ADDPLAN DF: Designing More

Accurate Dose Escalation Studies

in Exploratory Drug Development
An ICON White Paper

Executive Summary
The determination of the maximum tolerated dose (MTD)
level is a critical step in oncology drug development.
High doses are needed to improve the efficacy of the
drug, but can result in an increased number and severity
of undesired drug limiting toxic (DLT) reactions. Phase
I oncology trials aim to determine the MTD using dose
escalation strategies, resulting in the recommendation
of a dose or drug combination for Phase II efficacy
testing. The selection of the dose escalation strategy
has an impact on the recommended dose level and
inadequate dose escalation schemes may put the
whole drug development program at risk.
Oncology Phase I trials differ from most general Phase
I trials in that the medication is examined in the target
population of diseased patients. Patients included into
these trials often suffer from advanced cancer, and
have often exhausted the standard treatment options.
Therefore in addition to the appropriate detection of the
MTD, dose escalation designs should enroll the majority
of patients to therapeutic levels of the drug,
while controlling the numbers of DLT events. These
competing objectives for dose escalation designs
make it unlikely that one design will be the best in
all circumstances.
Although the determination of the MTD is of such
critical importance in oncology, in the vast majority
of dose escalation trials a simple common method
has been used. The 3+3 design is a simple rule-based
escalation scheme, and has been used in approximately
95% of the published Phase I oncology trials over the
last two decades.1 During the same period, a number
of innovative rule-based and model-based dose
escalation designs have been developed and studied,
for example the Continual Reassessment Method (CRM)
or interval-based escalation schemes. These innovative
approaches allow tailored escalation towards the dose
level providing the specified maximal tolerable rate of
toxic events.

innovative dose escalation designs in the fully validated

software ADDPLAN DF for designing, simulating and
analysing dose-finding trials. The methodology
underpinning these innovative dose escalation
approaches are described in this paper and their
performance is illustrated in a simulation study.
The overall scope is to provide insight into the capability
of ADDPLAN DF to design, simulate and analyse dose
escalation trials. Future versions of ADDPLAN DF will
expand the set of available dose escalation methods,
and will include approaches targeting efficacy and
safety simultaneously, time to event data, and more.

The Critical Importance of Accurate Dose Selection

The process of defining the dose and dosing regimen
has been identified by regulatory authorities and industry
as a major factor impacting late-phase attrition.
Improved dose selection in both Phase I and Phase II
trials is generally considered to increase R&D efficiency
and effectiveness. Many groups of methodologists
in the pharmaceutical industry and in academia have
developed innovative statistical methods for designing
and analysing dose-finding trials. The acceptance of
innovative dose-finding methodologies was supported
this year by the European Medicines Agency (EMA)
qualification opinion on the Multiple Comparison
Procedure and Modeling (MCP-Mod) approach
developed by Novartis for dose-finding under
model-uncertainty.3
The list of innovative design and analysis methods
applied in drug development is increasing. Considerable
effort is being spent on the development and
implementation of innovative approaches for early
phase drug development. Particular examples for
these novel methodologies are toxicity interval-based
dose escalation such as the Novartis version of the
CRM4 and the modified toxicity probability interval
(mTPI) approach, which has been utilized by Merck
in a number of Phase I oncology trials.5

In addition to the novel MCP-Mod methodology,2

ICON has implemented a selection of these

The inclusion of novel statistical approaches into the

standard toolbox of design and analysis techniques will
lead to improved decision making in drug development.
The consequences of improved dose selection in early
phase drug development can amount to billions of
dollars of additional value across a product portfolio.

Traditional Approach to Dose Escalation

The MTD is defined as the maximum dose for which
less than a given proportion of the population suffer a
DLT. In oncology studies the proportion is often taken
to be between 20% and 35%. Dose escalation designs
approach this MTD via an adaptive allocation procedure,
which either increases or decreases the dose-level
for the next cohort of patients based on observed
outcomes. As a limited measure of overdose control,
many dose escalation algorithms adjust the dose levels
to approach the MTD from below.

3+3 Design
Approximately 95% of all published Phase I oncology
dose escalation trials have used a 3+3 design.
The 3+3 design (Figure 1) can be described as follows.

Cohorts of 3 patients are entered at given dose level i. If

no patients have a DLT, then the dose will be escalated
to the next dose level, i+1. If 2 or more patients have a
DLT then the previous dose level, i-1, will be considered
as MTD. If 1 patient has a DLT an additional 3 patients
will be treated at this dose level, i. If no further patients
suffer a DLT then the dose level will be escalated to i+1
and if any further patients have a DLT then the previous
dose level, i-1, will be considered the MTD. In other
words, the MTD level will be the maximum dose level
with an observed toxicity rate of 0% or 17%. Depending
upon the maximum tolerable toxicity rate for the trial
and the numbers of dose levels in the trial, the resulting
estimate of the MTD may be much too conservative: the
algorithm will reject doses with 20% DLT-rate in at least
29% of the cases. The probability of underestimating
the MTD increases with increasing numbers of dose
levels below the true but unknown MTD, while additional
patients will be treated at sub-therapeutic dose-levels.
The 3+3 design is used for its simplicity and the very
limited number of patients which are needed to get a
decision on the MTD.

