WHO Emergency Use Assessment and Listing (EUAL) Procedure. Robyn Meurant WHO PQ Team Diagnostics Assessment

Transcription

1 WHO Emergency Use Assessment and Listing (EUAL) Procedure Robyn Meurant WHO PQ Team Diagnostics Assessment 1

2 Aim of WHO Prequalification: Diagnostics Assessment To promote and facilitate access to safe & appropriate IVDs of good quality in an equitable manner Customers WHO Member States UN agencies Funding and procurement agencies

3 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

4 Health Alerts: Week of 09 May

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

6 Life Cycle of an IVD Concept Design Development Validation Manufacture Packaging Labelling Advertising Marketing Approval Sales Supply Use Disposal Manufacturer NRA Pre Market Controls NRA Post Market Controls Users, patients 6

7 Life Cycle of an IVD Concept Design Development Validation Manufacture Packaging Labelling Advertising Marketing Approval Sales Supply Use Disposal Manufacturer NRA Pre Market Controls NRA Post Market Controls Users, patients WHO Prequalification QA Mechanisms 7

8 Prequalification Procedure Pre-submission form Priority product Yes No Dossier screening Dossier incomplete Dossier complete Dossier review Site inspection Laboratory evaluation PREQUALIFICATION DECISION Post - Prequalification activities

9 WHO QA Mechanisms Eligibility WHO QMS review WHO Lab Evaluation Analytical performance Clinical performance Stability Rolling submissions Listing Post approval Prequalification Any time Prioirity product On site inspection Comprehensive (1000s) Comprehensive Comprehensive Real time No Until delisted PMS, re-inspection, changes

10 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.

11 WHO QA Mechanisms Eligibility Prequalification Any time Prioirity product ERPD Expression of Interest WHO QMS review On site inspection Desk top WHO Lab Evaluation Analytical performance Clinical performance ++++ (1000s) None Stability Real time Accelerated if novel Rolling submissions No No Listing Until delisted 1 year Post approval PMS, re-inspection, changes Complete PQ

12 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

13 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.

14 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

15 WHO QA Mechanisms Eligibility Prequalification ERPD EUAL Any time Prioirity product Expression of Interest Expression of Interest PHEIC WHO QMS review On site inspection Desk top Desk top WHO Lab Evaluation Analytical performance Clinical performance ++++ (1000s) None s /+ Stability Real time Accelerated if novel Accelerated Rolling submissions No No yes Listing Until delisted 1 year 1 year (+) Post approval PMS, re-inspection, changes Complete PQ Complete development, PMS

16 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.

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

18 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

19 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 Nocht Institute, Germany) Sierra Leone clinical performance study (Nigerian and PHE Labs)

20 EUAL The Ebola Virus Experience 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

21 EUAL The Ebola Virus Experience

22 EUAL IVDs for Zika virus Similar process as for the EUAL for Ebola virus Invitations to submit sent to over 30 manufacturers

23 EUAL IVDs for Zika virus Collaborative 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

24 WHO Zika EUAL Requirements

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26 EUAL Requirements IVDs for Zika virus

27 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.

28 EUAL Requirements IVDs for Zika virus 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 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

29 EUAL Requirements IVDs for Zika virus 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.

30 Stock Virus Titre Serial 10-Fold Dilution Factor PFU/mL or TCID 50 /ml Dilution Tested EUAL Requirements IVDs for Zika virus 6.4. Limit of Detection (NAT) Virus Strain Tested Run 1 C t Run 2 C t Run 3 C t Run 4 C t Run 5 C t Example: (analyte) Call Rate Lowest Concentrati on with Uniform Positivity per Analyte Limit of Detection (LoD) per Virus Strain

31 EUAL Requirements IVDs for Zika virus 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 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.

32 EUAL Requirements IVDs for Zika virus 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.

33 EUAL Requirements IVDs for Zika virus 6.4. Analytical Specificity (Ab) 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. 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.

34 EUAL Requirements IVDs for Zika virus 6.4. Analytical Specificity (Ab) 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.

35 EUAL Requirements IVDs for Zika virus 6.4. Analytical Specificity (Ab) Cross-Reactivity (Ab) Disease/Infectious agent Positive Sera Anti-chikungunya virus Anti-cytomegalovirus (CMV) Anti-dengue virus (each of the four serotypes) Number of specimens N = 3-5 each condition Assay Equivocal or positive results % Crossreactivity Anti-Epstein Barr virus (EBV) Anti-parvovirus B19 Anti-varicella zoster virus Yellow fever virus post-immunization Anti-West Nile virus Anti-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)

36 EUAL Requirements IVDs for Zika virus 6.4. Analytical Specificity (Ab) Interfering Substances (Ab) Potential interfering substance 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) Concentration Results (Detected X/3) Anti-nuclear antibodies

37 EUAL Requirements IVDs for Zika virus 6.4. Analytical Specificity (Ab) 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 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.

38 EUAL Requirements IVDs for Zika virus 6.4. Analytical Specificity (NAT) 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 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.

39 EUAL Requirements IVDs for Zika virus 6.4. Analytical Specificity (NAT) 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 crossreactivity 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.

40 EUAL Requirements IVDs for Zika virus 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.

41 EUAL Requirements IVDs for Zika virus 6.8. Clinical evidence (Ab) 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).

42 EUAL Requirements IVDs for Zika virus 6.8. Clinical evidence (Ab) 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).

43 EUAL Requirements IVDs for Zika virus 6.8. Clinical evidence (NAT) 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.

44 EUAL Requirements IVDs for Zika virus 6.8. Clinical evidence (NAT) Clinical/diagnostic specificity A minimum of 100 negative specimens must be tested Of these, at least 25 must be sourced from pregnant women

45 EUAL Requirements IVDs for Zika virus 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.;

46 EUAL Requirements IVDs for Zika virus 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.

47 EUAL Requirements IVDs for Zika virus

48 EUAL Requirements IVDs for Zika virus Any inquiries regarding the EUAL should be addressed to:

49 EUAL Requirements IVDs for Zika virus Mark McDonald Coordinator PQ Irena Prat Team Lead PQDx Deus Mubangizi Team Lead Inspections Willy Urassa PQDx Robyn Meurant PQDx Anita Sands PQDx Mercedes Perez Gonzalez PQDx Kim Richards PQ Inspections Deirdre Healy PQDx Helena Ardura PQDx Sapna Maglani PQDx Virgie Largardo PQDx Natalya Olin PQDx Ana Garcia PQ Inspections