blocks of contemporaneous control groups, randomization,
and blinding, they assemble a clear picture of the nature of the
treatment-effect relationship. This accomplishment has earned
them the star ascendant position in cardiovascular research.
Their advantage was demonstrated with Bradford Hill’s work
on streptomycin, and as knowledge of the pathogenesis of ath-
erosclerotic disease produced possibilities for new treatments,
cardiovascular researchers applied this new research tool to
identify effective therapies in a sequential approach (Figure 1).
This work accelerated with clinical trials demonstrating
treatment benefits for chronic diseases such as hypertension,1,2
lipid abnormalities,3,4 and heart failure,5,6 cementing their role
in identifying new therapies to prevent the sequela of cardio-
vascular disease in vulnerable populations.
However, the limitations of early clinical trial interpretation also
appeared. The findings of the Multiple Risk Factor Intervention
Trial (MRFIT),7 the International Verapamil SR/Trandolapril
Study (INVEST),8,9 the Early Versus Late Intervention Trial With
Estradiol (ELITE),7,10 the Cardiac Arrhythmia Suppression Trial
(CAST),11,12 and the US Carvedilol program controversy13–19
together served to undermine the confidence of cardiologists in
the interpretation of clinical trial results. Thought leaders in the
field identified the interpretation problem (ie, the hyperreliance
on P values to reflect positive results for any analysis in a clini-
cal trial) and called for a fundamental change in the design and
analysis of clinical trials.
Subsequent work produced the following clinical trials
principles: (1)There should be clear and prospective declara-
tion in the written protocol about all important aspects of the
clinical trial with particular emphasis on the end points of the
study; (2) end-point assessments must be planned with clear
linical trials demonstrate the best of medical expertise
and epidemiological elegance. From the simple building
and declared assessments of type I error penalties; and (3) the
rules of the protocol must be followed in the trial (“First say
what you will do, then do what you said”).
The widespread acceptance of the 0.05 type I error level,
in concert with the multiple testing issue, generated clini-
cal trials with only a small number of primary end points
or confirmatory analyses, buttressed by a larger number
of prospectively declared secondary or supportive evalua-
tions. The remaining post hoc analyses, data dredging, and
subgroup analyses20–22 were now unpersuasive, giving way
to the prospectively declared primary analyses with their
attendant α spending functions and multiplicity corrections.
Over time, these principles were absorbed by the cardio-
vascular community. Contemporaneous Protocol Review
committees, Data Safety and Monitoring boards, the federal
Food and Drug Administration, top-tier journals, and knowl-
edgeable audiences of international cardiology meetings now
expect these conditions to be met.
Phase II Investigations Living
in a Phase III World
Executing research in accordance with these confining prin-
ciples is a daunting, expensive, and time-consuming task, yet
the investigators, epidemiologists, and biostatisticians who
conduct phase III studies are well equipped for the mission. A
wealth of preliminary data in animals and in humans is com-
monly available to serve as the foundation for the selection of
a small number of community-accepted primary end points.
This leads to the identification of appropriate end points and
their effect sizes that, if is adequate availability of finances
and subjects, can produce an executable phase III study. This
is clinical trial design at its finest.
© 2013 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.112.000779
From the University of Miami Miller School of Medicine, Miami, FL (J.M.H.); University of Louisville School of Medicine, Louisville, KY (R.B.);
Stanford University School of Medicine, Stanford, CA (J.P.C., P.C.Y.); Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, MN
(T.D.H., J.H.T.); University of Minnesota School of Medicine, Minneapolis (T.D.H., J.H.T.); Texas Heart Institute, St. Luke’s Episcopal Hospital, Houston
(E.C.P., J.T.W., D.A.T.); Indiana University School of Medicine, Indianapolis (K.L.M., M.P.M.); University of Florida School of Medicine, Gainesville
(C.J.P., A.D.S.); Mayo Clinic, Rochester, MN (R.D.S.); National Heart, Lung, and Blood Institute, Bethesda, MD (S.I.S., D.J.G.); and University of Texas
Health Science Center School of Public Health, Houston (R.W.V., L.A.M.).
