The secrets to conducting a rapid safety trial


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The secrets to conducting a rapid safety trial

  1. 1. THE SECRETS TO CONDUCTING A RAPID SAFETY TRIAL OF (INFLUENZA) VACCINE<br />David W. Scheifele MD<br />Vaccine Evaluation Center<br />UBC and BC Children’s Hospital<br />Vancouver<br />
  2. 2. PERSPECTIVE<br />Speed is normally anathema for vaccine trials<br />Slow, progressive enrollment is preferred:<br />for optimal safety monitoring<br />for best practices by staff<br />for full attention to subjects<br />Staggered starts are usual in multicenter trials, reflecting administrative challenges, delays<br />
  3. 3. NEED FOR SPEED<br /><ul><li>Unique to pre-season or pandemic influenza vaccine trials (or for novel vaccines in crisis situations)
  4. 4. Pre-season influenza vaccine trials required of companies by BGTD
  5. 5. Typically done by CRO’s (results confidential, unpublished)
  6. 6. Trial design modifications not publicized or widely known but small N
  7. 7. Complete in ~6 weeks, in summer, for regulatory review</li></li></ul><li>PCIRN RAPID TRIALS NETWORK<br />Charged to demonstrate capability to conduct suitably rapid trials of (pandemic) flu vaccine<br />Events in 2009 conspired against rapid trials<br />Safety trial of seasonal TIV completed in 5 weeks in summer of 2010, meeting the challenge<br />What were the secrets of success?<br />
  8. 8. KEY CONSIDERATIONS FOR RAPID TRIALS<br />Participating trial center selection<br />Subject numbers and recruitment strategy<br />Administrative approvals<br />Study design considerations<br />Data assembly and reporting<br />
  9. 9. PARTICIPATING CENTERS<br />Ideal: experienced, well-staffed centers with access to ample numbers of potential subjects<br />5 is an optimal number, to keep enrollment quotas reasonable, minimize organizational complexity (training, monitoring, equipping etc)<br />Beware of extra challenges of mid-summer!<br />
  10. 10. SUBJECT NUMBERS<br />We set group size at 320, sufficient to detect severe or unusual AEs occurring at ≥1% incidence rate and ample for immunogenicity assessment<br />Quotas per center were 64 subjects (modest)<br />Loss of a center would add only 16 subjects to others<br />
  11. 11. SUBJECT ELIGIBILITY<br />Fast recruitment facilitated by:<br />wide age range (20-59 years)<br />acceptance of stable health conditions<br />short term involvement (summer)<br />limited demands on subjects<br />
  12. 12. ADMINISTRATIVE APPROVALS<br />Funding arrangements simplified by prior agreements between PCIRN and institutions<br /> (A notable value of established networks)<br />Ethics approvals were major consideration as some REB’s met less often in summer<br />Key measures: timely availability of documents for submission, liaison with REB chairs, begging<br />
  13. 13. ADMINISTRATIVE APPROVALS (2)<br />Working with “unlicensed” vaccine requires BGTD Clinical Trial Application; approval can take up to 30 days<br />Obtaining unlicensed vaccine from a company requires internal reviews, formal Material Transfer Agreement, shipping arrangements<br />
  14. 14. VOLUNTEER RECRUITMENT<br />Essential to identify volunteers in the weeks before vaccine is available (phone, email)<br />Permits rapid completion of formal enrollment at first visit, leading to vaccination<br />Volunteers can be booked into large clinics, amply staffed, for maximal efficiency<br />Clustering visits within one week aids all subsequent steps in protocol<br />
  15. 15. STUDY DESIGN OPTIONS<br />Companies use open, parallel group design<br />Cross-over design optimal for safety concerns, allows randomized, placebo-controlled observations (each subject acts as own control), yielding vaccine-attributable adverse event rates<br />Cross-over interval 7-10 days<br />
  16. 16. SAFETY ASSESSMENT<br />Common AE’s after influenza vaccine peak at 24 hr and mostly resolve by day 6, allowing short-term observations<br />Daily symptom diary captures key observations<br />Interview at 24 hr detects severe events, if present<br />Interview at day 7 provides full overview<br />
  17. 17. SAFETY DATA ASSEMBLY<br /><ul><li>Electronic data reporting platform is essential
  18. 18. Need site staffing for same or next day data entry
  19. 19. Study statistician can monitor AE reports daily
  20. 20. Quick data clean-up needed with sites
  21. 21. Pre-programmed analysis tables speed process
  22. 22. DSMB can be kept informed of severe AE’s, review possible prior to cross-over</li></li></ul><li>PCIRN RT06 TRIAL TIMELINE<br /><ul><li>All 5 centers started enrolling same day</li></ul> (August 9)<br /><ul><li>All completed enrollment during that week!
  23. 23. All day 1 interview data reported early Week 2
  24. 24. All day 7 interview data reported early Week 3
  25. 25. Similar after dose 2 on Day 10
  26. 26. Safety report to PHAC on Sept 10 (Day 33)</li></li></ul><li>IMMUNOGENICITY ASSESSMENT<br />Final blood samples obtained 21-31 days after first visits (all 21 days after TIV vaccination)<br />Subsequent steps typically take 4-6 weeks<br />to catalogue and ship sera to NML (1-2 wk)<br />testing at NML lab (2-3 wk)<br />data analysis, reporting (1-2 wk)<br />We did not seek rapid completion for this trial<br />
  27. 27. SECRETS IN SUMMARY<br /><ul><li>Small number of experienced, well staffed centers
  28. 28. Efficient completion of administrative approvals
  29. 29. Moderate enrollment numbers, broad eligibility
  30. 30. Advance recruitment of volunteers
  31. 31. Simultaneous start, rapid completion V1’s
  32. 32. Electronic data platform, rapid data entry
  33. 33. Well prepared data analysis plan, staff</li></li></ul><li>IMPLICATIONS <br />Accomplishing a rapid trial is only feasible for an established network (or CRO)<br />Maintaining this capability beyond the 3 year life of PCIRN will require additional infrastructure support or it will be lost<br />Few of the participating centers have stable funding otherwise and could disappear at any time<br />
  34. 34. ACKNOWLEDGEMENTS<br />PCIRN RT06 Trial Centers and Investigators:<br />Quebec City – M Dionne, G De Serres, V Gilca<br />Montreal – B Ward, C Quach<br />Ottawa – C Cooper<br />Calgary – O Vanderkooi, J Kellner, J MacDonald<br />Vancouver – D Scheifele, S Dobson, L Sauvé,<br /> T Kollmann<br />Project manager: C LaJeunesse<br />Statistician: Shu Yu Fan<br />Funding: CIHR Vaccine: GSK (A Chit, J DasGupta)<br />