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SCIENCE & TECHNOLOGY
Maximizing the Value of Early Phase Drug Development
By Cecil Nick, BSc, FTOPRA and John Lambert
MD, PhD
In the current environment of increasingly rigorous regulatory requirements and tightening
fiscal constraints, it is more critical than ever
for sponsors to optimize selection of new drug
candidates and develop them effectively. Early
phase clinical studies provide pivotal decision
points that support selection of the right candidate and the right dose to maximize success
during the dollar-hungry Phase 3 program. A
mistake in early phase development could escalate to a costly failure of the Phase 3 program.
According to current estimates, over 55% of
drugs fail while in Phase 2 and over 36% fail
while in Phase 3 development.
In many cases, the reasons for failure are
underinvestment in the early phase program
or premature entry into Phase 3 to meet market
expectations. Either can result in insufficient data
to design and successfully conduct the Phase 3
program. This article explores ways of accelerating the completion and maximizing the value
of the early phase clinical development of new
medicines, rapidly providing informative data
to drive informed decision making in the design
and conduct of the Phase 3 program.
Preclinical to Phase 1
Drug development starts with Phase 1 and, in
effect, the success of the whole program pivots
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on a well-thought-out and well-executed group
of studies. These studies will provide critical
information on safety, pharmacokinetics (PK)
and pharmacodynamics (PD) and often proof
of mechanism for appropriate design of the
subsequent Phase 2 trials. These exploratory
studies, along with drug interaction, ethnicity,
elderly, gender and translational studies, provide
detailed information about the drug necessary to
progress the development program.
Because preclinical work will never be 100%
predictive of a drug’s effects, safety is always the
first objective in early human trials. These should
proceed cautiously. Many drug safety issues
that arise at later stages of clinical development
could have been anticipated with better analysis
of safety signals from data in earlier trials. An
example is the cardiac QT ECG changes occurring with prokinetic agents being developed to
improve gastric emptying; more-intensive review
of cardiac safety data may have revealed these
changes earlier.
Typically, the initial clinical dose of a new
drug is based upon the results of acute and
14-day animal data with a 10- to 100-fold safety
margin over the no effect level (NOAEL) in
the most sensitive and relevant animal species.
The exact safety margin will depend upon the
expected therapeutic window and potential risk
to the trial subjects. Generating interpretable preclinical data can present a challenge, particularly
when working with some biological products.
An example is a protein that shows no or limited
pharmacological activity in animal species or is
rapidly neutralized or cleared due to early generation of anti-drug antibodies in animals. Thus, it
may not always be possible to conduct the generally expected preclinical program before moving
into the clinic. In these situations, greater caution
will be needed in Phase 1, i.e., starting with very
low doses in a limited number of trial subjects.
Animal doses need to be converted to
human equivalent doses to accommodate differences in body surface area; for example, NOAEL
is divided by 12.3 for a mouse, 6.2 for a rat, 1.8
for a dog and 3.1 for a cynomolgus or rhesus
monkey. However, for biologics, the introduction
of an arbitrary safety factor may be too simplistic an approach because results in the animal
may not be clearly translatable into an expected
clinical effect in humans. Thus, additional
considerations such as the calculated percentage
receptor occupancy and “minimal anticipated
biological effect level” (MABEL) based upon predicted plasma levels as a function of the in vitro
biological effect ought also to be considered in
setting the target dose. In drugs with significant
potential toxicity, including cytotoxic agents
for cancer treatment, the lethal dose in relevant
animals is also used to assist in dose selection in
man.
To optimize the development program,
translation of preclinical biomarkers of disease,
as well as drug safety or efficacy to humans, is
important to consider early. This process includes
validation of the biomarker in the laboratory as
well as qualification in humans to confirm its
usefulness. The development of effective biomarkers as companion diagnostics to stratify
an individual patient’s response in relation to a
drug’s adverse events and disease responsiveness is important on our quest for personalized
medicines.
First-in-man studies generally involve single
dose escalation in healthy young males. In this
design, the first cohort of subjects receives the
lowest dose, after which subsequent cohorts
receive progressively higher doses, up to either
a predefined top dose or the maximum tolerated
level. Doses are initially escalated by a factor
of between 2 to 4, then as one approaches the
predefined top dose, escalation proceeds more
cautiously with 1.5–2 fold increments. The exact
dose escalation scheme will depend upon the
drug’s target and off-target effects and will take
into consideration the potential for any adverse
effects and that the exposure and pharmacological effects on the subjects may not increase
in proportion to the dose. The possibility of a
nonlinear dose response, particularly a greaterthan-expected overproportional increase in drug
effect or exposure, demands a cautious drug
escalation regimen. Different subjects may be
recruited to each escalation group, although
sometimes the same subjects can be recruited to
receive higher single doses using the so-called
“leapfrog” design. However, repeated escalation
in the same subject is not always appropriate as
there is the potential for a carryover effect and
development of an immune response to the drug
(particularly with biological agents). Also, fewer
subjects are exposed to the drug, limiting the
safety data.
