U.S. FDA Requirements

Transcription

1 UNICEF Zika Vaccine and Diagnostics Industry Consultation, UNICEF Supply Division U.S. FDA Requirements Kristian Roth, Ph.D. Branch Chief Division of Microbiology Devices FDA/CDRH 1

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3 Overview Emergency Use Authorization (EUA) Review Templates Overview Molecular-Based Assay Requirements Serological IgM Assay Requirements 3

4 Emergency Use Authorization (EUA) During certain circumstances: Under section 564 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the FDA Commissioner may allow use of unapproved medical products or unapproved uses of approved medical products to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by Chemical, Biological, Radiological, or Nuclear (CBRN) threat agents when there are no adequate, approved/cleared, and available alternatives. 4

5 Determination and Declaration Regarding Emergency Use of In- Vitro Diagnostic Tests for Detection of Zika Virus and/or Diagnosis of Zika Virus Infection 26 th February 2016 The Secretary of Health and Human Services (HHS) is issuing this notice pursuant to section 564 of the Federal Food, Drug, and Cosmetic (FD&C) Act, 21 U.S.C. 360bbb-3. On February 26, 2016, the Secretary determined that there is a significant potential for a public health emergency that has a significant potential to affect national security or the health and security of United States citizens living abroad and that involves Zika virus. On the basis of this determination, the Secretary also declared that circumstances exist justifying the authorization of emergency use of in vitro diagnostic tests for detection of Zika virus and/or diagnosis of Zika virus infection pursuant to section 564 of the FD&C Act, subject to the terms of any authorization issued under that section. 5

6 Emergency Use Authorization (EUA) (cont. I) 6

7 Emergency Use Authorization (EUA) (cont. II) 21 U.S. Code 360bbb 3 - Authorization for medical products for use in emergencies (c)(2)(a) the product may be effective in diagnosing, treating, or preventing (c)(2)(b) the known and potential benefits of the product, when used to diagnose, prevent, or treat such disease or condition, outweigh the known and potential risks of the product (c)(3) that there is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating such disease or condition 7

8 Emergency Use Authorization (EUA) (cont. III) 21 U.S. Code 360bbb 3 - Authorization for medical products for use in emergencies FDA determines the benefits and risks of each product for which an EUA is requested independently. Authorization is based on the totality of available scientific evidence. Performance criteria based on benefit/risk assessment for each EUA application during the outbreak or epidemic. Compliance with design and manufacturing control regulation may be waived. The letter of Authorization names conditions which must be met. (i.e., periodic reporting, patient fact sheet, and duration). 8

9 CDC MAC-ELISA (February 28) The CDC Zika MAC-ELISA is intended for the qualitative detection of Zika virus IgM antibodies in human sera or cerebrospinal fluid (CSF) that is submitted alongside a patient-matched serum specimen, collected from individuals meeting CDC Zika virus clinical criteria (e.g., a history of clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (e.g., recent history of travel to geographic regions during a period of active Zika virus transmissions at the time of travel, or other epidemiologic criteria for which Zika virus testing may be indicated as part of a public health response). The assay is intended for use in qualified laboratories designated by the CDC, as a part of a multi-test algorithm. Assay results are for the presumptive identification of IgM antibodies to Zika virus. Positive and equivocal results are not definitive for diagnosis of Zika virus infection. False positive results are possible in patients with a history of infection with other flaviviruses. Confirmation of the presence of anti-zika IgM antibodies in equivocal or presumptive positive specimens requires additional testing by CDC, *Negatives do not require follow up 9

10 CDC Trioplex RT-PCR (March 17) The Trioplex Real-time RT-PCR Assay (Trioplex rrt-pcr) is intended for the qualitative detection and differentiation of RNA from Zika virus, dengue virus, and chikungunya virus in human sera or cerebrospinal fluid (collected alongside a patient-matched serum specimen), and for the qualitative detection of Zika virus RNA in urine and amniotic fluid (each collected alongside a patient-matched serum specimen). The assay is intended for use with specimens collected from individuals meeting CDC Zika virus clinical criteria (e.g., clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (e.g., history of residence in or travel to a geographic region with active Zika transmission at the time of travel, or other epidemiologic criteria for which Zika virus testing may be indicated as part of a public health investigation). Testing is limited to qualified laboratories designated by the Centers for Disease Control and Prevention (CDC). 10