Correspondence to Lemuel A. Moyé, MD, PhD, University of Texas School of Public Health, 1200 Herman Pressler W-848, Houston, TX 77030. E-mail
Phase II Clinical Research Design in Cardiology
Learning the Right Lessons Too Well: Observations and Recommendations
From the Cardiovascular Cell Therapy Research Network (CCTRN)
Joshua M. Hare, MD; Roberto Bolli, MD; John P. Cooke, MD, PhD; David J. Gordon, MD, PhD;
Timothy D. Henry, MD; Emerson C. Perin, MD, PhD; Keith L. March, MD, PhD;
Michael P. Murphy, MD; Carl J. Pepine, MD; Robert D. Simari, MD; Sonia I. Skarlatos, PhD;
Jay H. Traverse, MD; James T. Willerson, MD; Anita D. Szady, MD; Doris A. Taylor, PhD;
Rachel W. Vojvodic, MPH; Phillip C. Yang, MD; Lemuel A. Moyé, MD, PhD; for the Cardiovascular
Cell Therapy Research Network (CCTRN)
Hare et al Phase II Clinical Research Design in Cardiology 1631
It is only natural for the designers of phase II clinical tri-
als to embrace these same research standards. However, phase
II clinical trials themselves have a much weaker foundation.
Traditional end points may not have been implemented in the
early pilot studies or case series on which the phase II study
itself relies. There may be insufficient evidence for the selec-
tion of effect sizes necessary for the computation of a sample
size. Traditionally accepted biomarkers may not adequately
detect the underlying biological effect of a novel therapeutic.
The human ability to successfully embed the conclusions
from preclinical studies into the design of phase I/II studies is
both intricate and rare, its absence aggravated by the press of
time. An uncertain funding future, along with the finite patent
period, drives the perceived need for speed as investigators
hasten from phase I/II to phase III studies. Yet it is time itself
that is required to ensure that the best population, the best
therapy dose, and the best statistical estimates are obtained.
The lack of human and financial capital, amplified by the lack
of time, is a combination that injects structural weakness into
the research enterprise.
This may not be the case in all areas of early clinical
research (eg, low-density lipoprotein cholesterol reduction
or the development of new cephalosporins) that continue to
benefit from well-developed, time-tested in vitro and in vivo
models that serve the phase I/II community well.
However, novel therapies or targets subject to the standard
clinical trial metric (ie, driving a single primary end point to
a 0.05 statistically significant level) suffer when that novel
therapy has no natural biomarker, possesses mechanisms of
benefit that might differ between animals and humans, and
is researched by consortiums with limited resources that can-
not afford sequential studies, each with a single primary end
Nowhere are these considerations more crucial than in the
burgeoning study of cell therapy, where enormous enthusiasm
overlays a young and immature area in which preliminary
end-point findings, while promising, are based on a relatively
small number of subjects. Thus, the issue of end-point selec-
tion, a problem that has bedeviled large clinical trials,23 is even
more challenging for this nascent field.
The situation is complicated by a change in the standard
paradigm of clinical trial progression in the evaluation of a new
therapy. In the traditional paradigm, first-in-human studies are
historically conducted in normal volunteers in whom dose
escalation can take place in well-monitored circumstances,
with testing terminated if there is a sign of harmful effects.
However, as well demonstrated in oncology, medications that
are believed to hold out efficacy can be expected to produce
considerable side effects. Because it is unethical to subject
normal individuals with no disease to this anticipated level of
risk without benefit to the normal population, these first-in-
human studies can be conducted only in the target population.
Such individuals with ongoing, commonly progressive dis-
ease can be willing, under the right safeguards and oversight,
to assume the burden of risk to have an opportunity to receive
benefit, yet there are no human data on which to base the mea-
sure of efficacy in these trials.