Innovative Approaches to Dose Escalation

The obvious limitations of the 3+3 design have led to
numerous improved dose escalation approaches.

Continual Reassessment Method (CRM) 6

An alternative class of dose escalation algorithms is
given by the model-based approach known as the
continual reassessment method (CRM). The basic
procedure is described in the flow chart (Figure 2).

is both the strength and weakness of CRM designs.

Model-based analysis allows the utilisation of all
available data for predicting the probability of toxic
events at any dose level. Bayesian modelling allows the
inclusion of uncertainty in the model-parameters into
the analysis. However, the administration of a dose
level to patients based on a set of modelling
assumptions may result in doses that are too toxic,
if the wrong dose-toxicity curve was selected or if
inappropriate parameters were specied. Overdose
control options may be adjusted to prevent the CRM
from administering these doses.

Bayesian Logistic Regression with Overdose

Control (BLOC) 4
Overestimating the dose-toxicity curve may lead to
suboptimal allocation of patients to sub-therapeutic
doses, whereas underestimating the curve may
recommend toxic doses. An alternative approach for
the estimation of an appropriate dose was proposed
by Neuenschwander (2008). The basic idea is very
similar to the CRM approach. The toxicity data
are analysed using Bayesian modelling on a exible
two-parameter dose-toxicity model. However, instead of
targeting the MTD rate, the authors recommend that the
target dose is selected based on a classication of the
drug-limiting toxicity probabilities into four regions:
In the design phase of the CRM, a dose-toxicity
model, stopping rules and overdose control options
need to be dened. Given the toxicity data, a Bayesian
dose-toxicity model is tted to the data and the dose
with a posterior expected toxicity probability closest
to the maximum tolerable toxicity rate is determined.
is dose will be administered to the next cohort,
unless a stopping rule is met or the dose level is not
admissible due to overdose control options. The CRM
design stops allocation, if a stopping criterion is met
or if the maximum number of patients have been
analysed in the trial. The dose with posterior expected
toxicity rate closest to the maximum tolerable toxicity
rate will be declared the MTD. The estimation is
based on the assumed dose-response model and
the toxicity data of all dose-levels.

Under-dosing:
Target toxicity:
Excessive toxicity
Unacceptable toxicity

(0,0.2]
(0.2,0.35]
(0.35,0.6]
(0.6,1.00]

The posterior probabilities that the toxicity is located

within each of the four toxicity regions can be calculated
for each dose level based on Bayesian modelling.
A dose may then be recommended based on the
observed posterior distribution and some specied
considerations on the risks and benets of the dose
categories. This Bayesian logistic approach provides a
mechanism to control both under- and over-dosing.

The assumption of a Bayesian dose-toxicity model

5

Modified Toxicity Probability Interval

(mTPI) Approach 7

ADDPLAN DF - A Tool to Design, Simulate, and

Analyse Innovative Dose Escalation Studies

A compromise between model-based and rule-based

dose escalation methods is given by the modied
toxicity probability interval approach (mTPI). Similar to
Neuenschwanders BLOC approach, mTPI provides a
recommendation to escalate, de-escalate or stay at the
current dose level, based on the posterior probability
of toxicity regions. The equivalence interval species a
range of toxicity probabilities, close to the maximum
tolerable toxicity, which is equivalent to the target toxicity
range of Neuenschwander. One difference compared
to CRM is that there is no formal dose-toxicity model
linking responses at the various doses tested. For each
dose level, a Beta-prior on the probability of toxic events
is used to model the uncertainty on the true toxicity
probability. Given observations at this dose level, the
posterior probabilities of under-dosing, target-dosing or
over-dosing are calculated. The dose-level to be used
at the next stage is determined from the unit posterior
probability mass of the toxicity ranges. The resulting
dose escalation scheme can easily be specied for
a range of toxicity outcomes as described in Ji and
Wang.5 Additionally, Bayesian modelling allows the
inclusion of an overdose control into the mTPI based
on the posterior probability of the toxicity rate.

The characteristics of dose escalation designs can

be studied using the simulation engine of ADDPLAN
DF, which provides four different dose escalation
methods and allows the specication of additional
options.

