Clinical Trial Simulation:

An Efficient Tool for Improved

An Executive Study Designs, Dose Selection,
Summary and Go/No-Go Investment Decisions

How can modeling and simulation improve the

clinical trial go/no-go decision-making
process, accelerating drug development?

Per Olsson Gisleskog Overview

Principal Consultant In July 2017, US Food and Drug Administration (FDA) Commissioner Scott Gottlieb, MD,
SGS Exprimo
announced the agency’s Innovation Initiative to support “in silico tools in clinical trials for
improving drug development and making regulation more efficient.”1
In silico clinical trials involve the use of computer models and simulations to develop and
evaluate devices and drugs. Modeling and simulation involve taking critical information about
the human body, the disease, the drug, how they interact, and how such interactions change
over time, and using mathematical equations and statistics to create a model, which is a
description of these relationships. We can then use the model to create an imitation of reality
Alberto Russu by simulation. In clinical trial simulation, we apply a study protocol to the model, thus recruiting
Senior Scientist Pharmacometrics, “virtual” subjects, dosing them and making observations based on the model. The informa-
Global Clinical Pharmacology
Janssen Research and tion we gather can help shape study design, accelerate the drug development process and
Development increase regulatory efficiency.

Why Model and Simulate?

Using models, we can integrate information over time, across dose levels, among subjects,
across different studies and from other drugs, even combining data from in-vitro, animal and
man. Simulations based on these models can help us optimize future studies and predict
outcomes of scenarios we have not yet studied. We can quantify variability and uncertainty
as well as identify the gaps in the knowledge used to build the model.
In addition to using such models to guide and justify dose selection and study designs,
pharmaceutical companies have saved or reduced their R&D costs by as much as $500
million using modeling and simulation techniques that increased clinical study success rates
and improved drug-development–related decision-making.2 At the FDA, the Agency’s use of
models and simulations allows it to review and assess sponsors’ clinical study designs that
support effectiveness, optimize dosing, and predict safety and adverse events.

On a nuts-and-bolts level, models can help answer questions like:

• What is the minimum efficacious and safe dose?
• How do dose regimens compare?
• What are the differences between the study and comparator drugs?
• How big a patient population is needed to achieve adequate power?

SPONSORED BY
 CLINICAL TRIAL SIMULATION

Performing clinical trial simulations

Figure 1: Model for clinical trial simulations.

Design 0p*miVa*on
Scenario Protocol A Protocol B
Model Replicat
Protocol Replicate Replicat
Protocol Replicate e #1
Replicat
A #1 result e #1
Protocol Study Protocol Replicate
#2 result result
e #1
B Replicate Replicate
result
B #3 result
#4 result result
#4 result
Treatments Doses 0(serHa*ons

Inclusion Dose Study

Criteria Adapta*on Dura*on
Analysis Analysis
A B

Scenario Comparison and Summary

Scenario
Scenario Analysis A Analysis B
Analysis A Analysis B
Protocol A
Protocol A 80%
Yes 8.6 (7.8-9.2)
8.6 (7.8-9.2)
8.2 mg/L
Protocol B 71% 9.0 (8.3-9.6)

• What is the minimum Figure 2: Proposed inputs for a clinical trial simulation model.
duration of treatment?
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• What is the effect of •  Key motivation: High proportion of clinical trials fails in late
treatment with more stage ⇒ Large expenditure of money and time
than one drug?
• Are there differences •  Idea: Simulate study outcome upfront ⇒ Evaluate P(“success”)
in response between Prior knowledge
different patient’s
subgroups? Patient Disease Placebo
PK PK/PD population progression response

In ad d i ti o n to d e s i g n i n g
the studie s and answering Trial model (clinical endpoint, trt duration, active ctrl, sample size, …)
and quantifying study design-
related questions, dif ferent
study designs can be com-
Probability of “success”
pared to assess how well they
answer the questions posed
and deliver the biggest bang
for the buck. In other words, given that a high proportion and comprehensive software packages that allow the use
of late-stage clinical studies fail, models can be used to of existing clinical study data and other prior knowledge to
simulate clinical study outcomes and to quantify the prob- build models and simulations that facilitate the exploration
ability of success and facilitate the “go/no-go” decision- of a wide variety of scenarios inherent to the design clinical
making process. of studies. Simulo, developed by SGS Exprimo in partner-
There is no one-size-fits-all model or simulation; the ship with Roche, is one of these clinical trial simulator
model is shaped by the questions that need answering, softwares with a user-friendly interface, to provide a clear
the available data, and mathematical and statistical descrip- but solid simulation framework. Simulo offers a platform
tions of physiological and pharmacological processes as on which mathematical/statistical drug-disease models
well as company preferences (see Figure 1 and Figure 2 ). easily can be implemented and efficiently run, based on
Nonetheless, there are qualified and validated generalized pre-programmed modules.
 CLINICAL TRIAL SIMULATION