There will be occasions when the use of
healthy volunteers is not ethical or feasible, particularly when the potential for toxicity exists
even at low doses, as with cytotoxic products,
Regulatory Focus
39
or when disease-specific factors mean that data
from healthy volunteers will have little relevance
for the target patient population. These single
dose studies are generally followed by administration of multiple doses either in an ascending
or parallel design depending upon the potential
risk factors.
Phase 1a studies will also generate important pharmacokinetic data such as bioavailability,
tissue exposure and dose linearity, as well as
pharmacodynamic data on measurable target
and off-target effects. These data will facilitate
decisions such as the proposed dose and regimen
and guide requirements for safety monitoring
during later phase studies.
Studies in healthy subjects can also be useful to assess the therapeutic effect in a human
disease model by providing early proof of mechanism or principle; an example is pain models
involving assessment of protection against pain
induced by, e.g., UV sunburn, topical skin agents,
or electrical stimulation of skin. Early phase
studies will also allow comparison of human and
animal pharmacokinetic and pharmacodynamic
effects and any observed differences will clearly
impact the planned doses for later studies. The
appearance of significant amounts of a novel
metabolites in humans compared to animals will
necessitate further toxicological investigation.
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Late Phase 1 studies, known as Phase 1b studies, are useful in assessing the potential for drug
accumulation and the relevance of potential biomarkers during later phase studies.
Other Phase 1 studies that are generally
non-rate-limiting include studies in special populations such as people with liver or renal disease
or the elderly, drug interaction studies, ethnicity
bridging and comparative bioavailability following formulation or manufacturing changes
(particularly for biologicals).
Patient safety, particularly in Phase 1 studies, is of the utmost importance and has been
reviewed in the European guideline (EMEA/
CHMP/SWP/2837/07). Mitigation of risks is an
important part of study planning and key measures need to be clearly documented in the study
protocol and related documents. Suitable clinical trial sites (generally hospital-based for rapid
access to emergency support) using experienced
and well-trained staff are an important part of
risk mitigation. Safety considerations will drive
the study design by impacting population, dose
selection (particularly starting and highest dose),
route and rate of administration, number of
subjects per dose, increment in each cohort, dosing sequence and interval of subjects within the
same cohort, criteria for advancing to the next
dose level and study stopping rules.
The Phase 1 development program can often
be accelerated by using a combined, so-called
“fusion” protocol, which integrates elements of
the Phase 1a and Phase 1b studies into one seamless adaptive study. This approach supports a
single ethics and regulatory approval submission
as well as the application of adaptive approaches
in the conduct of the studies. It is our experience that such “fusion” studies can provide time
savings of up to 30% and cost savings of up to
20%. ”Fusion” protocols require clear justification of the study design and detailed criteria for
progressing, such as clear, pre-defined stop/go
criteria at critical points. These fusion studies are
best conducted in clinical pharmacology units
where investigators, the local ethics committee
and the government regulatory body already
have experience with this approach. The progress of fusion studies can be further facilitated
by conducting these at centers that have rapid
access to patients in addition to healthy volunteers so as to facilitate rapid transition to the
Phase Ib part of the study.
Phase 2 Development
Detailed assessment of the Phase 1 information is
essential to support the Phase 2 program, which
is generally designed to provide proof of concept
and to select one or a maximum of two dosing
schedules that will be investigated in the pivotal
Phase 3 studies. By addressing potential issues
during the preclinical and Phase 1 programs,
many pitfalls of Phase 2 trials can be avoided.
Applying adaptive trial design principles
is particularly useful to accelerate the Phase 2
program. Sometimes it may even be possible to
integrate components of the Phase 1 and 2 studies into a seamless “learning phase,” followed by
a Phase 3 confirmatory program. This approach
is often used in developing biologicals, orphan
drugs and generics.
Adaptive trial designs involve using data
generated early in the study to guide and amend
the future progress of the study. However, any
changes to the ongoing study must adhere to
strict predefined criteria to avoid introduction of
bias. Furthermore, not all studies are suitable for
an adaptive design.
