proof of efficacy & effectiveness from human challenge trials

SKIPPING PHASE IIb TRIALS – PROOFS OF

EFFICACY AND EFFECTIVENESS FROM

HUMAN CHALLENGE TRIALS.

Adrian Wildfire

Project Director – Infectious Diseases and Human Challenge Unit

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”


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/

https://www.ncbi.nlm.nih.gov/books/NBK44029/


MARKERS VS MEASUREMENTS


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


GUIDANCE FROM THE

REGULATORY AUTHORITIES


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


POOR EFFECTIVENESS AND

THE PRICE OF FAILURE


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

https://aspe.hhs.gov/report/examination-clinical-trial-costs-and-barriers-drug-development
















NOVAVAX – A CASE STUDY IN PHIII FAILURE

$ per share: 5-day trading chart – Novavax shares fell 80%


ELEMENTS OF SUCCESS

GOOD DATA


WHAT WE DO – GOOD DATA


DATA, PHIIb AND

PROOF OF CONCEPT


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


THE HUMAN CHALLENGE TRIAL MODEL (it’s only as good as the agent)


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


SGS – REDUCING THE RISK OF FAILURE

OPTIMISING THE CHANCES OF SUCCESS


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


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


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 : [email protected]

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

https://www.linkedin.com/company/sgs-life-sciences


QUESTIONS ?

proof of efficacy & effectiveness from human challenge trials

Health & Medicine