Because large first-in-human studies are oxymorons, inves-
tigators who both are limited to a small number of subjects
for their phase II design and must labor under current phase
III research expectations are compelled to choose from 2
unpalatable alternatives: select modest and reasonable effect
sizes for which the small study is likely to be underpowered,
or select large effect sizes that lead to achievable sample
sizes, a decision that all but ensures that the effect the trial
was designed to detect does not exist. Each of these options
increases the likelihood that the phase II study will miss a
statistically and clinically significant finding. However, the
rationale for the phase II cell therapy clinical trial is to iden-
tify, perhaps for the first time, the potential benefits of the
therapy being assessed. This truism has been recognized by
the pharmaceutical industry, in which phase II clinical trial
results are scanned for signals on which phase III studies
are based with little regard for P values. In the development
of a novel therapeutic modality with uncertain biomarkers,
the rigors and requirements of phase III methodologies are
It is as though we in academia cannot distinguish between
the mission of a (phase III) army with its corps of human
and material resources and the charge of a smaller (phase
II) reconnaissance unit. They are both part of the same team
but have different tasks. The role of the phase II study is to
broadly survey the possible delivery mechanisms and possible
benefits of the study product. This knowledge is then passed to
the phase III trial investigators, who, with the target provided
by the phase II investigators, can now direct the appropriate
resources for a well-directed advance (Figure 3).
Phase II studies certainly have their limitations; their very
size makes them an unreliable foundation for therapy guide-
lines.24 However, large studies must have a data-based founda-
tion, and that foundation is built from small studies. The role
of a phase II study is not to confirm benefit for a new therapy
Figure 2. The traditional end-point hierarchy for end points in a
phase III clinical trial. A small number of primary end points with
multiplicity error correction are supported by a larger number of
secondary end points. The largest number of end points are non-
prospectively declared exploratory end points.
Figure 1. The traditional phases of clinical trials. *The study
takes place before Food and Drug Administration approval.
1632 Circulation April 16, 2013
but instead to identify its first signal, leaving confirmation to
the following larger studies (Figure 4).
Because the tasks of these 2 trial phases are different,
should not their metric of success be different as well?
The time-tested guidelines for a successful phase III trial are
sound and have served well; we do not advocate any altera-
tion in many of these established metrics for phase II studies.
Phase II studies should be based on prospectively declared,
detailed, and well-written protocols. These protocols should
continue to include close inspection by Protocol Review com-
mittees/Data Safety and Monitoring boards, the Food and
Drug Administration, and local internal review boards. How-
ever, there is growing appreciation that innovative designs of
phase II trials are required so that they can be true to their
mission, that is, to test a range of efficacy domains in the early
clinical testing of novel therapeutics to identify the range of
potential beneficial outcomes.
Specifically, we recommend that the measure for success
for a phase II clinical trial should be decoupled from the
achievement of statistical significance for a small number of
primary end points, a metric that is more in alignment with the
goal of a phase III study, but to provide phase II studies with
the ability to assess many primary end-point analyses without
the overriding concern of limiting the likelihood of a false-
positive finding. Because in this new domain false-negative
findings can stifle future research, we propose the following
metrics set as a first step that will help to maximize the utility
of phase II studies.
1. Evidence describing the safety of the study product and
its delivery coincident within the limitations of the study.
Small studies can only begin to define the safety profile
of an intervention, yet they are an essential first step. The
investigators must present all significant adverse events
to the community through publication or to the regula-
tory bodies that oversee its execution.
2. Many primary end points should be permitted; each
should be prospectively declared and then its findings re-
ported. The investigators who will use the findings of the
phase II study as a basis for phase III design must have
access to the findings of all end-point results as set out
in the phase II study protocol. To assess the coherence of
the findings, the phase II investigators should select end
points from different categories of effects (domains). In
cardiac cell therapy studies, useful domains would be the
• Structural evaluations: Measures of left ventricular func-
tion, for example, ejection fraction, end-systolic and
end-diastolic volumes, stroke volumes (and indexes),
infarct size, and ventricular sphericity.
• Cardiovascular physiological measurements: Measures
of contractility, for example, pressure-volume loops, rate
of rise of left ventricular pressure (peak +dP/dt), diastolic
performance, and loading conditions.
• Biomarkers: Atrial natriuretic protein, brain natriuretic
protein, cardiac enzymes, microRNAs, creatinine,
C-reactive protein, transcriptomic-based biomarkers.
• Functional capacity: Maximal oxygen consumption,
peak walking time, and 6-minute walk distance, which
are key components of an individual’s ability to function.
• Quality of life: Well-established measures in a given
field, for example, decreased need for target vessel
revascularization and recurrent myocardial infarction. In
addition, the Short Form-36, and the Minnesota Living
With Heart Failure questionnaires are well established
in the field.
