Real Time under an IDE

1
Real Time under an IDE

• CDCs PCR and ELISA Investigational Protocols

2
Real Time Under an IDE CDC SARS Laboratory
Response

• Phase I Agent Identification
• Phase II Assay Development
• Phase III Assay Deployment

3
CDC SARS Laboratory Response Phase I March
2003

• March 14 Outbreak investigation organized
• March 15-16-17 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

4
CDC SARS Laboratory Response Phase II April
2003

• 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

5
CDC SARS Laboratory Response Phase II April
2003

• 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

6
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• Unpublished reports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

7
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

8
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

9
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

10
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

11
CDC SARS Laboratory Response Phase III June
2003

• 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

12
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

13
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