PQT A/Coord. Lembit Rägo Safety & Vigilance SAV Coord. Clive Ondari Diagnostics, Medicines, Vaccines 2 Alliances

3 Contents Market share for HIV diagnostics WHO Prequalification of Diagnostics Remaining challenges Next steps 3

4 Total Volume of HIV Test Procurement PQ vs non-pq (all assay types, all data) Number of Tests Non PQ PQ % PQ % Non PQ

5 Contents Market share for HIV diagnostics WHO Prequalification of Diagnostics Remaining challenges Next steps 5

6 Regulatory environment for in vitro diagnostics (IVDs) Regulation specifically for in vitro diagnostics is often poorly understood and/or poorly enforced Different categories of IVDs regulated differently HIV IVDs (particularly for blood screening) attract greatest stringency Degree of stringency is usually risk-based Risk perception is different in different settings Procurement policies drive supply of quality assured products often acting as de facto regulatory control 6

7 Who sets international standards? Organization International Organization for Standardization (ISO) Certification of ISO compliance is made by an independent agency. Global Harmonization Task Force (GHTF) International Medical Device Regulators Forum (IMDRF) - replaced GHTF Comprised on national regulators & industry. Issues guidance on specific topics related to medical devices including IVDs. Comprised on national regulators. Maintains GHTF guidance documents. Clinical and Laboratory Standards Institute (CLSI) Issues guidance documents specific for testing processes. 7

8 WHO PQDX regulatory framework ISO and EN standards GHTF / IMDRF guidance documents CLSI guidance documents PQ requirements 9

9 Aim of WHO Prequalification of Diagnostics To promote and facilitate access to safe & appropriate diagnostic technologies of good quality in an equitable manner Through adoption of GHTF guidance and ISO requirements To increase in-country capacity to effectively regulate & to monitor quality in-market 11

10 WHO PQDx process Manufacturer submits application Application is screened Rejected Accepted Manufacturer signs letter of agreement, pays fee and submits product dossier Rejected Accepted Dossier is reviewed Product Laboratory Evaluation Does not meet WHO requirements Meets WHO requirements Meets WHO requirements Manufacturing Site Inspection Does not meet WHO requirements PQ criteria Product is prequalified Post-market surveillance Figure 1: Overview of the prequalification of diagnostics process See WHO website for more details 12

11 Prequalification Dx: outcomes Status Number Products PQed in Products PQed in Products PQed in Products PQ ed so far in Products closed (does not meet PQ requirements) 45 Products withdrawn (at request of manufacturer) 22 Status as of 30 Sept 2013, based on analysis of PQ tracking document 14

12 Timelines Time to PQ depends on the Mx ability to meet PQ requirements in each of the 3 components Time from first dossier submission to dossier ready for full assessment: Time taken (working days) Shortest Longest Average

13 Reasons for delays/challenges Lack of experience and (sometimes) expertise from manufacturers who have not been exposed to stringent regulations/regulators 18

14 Dossier screening: most common deficiencies Poor layout and organization (numbering, references) Sections missing Out of scope data included Regulatory version information: reference to product codes, differences between versions, version submitted Overview of Mx and flowchart Documented procedures used for the purchasing and verification of ingredients/products/services sourced from key suppliers 19

15 Dossier assessment: most common deficiencies Unclear product identification (regulatory version, change control, site of manufacture). Poor study design for product validation and verification. Unclear if studies involved the product version submitted for PQ. Poorly documented QMS procedures (purchasing, QC). Stability testing not suited for countries of use Labelling: content and translation Important differences between experienced and less experienced manufacturers. 21

16 Evaluations performed WHO evaluation protocols followed, based on existing international standards and best practice RDTs EIAs CD4 HIV Hep C 2 2 N/A Hep B 2 1 N/A WHO Collaborating Centres perform evaluation under supervision of WHO WHO Composite Reports of all products evaluated Report 17, no18 to be released 22

