WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR Overview of WHO...

WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR

Overview of WHO Prequalification of In Vitro Diagnostics Programme

Mercedes Pérez González

Department of Essential Medicines & Health Products

WHO Prequalification Team – Diagnostics


WHO work with in vitro diagnostics (IVDs)

HIV assays since 1988

HIV assays since 1988

Hepatitis B assays since 2000

Hepatitis C assays since 2000

Syphilis assays since 2001

Chagas assays since 2002

Malaria assays since 2002

CD4 technologies ad-hoc in 1996 & 2003

WHO has been assessing diagnostics performance and operational characteristics since 1988


PQDx Launch – 2008

Shift from test kit evaluations to Prequalification of IVDs:

• More stringent approach• Alignment with global standards for assuring

quality of IVDs

Identify diagnostics that meet the quality standards through a rigorous process


Regulation of IVDs

•Regulation specifically for IVDs is often poorly understood and/or poorly enforced•Production of many IVD products has been moved to countries with less strict regulatory framework•Different regulatory versions of the same product•Different categories of IVDs regulated differently

– Degree of stringency is usually risk-based– Risk perception is different in different settings– HIV IVDs, particularly for blood screening, attract

greatest stringency


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) Comprised on national regulators & industry.Issues guidance on specific topics related to medical devices including IVDs.

International Medical Device Regulators Forum (IMDRF) - replaced GHTF

Comprised on national regulators.Maintains GHTF guidance documents.

Clinical and Laboratory Standards Institute (CLSI) Issues guidance documents specific for testing processes.


Role of WHO

•To provide normative guidance to Member States on when and how to use IVDs to guide clinical decision-making

– WHO ART guidelines (supplement March 2014)– WHO HCV treatment guidelines (April 2014)

•To provide recommendations on quality and performance of IVDs through the WHO Prequalification of In Vitro Diagnostics Programme according to international standards•To increase in-country capacity to effectively regulate & monitor quality of diagnostics in their market


Aim of WHO Prequalification of IVDs

•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

•Customers– WHO Member States – UN agencies – Funding and

procurement agencies


Prequalification of In Vitro Diagnostics Programme

Pre-submission form

Dossier review Site inspection Laboratory

evaluation

Dossier incomplete

Prequalification decision

Dossier complete

Dossier screening

Priority product

Yes

No

Pre-submission form

Abbreviated site inspection

Laboratory evaluation


Yes

Full PQ assessment

No

Yes

Priority product

No

Decision on abbreviated PQ

assessment

Full prequalification assessment Abbreviated prequalification assessment


WHO prequalification assessment

Pre-submission form


evaluation

Dossier incomplete


Dossier complete

Dossier screening

Priority product

Yes

No


PQDx pre-submission form: requirements

•Manufacturer may submit a form at any time to [email protected]

– Must use the Prequalification of IVDs pre-submission form

– Instructions for the completion of the form available

– Instructions for use must be submitted

•The new form asks for more detailed information on regulatory versions of the product submitted to determine if eligible for abbreviated PQ procedure


Prioritization criteriaCurrent prioritization criteria Rationale

Already listed on WHO/UN procurement scheme and procured by UN organizations in significant levels

Ensure continuity of supply and quality of products procured

Assist diagnosis of infection with HIV-1/HIV-2, malaria and hepatitis C

Focus on priority disease areas – highest historical procurement

Rapid test format Bringing testing closer to the community

Original product manufacturers Ensure known supply chain; no duplication of effort, best possible prices

Few other prequalified products exist in the product category such as CD4, viral load

Focus on unmet market / procurement needs

Adult male circumcision devices Focus on the needs of WHO disease programmes

Prioritization criteria



Pre-submission form


evaluation

Dossier incomplete


Dossier complete

Dossier screening

Priority product

Yes

No


Dossier: requirements

•Based on best international practice (ISO, EN, GHTF, CLSI); follow the content of the GHTF STED

•Looks into critical aspects for WHO Member States often not dealt with/dealt with from a local prospective by SRAs (stability, IFU, RA, etc.).

