Update on WHO Prequalification of In Vitro Diagnostics Update 2 Improved aspect Impact Outstanding...

Update on WHO Prequalification of In Vitro Diagnostics

Robyn Meurant and Mercedes Perez Gonzalez

Prequalification Team – Diagnostics Assessment

Essential Medicines and Health Products

World Health Organization

Joint UNICEF, UNFPA and WHO meeting with manufacturers and suppliers of in vitro diagnostics, vaccines,

finished pharmaceutical products, active pharmaceutical ingredients, contraceptive devices and vector control

products

Copenhagen, Denmark

18 to 21 September 2017

1Copenhagen, Denmark 18-21 September 2017

2015 Update

2

Improved aspect Impact Outstanding challenges

Solutions for challenges

Progress

Streamlinedprocess

Focus on active applications, minimize effort into immature applications, assess more products, expanded programme scope

High priority products with immature applications / impact on overall timelines

Guidance, sample dossiers, technical assistance and training, TCs, WebEx

Expanded network for performance evaluations

Less burden for WHO CCs, wider utilisation of PQ outcomes through USAID

Timelines for specific technologies still challenging

Future laboratory evaluation pathway

Adoption of IMDRF principles

Alignment with best internationalpractice and reliance

MDSAP still in pilot, industry concerns over ToC/RPS

Further collaboration with IMDRF and other harmonization WPs

Implementedchanges assessment and PMS reporting

Better insight in post-PQ phase

Underreporting on vigilance, variable compliance for changes notifications

Updated changes assessmentprocedure, PMS WebEx, PMS training

2017 Progress Report

3

Improved aspect Impact Outstanding challenges


Progress

Streamlinedprocess

Focus on active applications, minimize effort into immature applications, assess more products, expanded programme scope







Adoption of IMDRF principles

Alignment with best internationalpractice and reliance

MDSAP still in pilot, industry concerns over ToC/RPS

Further collaboration with IMDRF and other harmonization WPs

Implementedchanges assessment and PMS reporting

Better insight in post-PQ phase

Underreporting on vigilance, variable compliance for changes notifications

Updated changes assessmentprocedure, PMS WebEx, PMS training

Streamlined process

Improvedaspect

Impact Outstanding challenges


Progress

Streamlinedprocess

Focus on active applications, minimize effort intoimmature applications, assess more products, expanded programme scope



Streamlined processPre-submission form Pre-submission form

Dossier review Site inspection

Laboratory evaluation

Dossier incompleteDossier incomplete

PREQUALIFICATION DECISION

Dossier completeDossier complete

Dossier screeningDossier screening

Eligible productEligible product

YesYes

NoNo

Maintenance of PQ Status

Pre-submission form Pre-submission form

Site inspection Laboratory evaluation


YesYes

NoNo



Abridged Procedure


Site inspection Laboratory evaluation


YesYes

NoNo



Abridged Procedure

Dossier AspectsDossier Aspects

Updates

• Increase in the number of malaria manufacturers

applying for WHO PQ

• Increase in the number of abridged PQ assessments

� Assessment of dossier aspects as part of the site

inspection

• Innovative products and new manufacturers continue to

apply to PQ

• Addition of new diseases requiring full PQ assessment

WHO Prequalified IVDs

• Overall

Prequalified

products: 67 IVDs

Products currently prequalified

HIV RDTs 16

HIV NAT Quantitative and qualitative 15

HIV Confirmatory Assays 3

HIV EIAs 13

HCV RDT 2

HCV NAT 1

HCV EIAs 3

HBsAg EIA 4

HIV/syphilis 1

CD4 Technologies 5

Malaria 12

Highlights

Prequalification:

•Prequalification of two HIV EID technologies:

–Performance evaluation conducted as a

collaboration between WHO, NHLS and CDC

under USAID/PEPFAR-WHO common quality

assurance mechanism.