Reducing the Risk that Studies Will Fail excluding patients with mild disease (changing the baseline),
The business case for modeling and simulation in drug devel- the power of the study was further improved. Another study
opment has been described in published studies. In addition simulated the effect of treatment with an Alzheimer’s drug
to optimizing study designs (i.e., study size and dose selection), compared to treatment with a placebo. Although the data
these models can be used to quantify the study’s probability showed that the drug did slow the progression of the disease
of success and facilitate go/no-go decisions. and that the patients receiving placebo got no benefit, mod-
Modeling can be used to quantify the probability that the eling allowed the simulation of a “delayed start” study design
drug product can deliver the needed effect or give a higher in which all study participants received the active drug after
effect than what is on the market, with acceptable side effects, one year of treatment. The results showed that although 250
in addition to quantifying how much more effect a drug has patients gave an 80% chance of having an effect, more than
over its main competitor at the highest financially viable dose. 600 patients would be needed in the delayed-start design to
For example, the probability of
success can be described as the
Figure 3: Estimating the probability of success using different margin values and
probability to demonstrate non-
number of patients for a hypothetical non-inferiority trial (endpoint: hazard ratio).
inferiority of one regimen over
another where the two treat- P(success) vs NI margin by sample size at randomization
•  For M=1.6: N=840 ⇒ Psucc=60%,
ment regimens are expected to however N=1000 ⇒ Psucc=75%
be similar. In this paradigm, the
90% confidence interval for a •  For Psucc=80%: if M=2.7 ⇒
N=390, but if M=2.15 ⇒ N=600
given test statistic (e.g., hazard
ratio of two treatment regimens) •  For N=840: M=2.2 ⇒ Psucc=90%,
were generated and compared but for more conservative M=1.6
⇒ Psucc=60%
to a predefined “margin” value.
Generally, non-inferiority is •  For Psucc=90%: if N=1000 ⇒
demonstrated if the test statistic M=1.9, but if N=600 ⇒ M=2.55
generated by the simulation is
less than the margin value and
the probability of success is the
percentage of the simulated Different study durations were evaluated by simulation
trials that show non-inferiority.
Using these results, the prob-
Increasing the duration to 12 weeks increased the power to >80%
Figure 4: Different study durations evaluated by simulation.
ability of success of different
combinations of margins and
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numbers of patients (i.e., sample
size) can be simulated (Figure 3).
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Improving, Optimizing, 20
and Justifying Clinical ●

Trial Study Designs

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also enable the exploration and

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iterative fine-tuning of clinical

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study designs. The “power” of

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a study is often a key consid-
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eration in study designs. For

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example, simulation showed that

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increasing study duration from

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six weeks to 12 weeks increased

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the power of the study from less

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than 70% to more than 80% (see 0

Figure 4).
0 4 8 12
U s i n g t h i s s a m e m o d e l, time
simulation also showed that by
 CLINICAL TRIAL SIMULATION

show the same 80% chance of having an effect.
Guiding dose selection
Mechanistic translation of PK and PD from animal to man
Mechanistic models translating PK and PD data from
animal to man and further refined using PK and PD data
from man enabled the simulation of drug exposure for a
Phase 1 first-in-man study. The simulation showed that the
pharmacokinetics were non-linear and that increasing doses

allows
Figure fortranslation
5: Mechanistic Phase 1 PDdose
of PK and selection
from animal to man. and design

Dose
Sampling frequency
Dura*on of s,u@y

1.0 mg/kg

0.5 mg/kg

0.25 mg/kg

0.05 mg/kg

0.01 mg/kg

Example of pediatric dosing to match adult exposure

Target-mediated drug disposition Uncertainty in scaling can be captured in
A large numberprofile
concentration-time of dose adjustment regimes wereinitial
simulations explored,
model until one
was found that matches exposure in children to exposure in adults
Figure 6: Comparison of exposures in children with and without dose adjustment. 28

6*/;,%7(&#(C#no dose adjustment 6*/;,%7(&#(C#proposed dose adjustment

Urug concentr'*on

Urug concentr'*on

Exposure in children

body weight Adult exposure body weight

31
 CLINICAL TRIAL SIMULATION

of drug could extend exposure to over 60 days. In addition comparing similar drugs against one another, the effect of
to answering questions about the starting dose, this simula- single and combination treatments, study size, or number
tion answered questions related to study duration (i.e., what of patients needed to achieve a defined power, as well as
should the frequency of measuring serum concentrations providing answers to many other clinical trial design-related
be and how long patients should be followed or monitored) questions. These simulations also help quantify the probability
(see Figure 5). of success that a particular clinical trial study design will pro-
For clinical studies evaluating comparator drugs, the likeli- vide the needed information. Looking to the future, the conflu-
hood of different doses of the study drug being better than ence of the mandated FDA investment in new ex silico drug
the comparator drug in achieving a desired effect or having development tools, the EU’s Innovative Medicines Initiative,
an impact on efficacy can be simulated. Studies like these and the use of modeling and simulation tools by sponsors will
can guide dosing for Phase 3 studies as well as choosing be increasingly used to support regulatory approval for the
comparator drugs. investigational use of and licensure of new drugs.
PK/PD models can be also used to support dose selection
and study design of pediatric clinical trials. For example, a References
model based on exposures in adults could be used to explore 1. S. Gottlieb, “How FDA Plans to Help Consumers
Capitalize on Advances in Science,” July 7, 2017,
a large number of dose adjustment regimens to simulate expo-
https://blogs.fda.gov/fdavoice/index.php/2017/07/
sures in children as a function of body weight or body surface how-fda-plans-to-help-consumers-capitalize-on-
area and find a regimen that matched the adult exposure (see advances-in-science, accessed Sept. 29, 2017.
Figure 6). 2. S.R.B. Allerheiligen, Clin. Pharm. Ther. Vol. 96, 413–415 (2014).

Summary To contact the authors: clinicalresearch@sgs.com

Robust modeling and simulation techniques have proven www.sgs.com\cro or www.exprimo.com
their worth for exploring adult and pediatric dosing regimens,

This executive summary is based on material presented in a

webcast that can be viewed on demand here.

SGS is a Life Sciences CRO offering clinical research and bio/analytical testing across Europe and Americas with a focus
on early phase trials and biometrics. SGS provides Phase I to IV trial services including medical writing, data manage-
ment, biostatistics, PK/PD Modeling & simulation, pharmacovigilance and regulatory consultancy. A side of the SGS
leading European biometric group of 250 people, SGS Exprimo focuses on the application of population PK, advanced
PK/PD and drug-disease modelling & simulation to help decision making in drug development.