In July 2016, the FDA published its development targets for 2018-2022. Among its goals, model-informed drug development and complex innovative design is seen as a key challenge for improving the drug development process. Using statistical and/or pharmacokinetic/pharmacodynamic (PK/PD) approaches, prior understanding of concentration (dose)-efficacy and of concentration (dose)-safety relationship can be integrated to ensure the right dose is being studied, for the right indication and in the right patient population. This session will feature a case study of model-informed drug development in Early Phase. The key advantages and challenges will be reviewed, empowering you to detect where model-informed drug development can provide a real benefit to clinical trials, helping you to reduce development time, cost and late stage failures. 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. HOW MODELING & SIMULATION CAN OPTIMIZE A
CLINICAL TRIAL
Ruben Faelens, SGS Exprimo, Scientist - Modeling & Simulation

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MODELING & SIMULATION
PDUFDA goals for 2018 - 2022:
3. To facilitate the development and application of
exposure-based, biological, and statistical models
derived from preclinical and clinical data sources
4. To facilitate the advancement and use of complex
adaptive, Bayesian, and other novel clinical trial designs
Source: PDUFA REAUTHORIZATION PERFORMANCE GOALS AND
PROCEDURES FISCAL YEARS 2018 THROUGH 2022

3. 3© SGS SA 2014 ALL RIGHTS RESERVED
POPULATION PK/PD M&S
THROUGHOUT DRUG DEVELOPMENT
Objectives of M&S should focus on the next phase(s)
of development to support decisions that need to be made
Pre-clinicalDiscovery Phase I Phase IIbPhase IIa Phase III
ConfirmExploreExplore ConfirmConfirmExplore
Candidate
Selection Drug Evaluation Global Development
(Semi-)mechanistic PK-PD
Descriptive Drug & Disease

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1. Translate the animal data to human
2. Define the first dose to be administered in human
 Non-effective dose
3. Define the dose escalation strategy
 Range of doses to be studied and interval between the dose
levels
4. Define the stopping rules
 When PK is sufficiently understood
 When dose covers a multiple of the expected efficacious
dose (single or multiple)
HOW PK-PD MODELING CAN
HELP IN FIRST-IN-MAN STUDY?

5. 5© SGS SA 2014 ALL RIGHTS RESERVED
A REAL EXAMPLE
STEP 1: ANIMAL DATA
 First data received from a multiple
dose study in animals indicated
linear kinetics
 However, data from single dose
studies with lower doses exhibited
non-linear kinetics probably due to
target mediated drug disposition

8. Production rate
Elimination rate
mAb
Elimination rate
Target

9. Production rate
Elimination rate
mAb
Elimination rate
Target
TMDD
Elimination rate

10. 10© SGS SA 2014 ALL RIGHTS RESERVED
TARGET MEDIATED DRUG
DISPOSITION (TMDD)
Target
Production rate
Elimination rate
mAb
Elimination rate
TMDD
Log(FreemAb)
Time
Log(Freetraget)
Time
Elimination rate
mAb - target
Time
Log(mAB-target)
Target
+
mAb-target

11. Production rate
Elimination rate
mAb
Elimination rate
Target
TMDD
Elimination rate

13. 13© SGS SA 2014 ALL RIGHTS RESERVED
ANIMAL DATA WERE MODELLED
AND EXTRAPOLATED TO HUMAN
 Animal data were analysed
using the appropriate TMDD
model
 Results were scaled to
human and simulations were
performed taking into
account the uncertainty
about the magnitude of
TMDD
Linear PK
Saturable PK

14. 14© SGS SA 2014 ALL RIGHTS RESERVED
A REAL EXAMPLE
STEP 2: SECOND DOSE IN HUMAN
 The observations are
compared with the prediction
range
 The observations help to
reduce the uncertainty on the
possible mechanisms
 TMDD appears to be present.
However, some uncertainty
remains and data can still be
described by two possible
competitive mechanisms
 Original model is fine-tuned
testing these two mechanistic
hypotheses

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NEXT DOSE TO BE GIVEN?
VMAX hypothesis
KM hypothesis
 Scenarios are simulated with
different possible doses under
different possible hypotheses
 These simulations help the
team to determine which dose
has to be given next

16. 16© SGS SA 2014 ALL RIGHTS RESERVED
A REAL EXAMPLE
STEP 2: THIRD DOSE IN HUMAN
 Again, the
observations are
compared to the
predictions based on
the two possible
hypothesis
 Data of the second
and third cohorts are
modelled together
using TMDD
assuming quasi
steady state. Run is
successful and fits
acceptable
mAbconcentration
Time (day)

17. 17© SGS SA 2014 ALL RIGHTS RESERVED
NEXT DOSE TO BE GIVEN?
 Simulations are performed
with the TMDD QSS model to
predict the concentration-time
profiles for different doses
 These simulations again help
the team to determine which
dose has to be given next

18. 18© SGS SA 2014 ALL RIGHTS RESERVED
 Before the first
administration, PK-PD
predictions are made
and a first dose with
marginal PD effect is
selected
 During the FIM, PD is
also modelled and
simulations are
performed to predict
effect-time profiles
 The combination of both
PK and PD increased
the confidence of the
team in choosing the
next doses
WHAT ABOUT PD ?
Target(%inhibition)

19. 19© SGS SA 2014 ALL RIGHTS RESERVED
A REAL EXAMPLE
STEP 3: STOPPING RULES
 In absence of tolerability and safety
issue, PK-PD can be help
determining the highest dose to be
tested
 PK and PD Monte Carlo
simulations are performed based
on the last fine-tuned model
 After single dose
 After multiple doses
 These simulations together with the
target product profile are use to
define the stopping rule and to
make sure that the drug has a
chance to reach expectations

20. 20© SGS SA 2014 ALL RIGHTS RESERVED
1. Translate the animal data to human
2. Define the first dose to be administered in human
 Non-effective dose
3. Define the dose escalation strategy
 Range of doses to be studied and interval between the dose
levels
4. Define the stopping rules
 When PK is sufficiently understood
 When dose covers a multiple of the expected efficacious
dose (single or multiple)
HOW PK-PD MODELING CAN
HELP IN FIRST-IN-MAN STUDY?

21. 21© SGS SA 2014 ALL RIGHTS RESERVED
 An integrated PK/PD modelling and simulation approach is key
to make informed decisions in first-in-man study.
 To ensure the value of PK/PD modelling in FIM study, it needs
to be organised operationally.
 SGS has the experience and the flexibility in providing such a
service, as both CRO and PK/PD modelling group.
 SGS Exprimo has extensive experience in using modelling and
simulation to aid our clients answer the questions they face in
their drug development process and regulatory interactions.
 The analyses we do are highly suitable for submission to regulatory
authorities.
 We have consistently received excellent feedback from regulatory
authorities about the quality and comprehensibility of our reports.
OVERALL CONCLUSIONS

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SGS BIOPHARMA DAY – OCTOBER 25, 2016
Life Science Services Ruben Faelens
Scientist - Modeling & Simulation
SGS Exprimo NV Phone:: + 32 (0) 494 06 72 59
Generaal De Wittelaan 19A Bus 5
B-2800 Mechelen, E-mail : ruben.faelens@sgs.com
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

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SGS BIOPHARMA DAY – OCTOBER 25, 2016
QUESTIONS ?

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SGS BIOPHARMA DAY – OCTOBER 25, 2016