•Prequalification of the first two HCV rapid diagnostic tests

•Prequalification of a HCV viral load assay

•Prequalification of the first HIV Self Test

Highlights

PQ scope expanded to include

• In 2016:HIV assays intended for self-testing

G6PD assays (for administration of primaquine

and tafenoquine for radical cure of P. vivax)

• In 2017 (applications to be accepted 1 January 2018):

Cholera RDTs

Highlights

New set of PQ documents

• Overview of the WHO PQ of IVDs Assessment

• PQ Assessment and Change Assessment Target Deadlines

• PQ Assessment and Changes Assessment Fees

• Eligibility Criteria for WHO PQ of IVDs

• Presubmission form IVDs

Purpose of the dossier – unique characteristics

13

Demonstrate that the manufacturer has considered the quality, safety and performance of in the countries where WHO PQ IVDs are procured

• Programmatic suitability: specific emphasis on issues of particular relevance to

resource-limited settings, such as:

� Stability of products (heat conditions)

� Adapted specimen type

� Labelling of products

� Ease of use (in terms of training

– and material)

• Performance evaluated in the global population

• Life cycle management of products

14

Update on dossier assessment – WHO perspective

• PQ working to increase transparency for manufacturers: through publication of WHO requirements, revision of WHO documents and alignment with other organizations, for example:

� Technical Specification Series

� Technical Guidance series

� Consultation with international experts on requirements for new eligible IVDs

� Influence on the development of new International Standards and reference panels

� Plans to update current “Instructions for compilation of a product dossier”

Highlights cont’d

Technical Guidance Series:• Standards applicable to the WHO Prequalification of IVDs

• Establishing stability of an IVD for the WHO Prequalification

• Principles of performance studies

• Test method validation of IVDs

• DRAFT Designing Instructions for use for IVDs

• DRAFT Panels for quality assurance and quality control of IVDs

Sample dossiers:• Sample Product Dossier for a CD4 IVD

• Sample Product Dossier for an IVD intended for HIV self-testing

• Sample Product Dossier for a Qualitative NAT to detect HIV-1 and HIV-2

• Sample Product Dossier for a Quantitative NAT to detect HIV-1 RNA

Technical Specifications Series:• HIV rapid diagnostic tests for professional use and/or self-testing

• Glucose-6-phosphate dehydrogenase (G6PD) activity

• Malaria rapid diagnostic tests

• DRAFT Detection of high-risk HPV genotypes in cervical cancer screening

Highlights cont’d

Dossier Assessors Training:• Training sessions provided to WHO PQ assessors to ensure

consistency and equity in the review process.

• Provided by WHO and by partner laboratories with experience in PQ activities

• Dossier assessors trained in assessing data quality and data integrity

• Aim is not to fail a good product!

Commitments to PQ:• Developing a rating system based on the severity of the dossier

requirement

• If non severe, results in a commitment to PQ

• Generally compliance reviewed at inspection


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Improvedaspect

Impact Outstanding challenges


Progress





Alternative mechanism for WHO PQ

performance evaluation


Change in evaluations

scheduling:

Shift from assessment to

pre-assessment phase to

streamline assessment

activities and avoid

sequential steps


Dossier review Site inspection

Dossier incompleteDossier incomplete

Prequalification decision

Dossier completeDossier complete

Dossier

screening

Dossier

screening

Priority productPriority product

Option 2: Performance

evaluation scheduled by

Mx and conducted by a

Prequalification

Evaluating Laboratory.



Mx and conducted by a

Prequalification

Evaluating Laboratory.



WHO and conducted by a

Prequalification Evaluating

Laboratory.