Examples of adaptive designs include:
• studies that increase recruitment into
the dosing arm(s) showing greater
efficacy
• repowering of studies based upon
interim determination of the coefficient
of variation for the blinded data
• increasing recruitment of subpopulations that appear to respond to the trial
therapy
• discontinuing ineffective doses according to strictly predefined criteria
• early stopping due to futility or obvious efficacy benefit over placebo; in
this situation there will be an alpha
CONFERENCES & EVENTS
23–24 March 2011
Preparing Compliant eCTD Submissions
Rockville, MD
RAPS.org/eCTD/march2011
7–8 April 2011
2011 RAPS Horizons
Vancouver
RAPS.org/Horizons2011
6–9 June 2011
RAPS Executive Development Program
Kellogg School of Management
Evanston, IL
RAPS.org/exec/june2011
spend, meaning there is the potential to
increase the total study population in
the event the early stopping rules are
not met
There is significant controversy about the statistical robustness of adaptive designs and data
analysis may involve a complex Bayesian statistical approach. Therefore, such studies are not
generally accepted as part of a Phase 3 confirmatory program but are considered to have value
during the early phases of development.
The application of biomarkers in Phase
2 studies also is receiving considerable attention. The US Food and Drug Administration
(FDA) Critical Path Initiative (Challenge and
Opportunity on the Critical Path to New Medical
Product, March 2004) and the recent update
(Critical Path Report on Key Achievements,
2009) highlight the need for biomarker discovery
to facilitate and speed up drug development.
Furthermore, the European Medicines Agency
and FDA recently concluded the first joint qualification process for biomarkers.
Biomarkers are measurable characteristics
that reflect physiological, pharmacological or
disease processes. A biomarker may be a physiological measure, a soluble, tissue or genetic
marker or an imaging endpoint. Generally,
changes in biomarkers can be detected earlier
and more readily than changes in the corresponding clinical endpoint. While biomarkers
have limited use in confirmatory studies because
they need to be validated, adequately qualified
biomarkers can be extremely useful in dose selection. Early review of potential biomarkers is an
important component of the overall development
program so that they can be used to support
early go/no-go decisions and differentiate
responder from non-responder populations. The
Regulatory Focus
41
latter could be run as a parallel program to support the development of companion diagnostics
and personalized treatment of individuals.
Biomarkers are not a new concept and a
number are well accepted:
• blood pressure for cardiovascular
diseases
• HbA1c for diabetes
• bone mineral density for osteoporosis
• CD4 count for HIV
• viral load for Hepatitis B and C
• antibody titer for autoimmune disease
or post vaccination
• MRI for multiple sclerosis
With the development of proteomics and genomics, substantial new knowledge about biomarkers
and disease drug targets is being generated,
which promises to broaden the utility of
biomarkers in clinical development. As a consequence, a number of innovative biomarkers have
been introduced into drug development, some
examples include:
• pharmacogenomic markers
• histology/histochemistry
• PET imaging endpoints in oncology
•
•
•
serum biomarkers and imaging of
unstable atherosclerotic plaque in cardiovascular disease
imaging and biochemical markers of
early neurodegenerative diseases
(e.g., mild Alzheimer’s disease)
osteoarthritis skeletal biomarkers
Conclusions
Drug development is complex. Early acquisition of knowledge is critical to enable clear,
predefined stop/go criteria at critical points in
the program to ensure progression or discontinuation in a timely manner to minimize financial
loss. The primary development challenge for
the biopharmaceutical industry is to ensure that
Phase 2 trials are adequately sized, rigorously
designed and conducted and thoroughly analyzed to reasonably judge the chance of success
in the later stages of development. Sound scientific data should form the basis of any decision
about transitioning a drug to Phase 3.
If internal resources are not available, partnering with an experienced drug development
company can provide the services and guidance
needed to navigate the clinical trial process and
help bring a new product to market. A development services company with knowledge and
expertise in biotechnology and the appropriate
therapeutic area can help its biopharmaceutical
partner design clinical trial protocols that produce all relevant data as quickly and efficiently
as possible. Perhaps most importantly, an outside
company can provide an unbiased analysis of the
data, which should form the basis for informed
and pragmatic decision making about which
drug candidates should move forward.
Some of the key success factors in early
clinical development are detailed knowledge
of the relevant regulatory, therapeutic and
disease guidelines, early development of data
using adaptive study designs and modeling/
simulation and application of biomarkers, disease models and early patient exposure (where
relevant). A clear development strategy defining
all the relevant points for the program review,
including regulatory interactions, is crucial.
Safety is clearly of critical importance and risk
mitigation planning along all parts of the development is essential.
Authors
Cecil Nick, BSc (Hons.) FTOPRA, is vice president, biotechnology at PAREXEL Consulting. Nick provides expert
consulting services to clients particularly on the clinical and
regulatory development of biotech and biological products. He
has been involved in the development and regulatory approval
of a number of innovative and biosimilar medicinal products.
Dr. John Lambert, MD, PhD, is vice president and chief medical officer of PAREXEL Early Phase, based in London. He
graduated in Medicine from Melbourne University, Australia.
He is board certified in Gastroenterology, Internal Medicine
and Clinical Pharmacology having trained in Melbourne,
Toronto and the UK.
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