1. Bridging to Bridges in Vaccine Development: Challenges in Comparing Multi-Serotype Vaccines – Jonathan Hartzel, Merck

2. Novel Multi-Serotype Vaccines in the Past 20 Years
Pneumococcal Conjugate Vaccine (PCV)
Prevnar® licensed in the US in 2000 to protect against 7 strains of pneumococcus bacteria
Prevnar 13® licensed in the US in 2010 to protect against 13 strains of pneumococcus bacteria (7 in Prevnar® plus 6 new strains)

3. Novel Multi-Serotype Vaccines in the Past 20 Years
Human Papillomavirus (HPV) Vaccine
GARDASIL® licensed in the US in 2006 to protect against 4 types of HPV
GARDASIL 9® licensed in the US in 2014 to protect against 9 types of HPV (4 in GARDASIL® plus 5 new types)

4. Future Next-Generation Vaccines
There are over 90 strains of pneumococcus bacteria and over 100 types of HPV.
As the existing vaccines control the targeted types, new types could become more prevalent.
Future PCV-XX and HPV-YY vaccines may be developed requiring “bridging” to formulations that are themselves “bridges” to the vaccines on which efficacy was established

5. Developing Next-Generation Vaccines
It’s hard for everyone (Sponsors, Regulators).
The challenges were recognized early on in the PCV space:
NIAID/FDA Joint Workshop: Correlates of immunity for pneumococcal conjugate vaccines (Vaccines, 2003)
WHO/Health Canada Consultation: Challenges in the evaluation and licensing of new pneumococcal vaccines, 7-8 July 2008, Ottawa, Canada (Vaccines, 2009)
These challenges become greater with the introduction of next-generation vaccines.

6. What endpoint should be used?
The basis for licensure for a novel vaccine is typically an efficacy study.
Both Prevnar® and GARDASIL® were found to be highly efficacious.
Efficacy often based on some composite endpoint (primary).
For next-generation vaccines:
Is an efficacy study possible?
Novel vaccine may already be in broad circulation (disease is well-controlled)
Unethical to conduct a placebo-controlled (or dummy-vaccine-controlled)
Possibly compare to novel vaccine for new types only (GARDASIL 9®)

7. What endpoint should be used?
For next-generation vaccines:
Is there a correlate of protection?
With highly efficacious vaccines (resulting in very few cases of disease in vaccine recipients), it can be very difficult to determine a correlate of protection.
For Prevnar®, a threshold of ≥0.35 µg/mL was recommended for the original 7 serotypes and for new serotypes, along with geometric mean concentrations (GMCs).
For GARDASIL®, GMCs were the primary endpoint for comparisons.
Likely need to measure endpoints using different assays as well.

8. What statistical approach should be used?
For types in common between both vaccines:
Non-inferiority (NI) of response rates and/or GMCs for each type (possibly at multiple time points).
For comparisons to Prevnar 13®, there are 13 NI comparisons for % ≥0.35 µg/mL following the primary series, and 13 NI comparisons for GMCs following the primary series and following the toddler dose (39 NI comparisons in total).
Future PCV-XX will potentially have 3*XX NI comparisons.

9. What statistical approach should be used?
For new types :
It may be possible to evaluate efficacy (GARDASIL 9®).
Non-inferiority (NI) of response rates and/or GMCs for each type (possibly at multiple time points):
To an “aggregate” response of the common types
To the lowest response of the common types
Superiority of response rates and/or GMCs for each type (possibly at multiple time points) or Super-superiority.

10. What is the criterion for study success?
In general, meeting NI for all endpoints is the goal.
For PCV it is recognized that, due to chance alone, one may fail a NI comparison.
NIAID/FDA Joint Workshop: As the number of independent evaluations increase, equivalent seroconversion to all serotypes may not be achieved.
WHO/Health Canada Consultation: Comparisons of immunogenicity would usually be designed to demonstrate non-inferiority but…it may not be necessary to reach pre-defined non-inferiority criteria for all 7 serotypes that can be directly compared.

11. What is the criterion for study success?
Indeed, Prevnar 13® failed NI for certain serotypes: From FDA Clinical Review of Biologics License Application for Prevnar 13®)

12. Challenges for Next-Generation Vaccines
It is unlikely that future vaccines will be able to perfectly “match” the performance of current vaccines.
It is clear that Regulators acknowledge this, and can take this into consideration during review.
However, it would be beneficial at the design stage of a Phase 3 program to plan for such allowances.

13. NI Sample Size Scenarios
Assumptions:
The control vaccine has 13 types, each with an assumed response rate of 90%.
The NI margin is 10%.
One-sided alpha of
Type W is associated with mild disease and low prevalence.
What is the required evaluable per-group sample size for 90% power?
#1: Test vaccine has 90% for the 13 common types: 365
#2: Test vaccine has 90% for 12 and 88% for Type W: 400
#3: Test vaccine has 90% for 12 and 86% for Type W: 650

14. Challenges for Next-Generation Vaccines
NIAID/FDA Joint Workshop: Prioritizing non-inferiority comparisons for candidate PCVs may be needed, but will be difficult in the context of changing disease prevalence.
With one proposal being: …to assign a weighted average based on serotypes associated with antibiotic resistance, common serotypes with PCV7, or new serotypes as a basis to demonstrate non-inferiority.
Require X out of Y serotypes to meet NI?
Varying NI margins for certain serotypes?

15. Challenges for Next-Generation Vaccines
Concern for “drift” in future vaccines even if NI is met: VaccineGEN1 NI to VaccineORIG VaccineGEN2 NI to VaccineGEN1 VaccineGEN2 NI to VaccineORIG?
Require more stringent NI margins for future vaccines?

16. Challenges for Next-Generation Vaccines
With changing epidemiology, “drift” may not be as critical for certain disease types.
Need to balance potential “drift” with the addition of new (potentially more relevant) types in the next-generation vaccines
Too high of hurdles could prevent alternative supply options.

17. Closing Remarks
Novel multi-serotype vaccines such as Prevnar® and GARDASIL® have set very high bars for future generation vaccines to meet.
There are many challenges for both Sponsors and Regulators in developing and approving next generation vaccines.
Reconsideration of alternative testing paradigms for showing NI to existing vaccines would help to speed development of the new vaccines.

18. Thank you