who emergency use assessment and listing (eual) procedure - unicef · who emergency use assessment...

WHO

Emergency Use

Assessment and Listing

(EUAL) Procedure

Robyn Meurant

WHO PQ Team – Diagnostics Assessment

1

Aim of WHO Prequalification:

Diagnostics Assessment

To promote and facilitate access

to safe & appropriate IVDs of

good quality in an equitable

manner

CustomersWHO Member States UN agencies Funding and procurement agencies

IVDs - a critical component

of clinical care

• Guiding clinical decisions

• Diagnosis, monitoring, prevention, prediction

• In resource-rich countries, influence directly the majority

of medical decisions

• Their importance will only increase, especially with the

need to avert antimicrobial resistance, and to tailor

other medical interventions

http://www.healthmap.org/en/

Health Alerts: Week of 09 May 2016

http://www.healthmap.org/en/

Thanks to J Hansen, J Kuelsow, M Gomes, S Recourt

6

Concept Design Development

ValidationManufacture

Packaging

Labelling

Advertising

Marketing Approval

Sales

Supply Use Disposal

Life Cycle of an IVD

Manufacturer

NRA Pre Market Controls NRA Post Market Controls

Users, patients

7

Concept Design Development

ValidationManufacture

Packaging

Labelling

Advertising

Marketing Approval

Sales

Supply Use Disposal

Life Cycle of an IVD

Manufacturer

NRA Pre Market Controls NRA Post Market Controls

Users, patients

WHO Prequalification QA Mechanisms

Pre-submission form

Dossier review Site inspection Laboratory evaluation

Dossier incomplete

PREQUALIFICATION DECISION

Dossier complete

Dossier screening

Priority product

Yes

No

Post - Prequalification activities

Prequalification Procedure

WHO QA Mechanisms

Prequalification

EligibilityAny timePrioirity product

WHO QMS review On site inspection

WHO Lab Evaluation

Comprehensive (1000s)

Analyticalperformance

Comprehensive

Clinical performance

Comprehensive

Stability Real time

Rolling submissions No

Listing Until delisted

Post approval PMS, re-inspection, changes

Expert Review Panel for Diagnostics (ERPD)

on behalf of Global Fund to Fight AIDS,

Tuberculosis and Malaria (GFATM)

products that are a priority for GFTAM and

UNITAID but for which too few WHO

prequalified and/or stringently assessed

products exist.

WHO QA Mechanisms

Prequalification ERPD


Expression of Interest

WHO QMS review On site inspection Desk top

WHO Lab Evaluation

++++(1000s)

None


++++ +++


++++ +++

Stability Real time Accelerated if novel

Rolling submissions No No

Listing Until delisted 1 year


Complete PQ

Emergency Use Assessment and Listing (EUAL)

Special procedure for assessment of health products in a

public health emergency

2014 Ebola crisis highlighted the need for an emergency assessment procedure for vaccines, medicines and IVDs

It was recognised that the procedure would be different to prequalification

• Decision to list based on minimal evidence of safety and efficacy/performance

• as few products at a mature stage in the product lifecycle

• based on immediate need

EUAL

• A rapid, time-limited procedure for the assessment of quality, safety and efficacy/performance during an outbreak,

• based on a minimal level of information, was established for vaccines, medicines and IVDs

• published in July 2015

• Listing provides guidance including product-specific technical information to UN procurement agencies, WHO product utilization advisory committees, national regulatory authorities (NRAs), and others involved in efforts to control an epidemic.

EUAL - Eligibility

The disease has been declared by the WHO Director General to be a Public Health Emergency of International Concern (PHEIC)

WHO agrees that, based on the contingencies of the specific health emergency, it is reasonable to consider the product for assessment in the following circumstances:

• There are no/few products that have undergone comprehensive premarket regulatory assessment for the indication or for a critical subpopulation

WHO QA Mechanisms

Prequalification ERPD EUAL


Expression of Interest

Expression of Interest PHEIC

WHO QMS review On site inspection Desk top Desk top

WHO Lab Evaluation

++++(1000s)

None ++100s


++++ +++ +++


++++ +++ -/+

Stability Real time Accelerated if novel Accelerated

Rolling submissions No No yes

Listing Until delisted 1 year 1 year (+)


Complete PQ Complete development, PMS

EUAL – Abbreviated Assessment

Some submissions submitted for WHO EUAL may have undergone a simultaneous assessment through other similar Member State review mechanisms.