11 Zika RT-PCR Focus Diagnostics (April 28) Zika Virus RNA Qualitative Real-Time RT-PCR test is a real-time RT-PCR test intended for the qualitative detection of RNA from Zika virus in human serum specimens collected from individuals meeting Centers for Disease Control and Prevention (CDC) Zika virus clinical criteria (e.g., clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (e.g., history of residence in or travel to a geographic region with active Zika transmission at the time of travel, or other epidemiologic criteria for which Zika virus testing may be indicated). Testing is limited to qualified laboratories designated by Focus Diagnostics, Inc. Test results are for the identification of Zika viral RNA. Zika viral RNA is generally detectable in serum during the acute phase of infection (approximately 7 days following onset of symptoms, if present). Positive results are indicative of current infection. Laboratories are required to report all positive results to the appropriate public health authorities. Negative results do not rule out Zika virus infection and should not be 11 used as the sole basis for patient management decisions

12 Draft EUA Review Templates Draft EUA Review Templates developed to stream line data submission as well as data review and review documentation Outlines FDA s current recommendations for the analytical and clinical validation studies needed in support of an EUA submission for an infectious disease IVD Dynamic Template: Draft document, adapted depending on specific circumstances of the outbreak, Analyte & Technology (e.g., molecular, serology), starting point Assist Sponsors and FDA Reviewers: Manufacturer fills out the template Template serves as basis for interactive review Template will later serve as sponsor s EUA Submission AND Review memorandum 12

13 Draft EUA Review Template Content 1 A. Executive Summary B. Purpose for Submission C. Measurand D. Applicant E. Proprietary and established names F. Product Description Incl. Device, controls and all accessories G. Test Principle H. Proposed Intended Use I. Unmet need addressed by the product 13

14 Draft EUA Review Template Content 2 J. Approval/Clearance status K. Product manufacturing Manufacturing sites and manufacturer s name for all components and accessories of the device, incl. Components/materials needed but not supplied Description of any available quality system, packagers, distributors L. Approved/cleared alternative products M. Interpretation of results Interpretation of controls Examination of patient results Interpretation of results 14

15 EUA Draft Review Template Content 3 N. Safety and Effectiveness Including (depends on the assay): 1. Analytical Sensitivity (LoD) 2. Analytical Specificity 3. Interference 4. Clinical Evaluation O. Risks and Benefits Risks (the risks / benefits section will change depending on the analyte and may change throughout the period of an outbreak) 15

16 Draft EUA Review Template Content 4 Attachments to be supplied with the Review Template at time of EUA Request when the intended use is finalized P. Fact sheet for healthcare providers, pregnant women and patients Q. Instructions for use (proposed labeling) R. Record keeping and reporting information to FDA Tracking & reporting adverse events (21 CRF 803) Post market surveillance (Device usage/ purchase records and collection of performance information) Record Maintenance and Record Availability for Inspection 16

17 Molecular-Based Assay Requirements 17

18 Safety and Effectiveness Studies (cont. I) Analytical Sensitivity (LoD) Characterized materials, live/inactivated virus from current/recent outbreak preferred* Tentative LoD in clinical matrix Serial dilutions 3-5 replicates Confirmatory LoD 20 replicates at LoD (19/20) Utilize the entire test system from sample preparation to detection for each clinical matrix claimed *Acceptable to use commercially available Zika viral stocks for wet testing when accompanied by extensive inclusivity in silico analysis with all known Zika strains Asian lineage required for wet testing. 18

19 Safety and Effectiveness Studies (cont. II) Analytical Specificity Reactivity Evaluated with additional isolates of the Zika virus tested at 1.5-2xLoD in clinical matrix utilizing the entire test system Location Year Reported Human cases 1952 Uganda 1963 Indonesia 1964 Uganda Nigeria Indonesia Ivory coast Micronesia, Yap Cambodia Australia 1 (imported) 2013 Indonesia New-Caledonia French Polynesia 8, New-Caledonia South America? 19

20 Safety and Effectiveness Studies (cont. III) Analytical Specificity Cross Reactivity List is intended to recommend testing of organisms that: Infection produces symptoms similar to those observed at the onset of Zika virus infection Have a significant likelihood to result in cross reactivity due to genetic similarity with Zika virus Are likely to be observed in the currently affected area Test specimens prepared by spiking cultured isolates into negative clinical matrix at the highest clinically relevant level, test three replicates 20