WHO and conducted by a

Prequalification Evaluating

Laboratory.


performance evaluation


Manufacturers free to choose one of two performance evaluations pathways:

Option 1: Performance evaluation coordinated by WHO

Option 2: Performance evaluation commissioned by the manufacturer and carried out at a Prequalification Evaluating Laboratory listed by WHO

Key principles

All evaluations carried out following WHO protocol

All sites audited and listed by WHO

Manufacturers free to choose the pathway


performance evaluation cont’d


WHO is auditing laboratories against predefined requirements based on ISO 15189 and ISO 17025

• 13 applications received

• 9 laboratories audited

• 6 laboratories already listed

2 lists of laboratories:• List 1 - laboratories work directly with WHO and participate in

Option 1

• List 2 – laboratories that work directly with manufacturers and participate in Option 2

Update on PQ performance evaluations of NAT-

based technologies


Progress in 2017• Completed evaluation: 9• Ongoing evaluations: 1• Scheduled: 2

Issues to note• Challenge to obtain certain types of specimens:

• Viral load ranges

• Infant specimens

• Certain genotypes

• Evaluations involve instruments adding complexity: training required, possible breakdowns, space

Performance evaluation of HIV Ab/Ag, HIV/Syphilis,

HIV oral fluid, HBsAg, HCV, CD4 technologies


Progress in 2017• Completed evaluations: 64• Ongoing evaluations: 4 (2 HIV serology, 1 CD4 and 1

HBsAg)• Scheduled: 4 (1 self-testing, 2 CD4)

Issues to note• HBsAg limit of detection of 0.13 IU/ml for RDTs• Obtaining ethical clearance in prospective studies (CD4,

self-testing (capillary whole blood)• Use of similar clinical samples when evaluation will be

conducted in new labs listed in ALE


23

Improved

aspect

Impact Outstanding

challenges

Solutions for

challenges

Progress

Adoption of

IMDRF

principles

Alignment

with best

international

practice and

reliance

MDSAP still

in pilot,

industry

concerns

over ToC/RPS

Further

collaboration

with IMDRF

and other

harmonization

WPs

Harmonisation and PQ adoption activities

Adoption of the IMDRF Table of Contents

Input into the IMRDF Good regulatory review

practice

Input into the IMDRF Adverse event terminology

Input into the IMDRF Common data elements

Participation in the IVD working group of the Asian

Harmonisation Working Party

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25

Improved

aspect

Impact Outstanding

challenges

Solutions for

challenges

Progress

Implemented

changes

assessment

and PMS

reporting

Better

insight in

post-PQ

phase

Underreporting

on vigilance,

variable

compliance for

changes

notifications

Updated

changes

assessment

procedure

PMS WebEx,

PMS training

Post-qualification activities

Revised guidance: Reportable changes to a

prequalified IVD medical device

• changes to the prequalified product or its manufacture;

• changes to the Quality Management System (QMS) that the product was designed and manufactured under; and/or

• other reportable administrative changes.

Changes identified as reportable or non reportable c.f. first version (minor or substantial).

Provides greater clarity on what to report

List of generic examples.

• Increased compliance, however, some manufacturers still implement changes prior to notification

Status of WHO complaint monitoring activities

• 59 complaints submitted to

WHO since Nov 2014

16 complaints were for NAT technologies

Signals came from both high and low resource settings

Typically, the FSCAs were revised labelling and recall/destruction of certain lots

A number of complaints have led to change notifications (revised manufacturing process, etc.)

• Importantly, 4 complaints for falsified products reported

Total complaints reported to WHO, by typeFalse negative

False negative andfalse positive

False positive

Falsification

Invalid rate

Mislabelled

Unreturnable result

Defective reagent

Weak reactivity

Software

Defective reagent

Handling complaints for NAT

28

The expiry date was changed from

2015-09 to 2017-09

• Complaints for NAT technologiesHigh rate of invalid results

Misclassification (downwards bias) for dried

blood spot specimens

• Typical corrective actions Change to manufacturing and/or QC

process

Change of key supplier

Enhanced detail of IFU, e.g. for specimen

collection, warnings, etc.

Global Diagnostics Working Group

• Global Diagnostics Working Group will establish a sub-

group on post-market surveillance to: Exchange of information on complaints

Enable coordinated action by GDWG and their partners

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Where to find information

Contact us by email

• [email protected]

Sign up for our mailing list

• By emailing [email protected]

Check our website

http://www.who.int/diagnostics_labor

atory/evaluations/en/

Update on WHO Prequalification of In Vitro Diagnostics Update 2 Improved aspect Impact Outstanding...

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