In situations where independent performance data are available, generated using a suitable reference assay, WHO will consider using these data to reduce the extent of a WHO-coordinated performance evaluation.

EUAL – Post Market Surveillance

For EUAL listed IVDs, appropriate post-market surveillance mechanisms should be in place to allow for the timely notification and evaluation of adverse events to WHO and the relevant NRAs.

The WHO IVD complaint form should be completed as much as possible and sent to WHO. The form is available at the following WHO web address:

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

Manufacturers must notify national regulatory authorities and WHO of adverse events associated with the use of a product in the EUAL.

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

EUAL – The Ebola Virus Experience

Few manufacturers had started to develop NAT and antigen detection assays• Most had very little technical documentation• Some had rudimentary QMS (ISO 13485) but

not manufacturing capacity• Clinical blood samples were not available for

validation• restriction in transportation of clinical

samples outside W Africa• Testing required BSL-4 laboratories Therefore the manufacturers had minimal analytical and clinical performance data

EUAL – International Collaboration

International support in the provision of EVD IVD expertise for Dossier and QMS review

• Dossier requirements and review

• Adoption of US FDA requirements for dossier (provided alignment and harmonised approach)

• USA, Belgium, Australia, Switzerland

International Support for WHO based Lab and

Field evaluations

• BSL4 lab and LOD studies (Bernhard NochtInstitute, Germany)

• Sierra Leone clinical performance study (Nigerian and PHE Labs)


• Enquiry for information on a rapid test being promoted in West Africa resulted in, amongst other actions, WHO informing FDA

• FDA compliance team identified numerous manufacturers on the US west coast illegally manufacturing and exporting EVD IVDs

EUAL – IVDs for Zika virus

• Similar process as for the EUAL for Ebola virus

• Invitations to submit sent to over 30 manufacturers

EUAL – IVDs for Zika virusCollaborative efforts underway

• Base of international SMEs for dossier review

• Agreement to share requirements (and align where possible)• FDA, ANVISA, etc.

• Confidentiality agreements in place or under development

• Cooperation for laboratory performance evaluation• Reference labs in the affected region

• European support, e.g. WHO Collaborating Laboratories

• Alignment /cooperation with other WHO/PAHO led initiatives

• Input into testing strategies

• WHO reference materials

• TPP development

WHO Zika EUAL Requirements

EUAL Requirements – IVDs for Zika virus

6.1. Specimen type (Ab and NAT assays)

Detailed information for each matrix and anticoagulant, when applicable

• The matrix in which the clinical studies are conducted is the comparator. All other matrices are to be shown to be equivalent to the comparator matrix.

• Negative specimens for each claimed specimen type are spiked with the same amount of the analyte and assayed and the results compared.

• Test contrived specimens consisting of negative, high negative, low positive, and 3-4 values across the dynamic range of your assay.

• Test 5 specimens in duplicate for each concentration and compare the results between the matrices.


6.3. Analytical sensitivity (Ab assays)

WHO requires each assay to be calibrated/tested against biological reference material when and where available:

• WHO-supplied ZIKV interim International Standard for serology assays, estimated availability 2017. This interim standard may be used by assay developers before final status of IS attained. (For those manufacturers who have already submitted to the EUAL, calibration studies with this standard are still required and results need to be submitted to the EUAL as soon as possible).

• For serology assays that simultaneously detect dengue virus antibodies, WHO Reference Reagent Anti Dengue, WHO Reference Panel NIBSC code: 05/248


6.4. Limit of Detection (NAT)

• The limit of detection (LoD) of the IVD should be determined

utilizing the entire test system from specimen preparation to

detection for each clinical specimen type/matrix claimed.

• If viral stocks from the currently circulating Zika virus (Brazilian

strain) are not available, it is acceptable to use commercially

available Zika viral stocks (from previously circulating strains)

for the calculation of LoD.

• A method for calculating LoD that would be acceptable to PQ is

provided.