When the trial is stopped, the MTD is estimated in

this approach using isotonic regression based on
the posterior mean toxicity probabilities at each
acceptable dose level. The resulting estimate of the
MTD is therefore based on a monotonic non-parametric
estimation of the dose-toxicity curve and may be
regarded as robust.
The fully validated dose escalation functionality
of ADDPLAN DF allows the design and analyses
of innovative Phase I oncology trials. Operating
characteristics of 3+3 designs, the classical CRM,
BLOC and the mTPI approach may be studied under
different dose-toxicity proles. is allows the selection
of an appropriate dose escalation design.

Classical 3+3 designs may be simulated to give a

reliable insight into the characteristics of the approach.
The classical CRM is implemented for two different
one-parameter probability models and a range of prior
distributions. There are different options to enable the
selection of the next stage dose which are based on
a range of estimates of the probability of toxicity. The
inuence of three dierent stopping rules, which may be
combined, can be studied using the CRM simulations.
The Bayesian logistic regression with overdose control
(BLOC) follows the approach to dose escalation
proposed by Neuenschwander. The toxicity probabilities
may be changed and an overdose control option
may be used to prevent excessive toxicity. The mTPI
approach can be simulated for dierent selections of
the Beta-prior and equivalence interval.
Active dose escalation may be analysed using the
dose escalation functionality in the analysis engine
of ADDPLAN DF. The analysis functionality provides
recommendations of the dose-level for the next cohort
of patients and the nal target dose. Additionally,
information on the posterior distribution is provided
when using any of the CRM approaches. The posterior
probability of the toxicity ranges and the posterior
probability for the doses being the MTD is displayed
after clicking the compute button. ADDPLAN DF
supports the implementation of innovative dose
escalation trials, from design to analysis in a fully
validated dose finding software suite.

Example: Identification of the MTD8

The continual reassessment method (CRM) was used
in 20098 to identify the MTD of an agent, intravenously
administered to subjects with solid tumours. The study
was separated into two parts. The first part aimed at
escalating to the MTD with about 50 subjects, whereas
the second part of the study aimed at confirming this
estimated MTD and to assess safety, tolerability and
preliminary efficacy in a group of 20 subjects. The CRM
design was used, since the targeted MTD dose range
was not well dened, implying that the application of the
standard 3+3 approach might result in an inefficient
dose escalation strategy.
The dose range considered during the planning stage
of the trial consisted of 20 doses, ranging from 10mg
to 319mg in increments of 20%. The target toxicity
range for the new compound was set at 18% to 33%
with a target toxicity of 25% being used for simulating
the operating characteristics of the CRM design. In
designing the dose escalation trial, a set of six different
dose-toxicity scenarios was considered. In the current
discussion, we focus on three scenarios, representing
target toxicity either at the low end, in the middle or at
the high end of the dose range (Figure 3).

Figure 3: Candidate shapes

Independent standard normal priors for the two

parameters of the logistic model were used in the
simulation of the BLOC. The toxicity regions were
specied with a target toxicity range of 18% to 33%.
The next stage cohort will generally be allocated to
the dose level having the highest posterior probability
of the DLT rate to be located within the target toxicity
range. A safety rule will additionally limit the number of
allocations to toxic doses. Cohorts will not be allocated
to dose levels with posterior probabilities of the DLT
rate exceeding the target toxicity range above some
safety boundary. The maximum acceptable posterior
probability of overdosing is set in the simulations at
25%. Increasing the overdose threshold would increase
the number of DLTs per patient, as the probability of
allocating cohorts to toxic doses will be increased.
The DLT probabilities using the CRM dose escalation
design were modelled using a one-parametric logistic
dose-toxicity model with normal prior on the logarithm
of the slope parameter. The probability of observing
DLTs is, in the CRM settings, assumed to follow a
straight line from 10% DLT probability at the minimum
dose to 70% DLT probability at the maximum dose.
If the posterior probability that a dose is the MTD
exceeds 70% after a run-in phase of 5 cohorts, the
corresponding dose will be claimed as the MTD.
Alternative prior distributions and stopping rules may
be studied using ADDPLAN DF.
Figure 4 displays the simulated probability of selecting
appropriate dose-levels for the MTD in the considered
scenarios. Throughout all three scenarios, the tendency
of the 3+3 designs to underestimate the target dose
is evident. In the first scenario with a target toxicity
range at the very beginning of the dose range, the
3+3 designs lead in about 70% of the simulations to
an under-estimated MTD. About 60% of the patients
are treated with doses, which may be regarded as
sub-therapeutic. Similar relations resulted for mTPI.
However, the estimates of the MTD were more reliable
in scenario 1 using mTPI. In about 50% of the cases,
the target toxicity region was reached, compared to
30% when using the 3+3 design. The mTPI provided
the minimum number of DLTs per patient throughout
all methods.

