Some challenge viruses show evidence of excessive attenuation. Data from challenge trials using such agents may provide poor proof of efficacy where peak viral loads and mild symptomologies evidence little deviation from baseline. Choosing the optimal challenge agent is integral to demonstrating the efficacy of new antivirals and vaccines where correlates of protection are lacking or of poor prognostic value. Newly drifted strains with strong, measurable signs of upper respiratory tract disease make good challenge agents but care should be taken during manufacture if passage-associated attenuation is to be avoided or minimized. This presentation will discuss some of the issues associated with objectives and outcomes and how a newly drifted strain can help achieve such aims. For more information visit: https://www.sgs.com/exprimo and contact us at: clinicalresearch@sgs.com Follow us on LinkedIn: https://www.linkedin.com/company/sgs

1. SKIPPING PHASE IIb TRIALS – PROOFS OF
EFFICACY AND EFFECTIVENESS FROM
HUMAN CHALLENGE TRIALS.
Adrian Wildfire
Project Director – Infectious Diseases and Human Challenge Unit

2. 2
SGS BIOPHARMA DAY – OCTOBER 25, 2016
INTRODUCTION
Proposal:
 Phase IIb trials traditionally provide efficacy and safety data
 Measurements of Efficacy derive from Correlates, e.g.
Correlates of Protection (CoP) or other objective markers
 Correlates relating to efficacy may not always be available or
appropriate; measurements of effectiveness may bridge the gap
 Measurements of Effectiveness derive from Observed events
e.g. Challenge Trials
Conclusion:
“Large Human Challenge Trials may establish ‘real world’
effectiveness as well as efficacy and facilitate progress to PhIII”

3. 3
SGS BIOPHARMA DAY – OCTOBER 25, 2016
DEFINITIONS
Source: DHHS - Agency for Healthcare Research and Quality (US)
Efficacy:
“Efficacy trials determine whether an intervention produces the
expected result under ideal circumstances.”
(e.g. neutralising antibody, viral load in healthy volunteers)
Effectiveness:
“Effectiveness trials measure the degree of beneficial effect under
“real world” clinical settings.”
(e.g. attack rates, symptom scores, time to recovery in the general
population)
Source: https://www.ncbi.nlm.nih.gov/books/NBK44029/

4. 4
SGS BIOPHARMA DAY – OCTOBER 25, 2016
MARKERS VS MEASUREMENTS

5. 5
SGS BIOPHARMA DAY – OCTOBER 25, 2016
CORRELATES VS HCT
– EFFICACY MEETS EFFECTIVENESS
(-) Responses to an intervention may
not be measurable or consistent
(markers for: yes / no or sliding
scale)
(-) Markers may not be directly or
even indirectly related to clinical
response (surrogates and correlates
vs endpoint)
(+) Highly predictive markers and
correlates accelerate pre-clinical work
(PoC)
(+) Licensure is granted on the basis of
safety and real world effectiveness
(+) Licensing agencies are moving towards
effectiveness over efficacy (e.g. Vaxchora)
no go
go

6. 6
SGS BIOPHARMA DAY – OCTOBER 25, 2016
GUIDANCE FROM THE
REGULATORY AUTHORITIES

7. 7
SGS BIOPHARMA DAY – OCTOBER 25, 2016
REGULATORY ADVICE – EMA / FDA
TODAY
 The FDA considers large (300+) HCTs to potentially provide
sufficient proof of concept data to proceed to a safety-only PhIII
study
 Vaccines have already been licensed on PhIIb HCT proof of
concept data plus a PhIII safety study
 Where proof of concept (efficacy) data is weak, HCTs are
accepted as defining real-world effectiveness
 The EMA has advised that HCTs can be used as a dose-
confirmation model and PoE combined
TOMORROW
 The WHO has a consultation paper out for comment regarding
‘Human Challenge Trials: Scientific and regulatory considerations’
 The Institut Pasteur and FAGG have asked for more information
and training on HCTs

8. 8
SGS BIOPHARMA DAY – OCTOBER 25, 2016
POOR EFFECTIVENESS AND
THE PRICE OF FAILURE

9. 9
SGS BIOPHARMA DAY – OCTOBER 25, 2016
FAILURE ($M) – PER PHASE
US DHHS: https://aspe.hhs.gov/report/examination-clinical-trial-costs-and-barriers-drug-development
Pre-clinical Phase I Phase II Phase III
PhIIb
PoC
failure