6.4. Limit of Detection (NAT)


Virus Strain Tested

Sto

ck V

iru

s Ti

tre

Seri

al 1

0-Fo

ld D

iluti

on

Fac

tor

PFU

/mL

or

TCID

50/m

L D

iluti

on

Tes

ted

Ru

n 1

Ct

Ru

n 2

Ct

Ru

n 3

Ct

Ru

n 4

Ct

Ru

n 5

Ct

Cal

l Rat

e

Lowest Concentration with Uniform Positivity per Analyte

Limit of Detection (LoD) per Virus Strain

Exam

ple

: (a

nal

yte)

6.3. Standardization/Calibration using international biological reference materials (NAT)

WHO requires each assay to be calibrated/tested against biological reference material when and where available:

• WHO-supplied ZIKV interim International Standard for nucleic acid tests (NATs), estimated availability April – May 2016. This interim standard may be used by assay developers before the final status as an International Standard is attained.

• For those manufacturers who have already submitted to the EUAL, calibration studies with this standard are still required and results need to be submitted to the EUAL as soon as possible.

• For multiplex NATs that detect Chikungunya nucleic acid, a reference standard is available from the Paul Ehrlich Institut, Germany.

• For multiplex NATs that detect other markers e.g. West Nile virus, dengue viruses, reference material is also available from FDA/CBER.


6.4.1. Cross-Reactivity (Ab)

Cross-reactivity should be evaluated by testing specimens from patients with antibodies to other microorganisms which could potentially cause false positive results.

• Preferably, for assays that detect Zika virus IgM, sera to be used in cross-reactivity studies should be sourced from patients with a documented infection as early as possible in the clinical course. This is especially important for Dengue virus.

• For assays that detect Zika virus IgG, sera should ideally be sourced from patients with both early and convalescent stages of an infection.


6.4. Analytical Specificity (Ab)





• To investigate the potential for cross-reactivity with dengue virus antibodies, sera from both primary and secondary dengue virus infections should be tested. Ideally, all dengue virus serotypes should be tested.

• Where significant cross-reactivity is observed, provide a plan to address these issues.





Disease/Infectious agent

Positive Sera

Number of specimens

N = 3-5 each condition

Assay Equivocal or positive

results% Cross-reactivity

Anti-chikungunya virus

Anti-cytomegalovirus (CMV)

Anti-dengue virus (each of the four serotypes)

Anti-Epstein Barr virus (EBV)

Anti-parvovirus B19

Anti-varicella zoster virus

Yellow fever virus post-immunization

Anti-West Nile virusAnti-tick borne encephalitis

Anti-malaria/anti-Plasmodium falciparum

Adenovirus (optional)

Enterovirus (optional)

Anti-leptospira (optional)

Anti-Eastern Equine Encephalitis (optional)

Anti-Japanese Encephalitis (optional)

Anti-hepatitis C virus (optional)

Anti-Ross River virus (optional)

Anti-Saint Louis encephalitis (optional)


6.4.2. Interfering Substances

(Ab)


Potential interfering substance Concentration

Results(Detected

X/3)Haemoglobin

Bilirubin

Serum proteins

Human anti-mouse antibody (HAMA)

Rheumatoid Factor

Human leukocyte antigen (HLA) (for assays constructed using viral lysate, if cell line of human origin is used)

Anti-nuclear antibodies


6.4.3. Hook Effect:• If the potential exists for high titre positive clinical specimens which may lead

to false negative results, please evaluate and establish at what titre the hook effect is observed.

• Any mitigation (e.g., dilution) steps should be described.

• If this potential does not exist please provide a rationale for not testing for the presence of a hook effect.

6.4.4. Immunoglobulin class specificity:

• You should evaluate the potential for human IgG to cross-react and therefore produce false positive results with your IgM assay (and vice versa for an IgG assay).

• Please provide data or the rationale used to determine if cross-reactivity with IgG/IgM (as applicable) is a potential assay interferent.


6.4. Analytical Specificity (NAT)

6.4.1. Reactivity/Inclusivity

• Reactivity is to be evaluated for additional isolates of Zika virus.

• Isolates should be tested at or near the LoD of the assay

utilizing the entire test system.

• Test levels should not exceed 1.5-2 x LoD.

• In addition, reactivity should also be demonstrated by providing

sequence alignments using genomic sequences of other Zika

virus isolates (including those tested) and the sequences of the

assay’s primers and probes.


6.4. Analytical Specificity (NAT)

6.4.2. Cross-Reactivity

• WHO requires testing of organisms whose infection produces symptoms

similar to those observed at the onset of Zika virus infection and also viral

strains which have a significant likelihood to result in cross reactivity due to

genetic similarity with Zika virus.