The simulations used in the model-based approach,

demonstrated the most promising results in terms of
accurately estimating the MTD. Both CRM and BLOC
allocated fewer patients to sub-therapeutic dose levels
and identified the MTD in the target toxicity range
in scenario 1 and 2 in more than 50% of the cases.
It is well known, that overdosing might be an issue
when using the CRM approach. The relative number
of DLTs per patient was in all considered scenarios
at the maximum when using the CRM approach. An
alternative implementation using escalation designs with
overdose control may minimise these shortcomings of
CRM, as displayed by the promising simulation results
for BLOC.
The total number of observations is at minimum when
using the 3+3 design and the trial will stop early when
using 3+3 designs, if there is a high probability of
observing toxicities at low doses, as given in scenario
1. For scenarios 2 and 3, the sample size among all
procedures was similar.
Using the ADDPLAN DF simulation results, the dose
escalation design options may be adjusted to obtain
a design, which fits well in all scenarios. Different
assumptions on the dose-toxicity model and prior
distributions, additional stopping rules and options
limiting the probability of overdosing may be verified
to further optimise the trial design.

Conclusion
The accurate estimation of the MTD is of critical
importance in the drug development process. This white
paper discusses innovative dose escalation designs and
their implementation in ADDPLAN DF.
The aim of the software is to support the process of
decision making in the design and analysis of dose
Finding trials using these innovative methods.
Uncertainty in the true underlying dose-toxicity profile
needs to be taken into account when designing efficient
and effective dose escalation trials.
ADDPLAN DF enables drug developers to study the
operating characteristics of standard and innovative
dose escalation methods under different scenarios,
allowing the selection of the appropriate methods for
successful Phase I dose escalation trials.

ICON is working closely with international academic

and industrial dose-finding methodology specialists to
further enhance and extend adaptive and innovative
approaches to dose-finding. Future versions of
ADDPLAN DF will include additional sets of innovative
dose escalation designs, targeting both safety and
efficacy endpoints. Adaptive components for Phase
II studies using multiple comparison procedures,
dose-response modelling and MCP-Mod1 are in
development for future software releases.

ICON - A Leader in Adaptive Trials

References

ICON offers design, simulation and execution of

adaptive clinical trials. We are the only CRO that offers
the knowledge, software, systems and global footprint
to make global adaptive trials a reality.

1. Le Tourneau, C., Jack Lee, J., Siu, L.L. (2009) Dose

Escalation Methods in Phase I Cancer Clinical Trials.
Journal of the National Cancer Institute, 101, 708-720.

More than a decade of experience in successfully

planning and managing nearly 200 adaptive clinical
trials for over 30 sponsors
Experts with direct involvement in regulatory agency
adoption of adaptive design trials and subsequent
agency guidance
Operational teams and technologies to apply the
power of adaptive techniques to drug and medical
device trials
Additionally, you have access to the ICON Adaptive Trial
Innovation Centre, a group of world leading experts in
adaptive design and execution, providing leadership in
these key areas:
Design, simulation and execution of adaptive trials
across all phases of development
Development of innovative trial methodologies
Customized training in adaptive trial statistical
methodology
Advice and guidance on the logistical and operational
requirements for successful adaptive trial execution

2. ADDPLAN DF An Advanced Tool for Optimizing Dose

Selection in Exploratory Drug Development. An Aptiv
Solutions White Paper.http://www.aptivsolutions.com/
addplan-df-landing-page/
3. EMA-CHMP (2014) Qualification Opinion of
MCP-Mod as an efficient statistical methodology for
model-based design and analysis of Phase II dose
finding studies under model uncertainty. EMA/CHMP/
SAWP/757052/2013.
4. Neuenschwander, B., Branson, M., Gsponer, T. (2008)
Critical Aspects of the Bayesian Approach to Phase I
Cancer Trials. Statistics in Medicine, 27, 2420-2439.
5. Ji, Y., Wang, S.-J. (2013) Modified Toxicity Probability
Interval Design: A Safer and More Reliable Method Than
the 3+3 Design for Practical Phase I Trials. Journal of
Clinical Oncology 31, 1785-1791.
6. OQuigley, H., Pepe, M., Fisher, L. (1990) Continual
Reassessment Method: A Practical Design for Phase 1
Clinical Trials in Cancer, Biometrics, 46, 33-48.
7. Ji, Y., Liu, P., Li, Y., Bekele, B.N. (2010) A Modified
Toxicity Probability Interval Method for Dose-Finding
Trials, Clinical Trials, 7, 653-663.
8. Perevozskaya, I., Han, L., Pierce, K. (2014) Continual
Reassessment Method For First-in-Human Trial: From
Design to Trial Implementation. KOL lecture series on
adaptive designs; Friday, March 14, 2014.

Additional ICON White Papers

Using Surrogates for Decision Making in Confirmatory
Adaptive Clinical Trials
Using Adaptive Design to Optimize Product
Development at the Program and Portfolio Level
ADDPLAN PE: Population Enrichment Designs for
Adaptive Clinical Trials

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