21 Safety and Effectiveness Studies (cont. IV) Analytical Specificity Cross Reactivity Table 1: Organisms to be wet-tested and analyzed in silico (for assays detecting Zika Virus) in blood sample: Other Flaviviruses Dengue virus 1, 2, 3 and 4 Yellow fever Yellow fever vaccine strain West Nile virus Organisms Alphaviruses: Chikungunya Mayaro virus Parvovirus (B19) Plasmodium falciparum 21

22 Safety and Effectiveness Studies (cont. V) Analytical Specificity Cross Reactivity Table 2: Organisms to be analyzed in silico (for assays detecting Zika Virus): Other Flaviviruses Organisms Organisms St. Louis encephalitis virus Alphaviruses including: Eastern Equine Encephalitis Virus (EEE) Western Equine Encephalitis Virus (WEE) Ross River virus Barmah Forest virus O nyong-nyong virus (Sindbis virus, Tonate virus and Una virus) Measles virus Epstein Barr Virus (EBV) Japanese encephalitis Rickettsia sp. virus Spondweni virus Rubella virus Borrelia burgdorferi Hepatitis C virus Enterovirus all serotypes Group A Streptococcus 22

23 Safety and Effectiveness Studies (cont. VI) Analytical Specificity Cross Reactivity Table 2: Organisms to be analyzed in silico (for assays detecting Zika Virus): Organisms Organisms Adenovirus all serotypes Leptospirosis Hepatitis B virus Plasmodium sp. Plasmodium vivax HIV Trypanosoma cruzi (Chagas) Varicella Zoster virus Schistosomiasis Cytomegalovirus (CMV) Hepatitis A virus vaccine - BIOVAC-A brand Salmonella typhi vaccine (Typhoid - Ty21a vaccine) 23

24 Safety and Effectiveness Studies (cont. VII) Analytical Specificity Interference Technology and matrix dependent For EUA not typically required for assays that use conventional PCR and RNA extraction steps during the assay protocol May be required for o Assays that use new or no extraction procedures o Isothermal methods 24

25 Safety and Effectiveness Studies (cont. VIII) Clinical Evaluation A minimum of 50 positive specimens Prospective/ Retrospective* A minimum of 50 to 100 negative specimens Tested in a blinded fashion Percent agreement should be calculated in comparison to a reference/comparator such as bi-directional sequencing For each claimed clinical matrix, symptomatic and asymptomatic *The number of natural positive clinical specimens (prospective/retrospective) should be at least 25 and, if necessary, may be supplemented with contrived specimens to generate the total of 50 positive specimens. 25

26 Serological IgM Assay Requirements 26

27 Safety and Effectiveness Studies (cont. I) Analytical Specificity Cross Reactivity Specimens from patients with antibodies to other microorganisms which could potentially cause false positive results Preferably early stage infection where IgM levels will dominate in the specimen Concentration/titer of IgM if known Methods used to characterize the specimens Min. 3-5 specimens for each microorganism listed, 10 for agents with known cross-reactivity with Zika IgM (Dengue 1-4, Yellow Fever vaccination, West Nile virus) 27

28 Safety and Effectiveness Studies (cont. II) Analytical Specificity Cross Reactivity Disease/Infectious Agent Positive Sera Disease/Infectious Agent Positive Sera Anti-Chikungunya virus Adenovirus (optional) Anti-Cytomegalovirus (CMV) Enterovirus (optional) Anti-Dengue virus Anti-Leptospira (optional) Anti-Epstein Barr Virus (EBV) Anti-Parvovirus B19 Anti-Varicella zoster virus Yellow fever virus post-immunization Anti-West Nile Virus Anti-nuclear Antibodies (ANA) Rheumatoid Factor Anti- Malaria/anti-plasmodium falciparum Anti-Eastern Equine Encephalitis (optional) Anti-Japanese Encephalitis (optional) Anti-Hepatitis (C) virus (optional) Anti-Ross River virus (optional) Anti-Saint Louis encephalitis (SLE) (optional) 28

29 Safety and Effectiveness Studies (cont. III) Analytical Specificity Interference Should be evaluated over the expected clinical range of the potential interfering substance Potential endogenous interferents: Hemoglobin Bilirubin Serum Proteins HAMA Rheumatoid Factor Evaluate the potential to generate false positive and false negative results 29