• Organisms/strains which are likely to be observed in the currently affected

areas should be tested since these organisms/strains will be an important

part of the differential diagnosis of Zika virus infection.

• Consideration should also be given to testing of arboviruses from regions

where the vector Aedes aegypti is endemic.

• The evaluation should reflect test specimens prepared at the highest

clinically relevant level of organism. Test specimens can be prepared by

spiking cultured isolates into negative clinical matrix and determining cross-

reactivity based on triplicate measurements.

• Tables are provided with lists of organisms, testing of some to include both

laboratory testing as well as in silico analysis.


6.8. Clinical evidence (Ab)

• When assigning clinical truth for all specimens, optimally specimens

obtained from patients with data demonstrating seroconversion

should be

• Acute and convalescent phase specimens should be chosen and

ideally tested in parallel.

• In the absence of such specimens, verification of antibody status

should be confirmation using a Plaque Reduction Neutralization Test

(PRNT). Rabbit immune serum may be used as control material for

PRNT.

• The specimens should ideally be collected from the intended use population.

• Manufacturers should attempt to demonstrate performance against the

different strains, if possible by using specimens sourced globally.

• The specimens may be collected prospectively or retrospectively for each

claimed type.



6.8.1. Clinical/diagnostic sensitivity

• WHO recommends testing 50 positive clinical specimens obtained from

patients confirmed positive for Zika virus infection.

• For CSF specimens, there may be a limited number of specimens available

for testing. To address this, WHO suggests the possibility of preparing

contrived specimens using synthetic CSF matrix spiked with a high titer

serum specimen (serum should not make up more than 10% of the

specimen volume).



6.8.2. Clinical/diagnostic specificity

• WHO requires that specimens from 50 pregnant women are tested

(commercial panels are available).

• WHO also requires testing 50 to 100 specimens from patients confirmed

negative for Zika virus infection. These samples should be verified to be

negative for dengue IgM and West Nile virus IgM and negative Yellow Fever

vaccination status (documented) if the assay is found to cross-react with

these viruses.

• A significant number of specimens from individuals in territories where other

flavivirus infections have significant prevalence should be included in the

study.

• The specimens should ideally be collected from the intended use population

and include a mix of symptomatic and asymptomatic individuals

(approximately 50 % mix).


6.8. Clinical evidence (NAT)

6.8.1. Clinical/diagnostic sensitivity

• A minimum of 50 positive specimens is required

• The number of natural clinical specimens should be at

least 25

• Manufacturers should attempt to demonstrate

performance with different strains, if possible using

specimens sourced globally.

• In order to reduce the level of biosafety required for

testing, specimens may be heated (for antigen assays) or

lysed (for NAT). Evidence that this does not affect the

performance of the test should be documented.


6.8. Clinical evidence (NAT)

6.8.2. Clinical/diagnostic specificity

• A minimum of 100 negative specimens must be tested

• Of these, at least 25 must be sourced from pregnant

women


8. Quality Management Systems

Provide evidence of the implementation of a

manufacturing quality management system

including;

A list of valid quality management documentation;

• QC and batch release procedure/s;

• procedure/s for the control of design and development changes;

• procedure/s relevant to control of non-conforming goods, including

but not limited to procedures for corrective and preventative actions,

recalls, field safety notices etc.;


8. Quality Management Systems;

• ISO 13485:2003 certificate;

• the most recent QMS audit report;

• a copy of the quality manual;

• a recent management review report;

• details of the production workflow including QC points (in process

and final release activities);

• critical supplier list including supplied products (components / raw

materials) and services;

• details on the experience with the product (when was the product

developed and when was it first placed on the market);

• details on the manufacturing capacity (existing inventory, minimum

time to provide finished product, maximum batch size);

• information on outsourcing or contact manufacturing for any of the

components.


Any inquiries regarding the EUAL should be addressed to:

[email protected]


mailto:[email protected]


Mark McDonald Coordinator PQIrena Prat Team Lead PQDx

Deus Mubangizi Team Lead InspectionsWilly Urassa PQDx

Robyn Meurant PQDxAnita Sands PQDx

Mercedes Perez Gonzalez PQDxKim Richards PQ Inspections

Deirdre Healy PQDxHelena Ardura PQDxSapna Maglani PQDxVirgie Largardo PQDx

Natalya Olin PQDxAna Garcia PQ Inspections

who emergency use assessment and listing (eual) procedure - unicef · who emergency use assessment...

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