An example of this approach is the recently published
Calcium Upregulation by Percutaneous Administration
of Gene Therapy in Cardiac Disease (CUPID) trial,25
in which the investigators prospectively selected end
points using this domain approach, permitting the study
to contribute estimates of effects of biomarkers, organ
function, and organism well-being in a nonexploratory
research environment. First Mononuclear Cells inject-
ed in the United States (FOCUS) study26 selected end
points of both left ventricular function and global func-
tion to provide useful and surprising data on the effect
of bone marrow mononuclear cells in the heart failure
population. Transplantation in Myocardial Infarction
Evaluation 2 to 3 weeks Following Acute Myocardial
Infarction (LateTIME)27 and Transplantation in
Non Data Driven Possibili?es
Func?on of the Organism
Quality of Life
Candidate Endpoints for phase III studies
Figure 3. The goal of the phase II study is to generate the first
data-based assessment of efficacy in a specific target popula-
tion. Its substrate is commonly non--data-based beliefs; its con-
clusions provide data in domains that can be targeted by phase
Mul?ple Cell Types
Alterna?ve cell delivery
Figure 4. The phase II study is the foundation of the phase III
study, providing assessments of multiple dose/timing/efficacy
combinations from which the phase III study selects.
Hare et al Phase II Clinical Research Design in Cardiology 1633
Myocardial Infarction Evaluation (TIME)28 reported
the first data on a new measure of left ventricular re-
gional wall motion. Similarly, the Percutaneous Stem
Cell Injection Delivery Effects on Neomyogenesis Pilot
Study (POSEIDON)29 examined end points in 3 domains:
quality of life, functional capacity, and left ventricular
structure and function, providing important insights and
guidance for future trials. Intelligently crafted end points
from a spectrum of well-chosen domains will serve well
as prospectively declared end points by revealing the
potential effects of cell therapy from the biomarker level
to that of the organism, providing data on which subse-
quent phase III trials may be designed.
3. End-point event rates or mean changes must be estab-
lished with predetermined precision. Although the inves-
tigators of a phase II study may not be able to predict a
priori how large or small the effect (eg, the change in left
ventricular ejection fraction over time in the cell therapy
group) will be, they can and should be expected to
determine that effect size, in the end (whatever its size),
with precision. The standard errors, anticipated mean
changes, and event rates must be determined a priori,
and a comparison of observed versus expected variabil-
ity may be considered one of the best measures of the
success of a phase II research effort. Because technology
(eg, cardiac magnetic resonance) changes rapidly, inves-
tigators must have the flexibility to use the most recent
procedures, even if they are introduced after the protocol
is written, to provide the most accurate and precise
estimates of the effect of therapy. To avoid control groups
that are inordinately small, full consideration should be
given to apportioning patients 1:1 active:placebo. The
use of a dose-escalation design and the availability of the
crossover option can enhance the likelihood of potential
subject interest in enrollment.
4. Hypothesis testing requiring small P values should not
be the primary goal of phase II studies, the goal of which
is to provide direction, not decision. The assessment of
safety and efficacy in the general population is the goal
of phase III studies; hypothesis testing with its multi-
plicity correction provides a measure of the likelihood
that the efficacy findings of these study are not due to
sampling error and that the patient population, who will
pay the financial cost and bear the side effect burden, is
likely to experience efficacy. Positive phase II studies
do not lead to approval and community use but instead
produce subsequent studies by providing foundational
evidence and generating hypotheses. One could argue
that hypothesis testing in these underpowered environ-
ments serves little use. Conventionally, phase 2 trials are
designed to elucidate the mechanism of action of the
therapeutic, to explore the dose-response relationship
using some quantitative measure of drug effect in vivo,
and to begin to explore the factors that contribute to vari-
ability of drug response. One can, in these 3 cases, apply
(distribution free) conventional statistical approaches to
“small” samples sizes. However, interpretations must
encompass all of the data. When grossly underpowered
clinical end points are measured in phase II to infer
safety or efficacy or when 2 biomarkers are measured
but only 1 is believed (eg, cholesteryl ester transfer
protein),30 the field can be misled. Phase II studies should
have the option to carry out testing at nominal 0.05 lev-
els or to carry out hypothesis testing at α levels >0.05,
for example, 0.15 or 0.20, while simultaneously being
released from the requirement of corrections for mul-
tiplicity. In addition, the Bayes perspective should be
considered because its use of prior information and loss
functions provides a different framework by which to
assess the results of clinical trials.