17 Key findings nonconformities (NCs) 30 Dx Mx first inspections. Canada -2, China -4, EU -8, India -5, Israel -1, Japan -1, S Korea -1, USA -7, Russia Mx had Levels 1-3 (minor) nonconformities only (EU_2; USA_6) 5 Mx had Level 4 (major) nonconformities (EU_3; Jap_1; USA_1) Mx had Level 5 nonconformities (rectification required prior to PQ) Canada_2; China_4; EU_2; India_5; Israel_1;S Korea_1; Russia_1; USA _1. 30% - 5/17 within SRAs (GHTF - US, HC, TGA, EU and Japan) 70% - 12/17 - less regulated environments Resource utilization: 2 Mx re-inspection after 1 yr Level 5 nonconformities persisted in both, 1 Mx with 2 nd re-inspection (1xLevel 5 NC persisting soon resolved) 24

18 Prequalification: outcome Final prequalification outcome depends on: Results of dossier assessment and acceptance of action plan Results of inspection and acceptance of action plan no critical nonconformities outstanding Meeting the acceptance criteria for the laboratory evaluation WHO Prequalification of Diagnostics Public Report is prepared and sent to manufacturer for comment WHO PQDx Public Report is posted on WHO website and product is added to the list of WHO prequalified products Product is eligible for WHO and UN procurement 26

19 Prequalification: fast track Fast track procedure has been implemented Inspection reports and evidence of conformity assessment by stringent regulators are reviewed Inspection can be shortened with fewer inspectors and few days on-site required Average times (including WHO & Mx) To prequalify fast track 12.4 months to prequalify after prioritization (LoA)18.6 months Time from application 32.2 months. 27

20 Contents Market share for HIV diagnostics WHO Prequalification of Diagnostics Remaining challenges Next steps 28

21 Challenges: regulatory environment Multiple regulatory versions for the "same" product Variable stringency of regulatory review by NRAs depends on risk classification if product is for export-only, minimal review Variable stringency of conformity assessment bodies/inspection agencies Some inspections may be outsourced to in-country agencies Differences in QC lot release procedures for CE-marked products for different notified bodies 29

22 Challenges: product related Still poor understanding and implementation of quality management systems (QMS) at manufacturing sites Inadequate product dossier to demonstrate performance claims including Product stability Both in-use and transportation stability QC and lot release procedure Customer service in resource-limited settings 30

23 Contents Market share for HIV diagnostics WHO Prequalification of Diagnostics programme Remaining challenges Next steps 31

24 Next steps: WHO PQDx Revision of the PQ process to design a more robust and clear process with clearly defined steps and using "clock stops" principle to set target timelines for WHO PQ Implementing efficiencies to reduce time to prequalify, including Clear distinction between pre-submission interactions and PQ Implement Advisory visits pre- PQDx assessment for innovative point-of-care technologies 2 conducted, others in the planning stage Implement an Expert Review Panel (ERP) for Dx quick structured risk assessment to enable procurement decisions before getting PQd Improving communications with manufacturers and stakeholders including 32

25 Next steps: WHO PQDx Improving post-market surveillance activities Should be the obligation of the manufacturer, but poorly executed Role for global/national entities to collect data on poorly performing products & feedback to Mx and other users Supporting strengthening of regulatory capacity in both country of origin and country of sale and use RDTs are often not widely, if at all, used in the country of origin 33

26 Next steps: all WHO prequalification programmes Across all prequalification programmes (medicines, vaccines, diagnostics) Implement a common quality management system Implement a harmonized IT platform processing applications, monitoring performance, storing technical information, etc. Improving inspections for all product categories Harmonizing NRA assessment by the three programmes with joint assessment tools to guide capacity building efforts Harmonized communication efforts 34

27 Updated information on PQDx The status of each PQDx application is posted on the WHO website & updated monthly The PQ Update newsletter is issued regularly & sent by direct mail & posted on the WHO website Thank you 35