•Dossier must demonstrate that the IVD conforms to the Essential Principles of Safety and Performance of Medical Devices (GHTF/SG1/N41R9:2005)


Dossier: requirements

Key Components

Product description

Design and manufacturing information

Product performance specifications & associated validation and verification studies

Labelling

Commercial history

Regulatory history

Quality management system


Dossier: submission

Clinical evidence to validate performance claims•One clinical evaluation* performed by Manufacturer•One clinical evaluation* performed independently

– Must clearly relate to the product undergoing prequalification (same name, same product code, same regulatory version)

*The EC Common Technical Specifications (CTS) for IVDs 2009 are a useful guide

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:039:0034:0049:EN:PDF

Performance characteristicsClinical (diagnostic) sensitivity including seroconversion sensitivity Clinical (diagnostic) specificityPositive and negative predictive values (high/low prevalence)Different clinical stagesGeographical distribution (consider intended use setting)Genotypic differences






Pre-submission form


evaluation

Dossier incomplete


Dossier complete

Dossier screening

Priority product

Yes

No


Inspection: requirementsThe manufacturer must demonstrate that the IVD is produced under a functional quality management system e.g. conforms to ISO 13485:2003

Key ComponentsQuality management system including documentation requirements Management responsibilityincluding customer focus, quality policyResource managementincluding human resources, work environmentProduct realizationincluding production and service provision, control of monitoring and measuring devices Measurement, analysis and improvementincluding control of nonconforming product, improvement


Inspection: requirements

Dossier submission data – to confirm its veracityProduction QC and lot release

– QC panels should be challenging enough to detect failure or drift

– Independence and adequately staffed QA/QC department– Deviation reporting procedures observed

WHO related/end user issues – IFU– stability (transport, in-use, expiry dates)– training– complaints reporting mechanisms



Pre-submission form


evaluation

Dossier incomplete


Dossier complete

Dossier screening

Priority product

Yes

No


Laboratory evaluation: requirements

•WHO evaluation protocols followed, based on existing international standards and best practice and adapted to assay type

– To evaluate performance and operational characteristics

•WHO Collaborating Centres performs evaluation under supervision of WHO•WHO Composite Reports of all products produced

– Report 17 published, Report 18 to come


Laboratory evaluation: outcome

•If RDT, results are read by 3 independent readers•Two production lots are submitted to assess lot-to-lot variation•Results of the WHO laboratory evaluation must meet the acceptance criteria

EIA (Laboratory) RDT (Point of Care or Laboratory)

HIV serologySensitivity: 100% Specificity: ≥ 98%

Sensitivity ≥ 99% Specificity ≥ 98%Inter-reader variability ≤5%Invalid rate ≤5%

HCV serologySensitivity: 100% Specificity: ≥ 98%

Sensitivity ≥ 98% Specificity ≥ 97%Inter-reader variability ≤5%Invalid rate ≤5%

HBsAg serologySensitivity: 100% Specificity: ≥ 98%

Sensitivity 100% Specificity ≥ 98%Inter-reader variability ≤5%Invalid rate ≤5%


Prequalification of Diagnostics

Application by Manufacturer

Meets Requirements

DossierAssessment

Manufacturing Site Inspection

Laboratory Evaluation

Product Prequalified

Post Market Surveillance



•Final prequalification outcome depends on: •Results of dossier assessment and acceptance of action plan •Results of inspection and acceptance of action plan

– no level 5 nonconformities outstanding

•Meeting the acceptance criteria for the laboratory evaluation

•WHO PQDx Public Report is posted on WHO website and product is added to the list of WHO prequalified products

Product is then eligible for WHO and UN procurement


PQDx Abbreviated Procedure (previously known as Fast-track)

Categories of products submitted to PQ:•Version submitted for PQ has been stringently assessed

– CE: List A, Annex 2; FDA: PMA or BLA; Health Canada: Class IV; TGA: Class 4; Japan: Minister's approval

•Version submitted for PQ has not been stringently assessed but a regulatory version exists that has been

•Where stringent assessment has been conducted by founding member of GHTF


PQDx assessment status for all products

Status of active applications to the prequalification of IVDs available at:http://www.who.int/diagnostics_laboratory/pq_status/en/index.html

http://www.who.int/diagnostics_laboratory/pq_status/en/index.html




Prequalification of Diagnostics

Application by Manufacturer

Meets Requirements

DossierAssessment

Manufacturing Site Inspection

Laboratory Evaluation

Product Prequalified

Post Market Surveillance


WHO post-market surveillance for IVDs

WHO is developing guidance for reactive and proactive post-market activities

Post-market surveillance continually monitors the safety, quality and performance of an IVD once it is placed on the market

WHO prequalified product

Reactive PMS

Field Safety Notice

Complaints Lot verification testing

Proactive PMS

Field Safety Corrective Action


Post-market surveillance

•Should be an obligation of the manufacturer, but poorly executed

WHO PQDx complaint form for end users to report issueshttp://www.who.int/diagnostics_laboratory/procurement/complaints/en/index.html

•Pilot project on PMS

Regulatory capacity building

Capacity building at the NRL level

http://www.who.int/diagnostics_laboratory/procurement/complaints/en/index.html




Contact us

Contact us by email

[email protected]

WHO Prequalification of In Vitro Diagnostics Programme

website

http://www.who.int/diagnostics_laboratory/evaluations/en/

WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR Overview of WHO...

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