Proper evaluation of these phase II studies requires the
community to remind itself of the necessary restraint that
must accompany interpretation of the promising results of
these smaller studies. Phase II research with its small sample
size can cast only a weak spotlight in its initial illumination
of potential clinical benefit of cell therapy. Its results are both
frequently promising and frequently reversed by subsequent
larger studies with their tighter focus and more precise estima-
tors. This is not a fault in the process but a required built-in
check to ensure that only the safest products with the stron-
gest assurance of efficacy move forward to be used in larger
populations. In the end, interpretations of phase II clinical
research are based on impressions as much as hard evidence.
This is precisely why the question of the causal nature of
the exposure-outcome relationship must be settled in a well-
designed, well-executed confirmatory phase III clinical trial.
Moderating our expectations of smaller studies requires that,
on their conclusion, we call for additional work, not rapid
We recommend that the criteria that the community should
use to assess phase II studies be the following:
1. Strength of association: Is there greater benefit in the cell
therapy group than in the control group?
2. Consistency and concordance: If there are other stud-
ies in the field, do the findings of this study align with
those? A persuasive argument for causality is much
more clearly built on a collection of studies involving
different patients and different protocols, each of which
identifies the same relationship between the interven-
tion and disease. Do a majority of the end-point findings
move in the same direction? This concordance or inter-
nal alignment of the findings of a single study can sub-
stantially ease the learning curve of the community. If
consistency and concordance are not present, are there
biological reasons for the differences that can readily
account for the effects (cells treated differently before
injection, dose, etc)?
3. Coherence: If there is a mechanistic component to
the study, do its results line up with other outcomes
in a comprehensible way? Is there any well-accepted
scientific principle that would argue against the effect? A
cell therapy that improves left ventricular volumes and
improves functional outcome (eg, improves performance
on the 6-minute walk) brings coherence to the results
through its physiological link of left ventricular and or-
4. Dose response: If there is dose-response component to
the study, is there a gradient of responses that track natu-
rally with the gradient in dose or duration of therapy?
1634 Circulation April 16, 2013
5. Safety: Risk must be determined objectively (ie, through
the use of blinding, at least of safety outcome determina-
tions) and with appropriate circumscription. Small studies
cannot determine whether a therapy is safe, only that the
incidence of events cannot exceed an upper bound identi-
fied by the size of the study. A phase II study with 100 pa-
tients and no deaths cannot conclude that the therapy does
not produce deaths, only that the death rate is <1 per 100.
These criteria are based on those of Bradford Hill,31 the
father of the same randomized, clinical trials on which the
cardiology research community relies. However, perhaps the
greatest legacy of Dr Hill’s work is to remind us that, regard-
less of the controversial nature of the research, the interpreta-
tion requires careful and independent thought. Just as justice
is more than reading from a rule book, the correct interpreta-
tion of a clinical trial requires more than a mere calculation of
P values assessing orthodox end points.
The CCTRN would like to thank Dr Milton Packer for participating
in seminal discussions that led to the writing of this paper.
Source of Funding
Funding for the Cardiovascular Cell Therapy Research Network was
provided by the National Heart, Lung, and Blood Institute under
cooperative agreement UM1 HL087318-06.
Dr Hare has grants funded by the National Institutes of Health to his
institution and has ownership interest and has done consultant work
for Vestion. Drs Bolli, Henry, March, Murphy, Pepine, Perin, Simari,
Willerson, and Taylor all reported grants funded by the National
Heart, Lung, and Blood Institute to their institutions. Dr Traverse has
grants funded by the National Heart, Lung, and Blood Institute and
a grant funded by the American Heart Association to his institution.
Dr Yang has grants funded by the National Institutes of Health. The
other authors report no conflicts.
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KEY WORDS: clinical trials, phase II ◼ research design ◼ stem cell ◼ therapy