Real Time under an IDE – CDCs PCR and ELISA Investigational Protocols

Real Time Under an IDE: CDC SARS Laboratory Response Phase I : Agent Identification Phase II: Assay Development Phase III: Assay Deployment

CDC SARS Laboratory Response – Phase I : March March 14: Outbreak investigation organized March : Samples arrived from Toronto, Thailand March 18-22: Virus isolated by cell culture, identified by EM and IFA assay March 23-24: Virus verified by PCR and sequencing; prototype ELISA developed

CDC SARS Laboratory Response – Phase II: April April 3: Initiated discussions for development of real-time PCR assay to be deployed to LRN laboratories April 3 – 8: Discussions with FDA regarding filing IDE for real-time PCR assay April 7- 18: Additional PCR signatures selected and assay optimized LRN protocols developed, written, approved internally

CDC SARS Laboratory Response – Phase II: April Synthesize primers and probes, optimize conditions, evaluate performance of assay Large scale production primers and probes, dispense and label, QC for performance Alert LRN members of reagents that will need to be purchased April 21: Large scale production EIA antigen complete April 28: FDA determines that ELISA assay is low risk; abbreviated IDE appropriate

IDE Process – Real Time PCR Published reports Unpublished reports Investigational Plan Purpose Protocol Risk Analysis Description of the Device Monitoring Procedures Manufacturing Information Investigator Information IRB Information Labeling Informed Consent Materials

IRB Documentation for Real Time PCR Assay – April 30 SARS Coronavirus PCR Assay Protocol Attachment A - Published Reports Attachment B - Health care providers information Attachment C - Informed consent Attachment D1 - Specimen Submission Form Attachment D2 - Specimen Submission Form - Planned Amendments Attachment E - Participant Information Sheet Attachment F - Laboratory Response Network (LRN) Procedure Coversheet Attachment F1 - F3 - Laboratory Response Network (LRN) Protocols Attachment G - SARS Assay History Attachment H - Primers and Probes Package Information Attachment I - SARS Primers and Probes Labeling Attachment J – Participating Labs Agreement Attachment K – Interim Guidance for those patients with mild or asymptomatic infection Attachment L – Fact Sheet for Clinicians

IRB Documentation for ELISA Assay SARS Coronavirus EIA Assay Protocol Attachment A: Informed Consent form Attachment B: Health Care Provider Instructions Attachment C1 & 2: Laboratory Submission form and laboratory submission amendment form Attachment D: Interim Guidance for Asymptomatic and Mildly Ill Patients Attachment E: Fact Sheet for Clinicians Attachment F: Participant Information Document Attachment G: EIA Assay Procedure

CDC SARS Laboratory Response – Phase III: May 2003 April 30: Submit preliminary IDE application for PCR assay to FDA May 2: FDA granted conditional approval of IDE for PCR assay May 1: Submit PCR assay protocol and associated documentation to IRB IRB responded that protocol written following FDA guidelines did not accurately reflect public health intent; protocol was re- written

CDC SARS Laboratory Response – Phase III: May 2003 May 14: EIA Protocol submitted for IRB approval May 15: Real time PCR protocol IRB approved May 19: EIA protocol IRB approved May 20: Discrepancies between Web documents and IRB approved EIA and PCR documents May 28 : Submitted amendments for EIA and PCR documents to IRB May 29: IRB approved amendments May 30: EIA and PCR documents posted on CDC, APHL, and LRN web sites

CDC SARS Laboratory Response – Phase III: June June 3: CSTE raises issues regarding instructions within Healthcare Provider letter June 4 – 10: Feedback from CSTE members June 16: Submitted amendments to IRB for EIA and PCR protocols June 18: IRB approved amendments to Healthcare Provider letter

Lessons Learned Definitions: protocol (human subjects) and lab procedures Language: CDC and FDA speak different languages – difficulties applying FDA regulations for manufacturers in a public health setting Due to public health emergency, multiple authors were needed and versions of documents resulted in confusion and contradictions in written documents CDC excels in developing assays rapidly for public health emergencies; not designed to be a manufacturing facility

Lessons Learned CDC IRB has no experience or perspective in reviewing device protocols in a public health response setting Necessity to obtain IRB approval delays the rapid release of current information in an outbreak situation Cooperation between CDC and FDA facilitated completion of this process