Bringing Zika vaccines to licensure Demonstration of efficacy and effectiveness Zika vaccine and study designs (with considerations to generating evidence that may contribute to inform regulatory review)

Ira Longini on behalf of R&D Blueprint Clinical trials working parties

Current situation • There are a about 30 Zika vaccine candidates in various stages of development – Some have undergone animal challenge studies – One may be entering phase IIb efficacy trial – None in phase III efficacy trials – Some may undergone human challenge studies • There is no established immune correlate or surrogate of protection

Important caveat

The clinical development program and regulatory pathway for a Zika vaccine must be tailored to the particular candidate vaccine being evaluated and may differ from that of other candidate Zika vaccines Bringing Zika vaccines to licensure Demonstration of efficacy and effectiveness

TRADITIONAL APPROVAL ACCELERATED APPROVAL ANIMAL RULE “Exceptional EUAL* Listing (only FDA) circumstances” EMA (WHO) RCT, clinical endpoint Accelerated evaluation to For serious/life threat. Special OR accepted correlate of treat a serious or life- conditions, when efficacy procedure. protection threatening condition on studies are unfeasible or The disease has Placebo-controlled one or more clinically unethical. Product cannot be been declared RCTs powered to significant endpoints. approved via traditional or PHEIC. Vaccine demonstrate Well-controlled trials accelerated approval. has oversight by clinical efficacy. establishing an effect on a Immune markers in animal a functional surrogate endpoint. models reasonably likely to NRA. Basic Individual RCT Human challenge studies predict protection against evidence Zika disease in humans considered the may support. including but not limited to gold standard. Require Post-licensure studies to verify clinical data, clinical benefit safety data. Justify that Expedited Development and Review Designations immunogenicity Breakthrough / PRIME status data are when preliminary clinical evidence indicates that the drug sufficient, if no may demonstrate substantial improvement /potential clinical data. benefit over existing therapies

* WHO Emergency use assessment and listing procedures for medical products during public health emergencies TRADITIONAL APPROVAL

Clinical disease endpoint • Classical RCT with a valid comparator in multiple populations where future transmission is likely – Multi-arm trials – Combining information across trial populations, epidemics, vaccine candidates

Well-established marker of protection (or vaccine efficacy surrogate) – There is no scientific well-established immune correlate or surrogate of protection for Zika – However, there are known immune correlates for other live and inactivated flavivirus vaccines, e.g., yellow fever, JE

ACCELERATED APPROVAL

• Immune correlates or surrogates (immune marker or impact on another clinical marker) – Ideally we would have both efficacy and immunogenicity data from phase IIb or III vaccine trials • In the absence of this, human immunogenicity data from phase I and II trials

• [Human challenge studies] Immune correlates

• Human and animal immunogenicity studies • Immunogenicity from related flavivirus vaccine constructs – 17D live, attenuated yellow fever vaccine • High VE, near 100% • FDA approved antibody surrogate of infection • neutralizing antibody titer > 10 is protective • Similar Zika vaccine construct may work – JE vaccines licensed may also be analogous

Human challenge studies

• Studies can directly assess many vaccine effects that cannot be observed in a typical Phase III trial – Includes detailed longitudinal data on viral load and persistence

• Approach has been used for bridging studies of vaccines for cholera, malaria, influenza and typhoid1

• In 1998, FDA determined that human challenge would have been acceptable to demonstrate efficacy of a cholera vaccine (live oral CVD103-HgR)2

• Limitations: – Extensive safety data still required for licensure – May be hard to replicate natural exposure (dose & pathway)

1 Herrington DA. Initial clinical evaluation of new vaccine candidates. Phase I and II trials of safety, immunogenicity, and preliminary efficacy. In: Woodrow GC, Levine MM, eds. New generation vaccines. New York: Marcel Deker, 1990, 43-49. 2 Food and Drug Administration. Guidance for Industry: General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases. 2011. What trial needs are anticipated post market authorization?

TRADITIONAL APPROVAL ACCELERATED APPROVAL ANIMAL RULE EUAL

Requires post Requires studies to Requires studies to verify The manufacturer marketing safety verify clinical benefit - clinical benefit - to submit human surveillance. effectiveness. effectiveness. efficacy data and/or correlates Additional Alternative designs of protection effectiveness may be suggested: e.g. cluster Approval contingent on data ASAP. needed – rare randomized. studies, studies are Plan to monitor outcomes conducted if and when quality, safety and Approval contingent on they become feasible efficacy in the if there is an additional studies, and ethical. field, and an accepted correlate of usually underway. undertaking to protection, then a submit any trial to show clinical new data ASAP. efficacy might not be required. Summary: Bringing Zika vaccines to licensure Demonstration of efficacy and effectiveness

TRADITIONAL APPROVAL ACCELERATED APPROVAL ANIMAL RULE EUAL (only FDA) (WHO) RCT, clinical endpoint or It may be necessary to EXCEPTIONAL accepted correlate of accumulate data on CIRCUMSTANCES This can always protection correlates and surrogates (only EMA) be done, but of VE from a large number must have PHEIC These trials can be of sources as trials and This would be carried out by studies are carried out done if human targeting phase IIb and III Human challenge VE trials are not populations that feasible are soon to studies experience Zika outbreaks Some preliminary discussions at the R&D Blueprint ad hoc group on clinical trial designs Designs we considered

• Individual RCT – Fixed populations sites – Reactive transmission clusters – Nested case control for rare outcomes, e.g. ZCS, GB • Cluster RCT – Possible two-stage designs • Case control studies – Test negative designs • Observational studies – Historical controls

Individual randomization within sites

Multiple sites Site: 1 2 ……………….. n

Sites Enrolled participants within sites

푰 VE = 1 - 풗풂풄풄 , combined across the n sites 푰 풖풏풗풂풄풄 Outcomes we considered

• Primary outcomes – Laboratory confirmed Zika illness – Infection, conditional on appropriate serological diagnostics – May be possible to screen for infection, e.g., testing urine • Secondary outcomes – Zika congenital syndrome – Guillain-Barré syndrome – Other surrogate endpoints Considerations for site selection Phase IIb or III VE trial

• Select 30 – 50 sites in the Americas that are likely to have Zika transmission in 2017-2018 – Individual randomization within sites with blinded vaccine or placebo in 1:1 or 2:1 ratios – Predefined vs responsive vaccination – Expand sample size using conditional power arguments • If transmission occurs in other parts of the world, additional sites could be added

Group 1 Members

Ira Longini (UF), Director Ron Brookmeyer (UCLA) Natalie Dean (UF) Christl Donnelly (Imperial Col) Betz Halloran (UW, FHCRC) Momodou Jasseh (Gambia, MRC) Martha Nason (NIH) Conall Watson (LSHTM) Judith Mueller (Inst Pasteur) James Russell (NERC, Sierra Leone) Ximena Riveros (WHO) Victor De Gruttola (Harvard)

Also contributing to the Zika vaccine trial design: Ana Maria Henao-Restrepo and Pierre Gsell (WHO) Thank you

Questions?