10. 10
SGS BIOPHARMA DAY – OCTOBER 25, 2016
NOVAVAX – A CASE STUDY IN PHIII FAILURE
$ per share: 5-day trading chart – Novavax shares fell 80%

11. 11
SGS BIOPHARMA DAY – OCTOBER 25, 2016
ELEMENTS OF SUCCESS
GOOD DATA

12. 12
SGS BIOPHARMA DAY – OCTOBER 25, 2016
WHAT WE DO – GOOD DATA

13. 14
SGS BIOPHARMA DAY – OCTOBER 25, 2016
DATA, PHIIb AND
PROOF OF CONCEPT

14. 15
SGS BIOPHARMA DAY – OCTOBER 25, 2016
CHALLENGE TRIALS VS TRADITIONAL PHII
Phase II Trial
 Large, cohorts (250-300)
 Uncontrolled environment
 Low attack rate (prevalence)
 Unknown inoculation date
 Long duration (>1yr)
 High cost (€5.5-6.5M)
 Restricted window for enrolment
 Extensive data analysis required for
decisions
 Efficacy plus safety
Challenge Study (IIb)
 Small cohorts (40-60)
 Defined environmental and
clinical conditions
 High attack rate
 Known inoculation date
 Short duration (28d)
 Low cost (€2-3M)
 Early go / no go decisions
 Predictive of field trial design /
performance
 Efficacy and effectiveness

15. 16
SGS BIOPHARMA DAY – OCTOBER 25, 2016
THE HUMAN CHALLENGE TRIAL MODEL
(it’s only as good as the agent)

16. 17
SGS BIOPHARMA DAY – OCTOBER 25, 2016
A/BELGIUM/4217/2015 H3N2
(A/SWITZERLAND/2013 PANDEMIC LINEAGE)
PNA150487NA
GHE_150482_NA
YRO_150479_NA
KTI_13799_NA
AME_15049NA
CCA5734NA
AEL150491_NA
SVE10369NA
A/Switzerland/9715293/2013
A/Switzerland/9715293/2013
MK
SME_150477_NA
SBO6110NA
A/Texas/50/2012 | HA | 440627
A/Victoria/361/2011 | HA | 408194
A/Perth/16/2009 | HA | 307676
A/Minnesota/11/2010 | HA | 465400
89
100
100
99
68 65
83
87
100
65
45
0.01
A/Belgium/4217/2015

17. 18
SGS BIOPHARMA DAY – OCTOBER 25, 2016
SGS – REDUCING THE RISK OF FAILURE
OPTIMISING THE CHANCES OF SUCCESS

18. 19
SGS BIOPHARMA DAY – OCTOBER 25, 2016
SUMMARY
1. Human Challenge trials can be used:
 to examine effects in target populations or populations of
interest (e.g. elderly, non-responders) at a reduced cost /
sample size
 to investigate
• novel or pre-existing biomarkers
• efficacy and effectiveness vs specific strains and serotypes
• in conjunction with systems biology, conserved epitopes
 to make decisions – go / no go prior to PhIII
2. Phase IIb HCTs can replace or augment measurements of
efficacy with vaccine or drug effectiveness, reducing the
chance of failure at PhIII
3. Phase IIb HCTs can provide sufficient proof of concept
data to move directly to PhIII safety studies

19. 20
SGS BIOPHARMA DAY – OCTOBER 25, 2016
TAKE HOME MESSAGES
 The quality of data defines success or failure
 Big Data isn’t always Good Data
 Failure is expensive
 The Human Challenge Model gives Real World
evidence sufficient to move PhIIb directly to PhIII
 SGS has a Human Challenge Unit and a new
challenge agent

20. 21
SGS BIOPHARMA DAY – OCTOBER 25, 2016
Life Sciences Adrian Wildfire
Project Director
Infectious Diseases and HCU
SGS Mobile: +44 (0)7894 392625
BELGIUM NV Work: +44 (0)1483 828894
Generaal De Witterlaan, 19a, Bus 5 E-mail : adrian.wildfire@sgs.com
B-2800 Mechelen
BELGIUM Web : www.sgs.com/lifescience
THANK YOU FOR YOUR ATTENTION
+ 41 22 739 9548
+ 1 866 SGS 5003
+ 65 637 90 111
+ 33 1 53 78 18 79
+ 1 877 677 2667
+ 33 1 41 24 87 87

21. 22
SGS BIOPHARMA DAY – OCTOBER 25, 2016
QUESTIONS ?

22. 23
SGS BIOPHARMA DAY – OCTOBER 25, 2016