30 Safety and Effectiveness Studies (cont. IV) Hook Effect Evaluated if high titer clinical samples produce false negative results 30

31 Safety and Effectiveness Studies (cont. V) Clinical Evaluation A minimum of 50 positive specimens Prospective/ Retrospective patients confirmed positive for Zika virus infection A minimum of 50 to 100 negative specimens from patients confirmed negative for Zika virus infection Tested in a blinded fashion Percent agreement should be calculated in comparison to clinical truth For each claimed clinical matrix, ideally from Intended Use patient population 31

32 Safety and Effectiveness Studies (cont. VI) Clinical Specificity A minimum of 50 to 100 negative specimens from patients confirmed negative for Zika virus infection Specimens should be verified negative for dengue IgM* and West Nile IgM* Specimens negative for Yellow Fever vaccination* (documented) * If assay cross reacts with these viruses Sources of symptomatic negative specimens from patients**: Reporting fever and rash Reporting fever and/or diagnosed with Influenza Taken for Dengue/West Nile testing and subsequently determined to be negative for these agents **Leftover and de-identified specimens 32

33 Safety and Effectiveness Studies (cont. VII) Clinical Truth A validated testing algorithm that includes a confirmatory assay to confirm both positive and negative samples* Serial bleeds from individuals that initially tested positive with a RT-PCR assay for Zika virus. *Plague Reduction Neutralization Assay (PRNT) is currently considered the gold standard 33

34 Thank You 34

35 Additional Slides 35

36 EUA Vs. Premarket: In Vitro Diagnostics Requirements Emergency Use Authorization (EUA) Premarket Notification or Application Special Circumstances Analytical Evaluation Clinical Evaluation Duration CGMP Requires declaration by the HHS Secretary of a public health emergency There is no adequate, approved, and available alternative to the product Limited Limited Temporary - remains in effect for the duration of the declaration unless revoked sooner Expected but limits or waivers may be granted in an EUA on a case-by-case basis No Extensive Extensive Yes Yes 36

37 Emergency Use Authorization (EUA) m_medium= &utm_source=govdelivery#zika 37

38 Authorization Letter FDA may establish conditions on an EUA necessary or appropriate to protect the public health. Some conditions are required to the extent practicable given the applicable circumstances of the emergency or threat, whereas others may be imposed entirely at the discretion of FDA. PolicyFramework/ucm htm 38

39 Conditions of Authorization Distribution and use conditions may be placed on who may distribute and who may use the product, and how distribution and administration are to be performed. In addition, conditions may be placed on the categories of individuals to whom, and the circumstances under which, the product may be administered. Advertising conditions may be placed on advertisements and other promotional printed materials relating to the EUA device 39

40 Conditions of Authorization Interim WHO Zika Standard: [Sponsor] will assess traceability of the [X PCR device] with the interim WHO Zika reference standard when the reference material becomes available. After submission to FDA and FDA s review of and concurrence with the data, [Sponsor] will update their labeling to reflect the additional testing. 40

41 Conditions of Authorization FACT Sheets a. Fact Sheet for Healthcare Providers b. Fact Sheet for Patients c. Fact Sheet for Pregnant Women To provide information on the significant known and potential risks and benefits of the use of the [device]. 41

42 Duration of an EUA FDA will specify the effective date of an EUA issued under section 564. In general, an EUA will remain in effect for the duration of the declaration under which it was issued Unless the EUA is revoked because the criteria of issuance are no longer met or Revocation is appropriate to protect public health or safety 42

43 EUA Diagnostics in Past and Current Emergencies PAHPRA (3/2013) H1N1 H7N9 MERS-CoV Ebola Enterovirus D68 Zika EUA Declaration April 26, 2009 April 19, 2013 May 29, 2013 August 5, 2014 February 6, 2015 February 26, 2016 EUA Diagnostics: Molecular Antigen * 0 Serology * Includes one product that was authorized for two different intended uses Note: All the 36 authorized diagnostic products were new 1 st to market - products 43

44 Resources Uwe Scherf, M. Sc., Ph.D. Director, Division of Microbiology, Office of In Vitro Diagnostics and Radiological Health, CDRH/FDA Contact directly for interactive review and regulatory guidance. We have many topic specific working groups who are willing to help. Information on: Crisis management Emergency response Emerging threats Disease or condition specific guidance documents state FDA study recommendations. 510(k) and PMA databases public disclosure of all device clearance and approvals including data summaries. 44