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RCDRC Guidelines for Clinical Trial Design
Applications to the RCDRC should address the following principles of
study design. The guidelines are written primarily for clinical trials
but most of the issues pertain also to observational studies including
case-control and cohort studies. Biometry Core biostatisticians are
available to consult with investigators on study design (contact Dr. Brian
Leroux at 543-7304 or firstname.lastname@example.org). Seeking advice
in the early planning stages is recommended. A short list of references
is also provided below for additional reading on clinical trial design.
A. Study Objective and Hypotheses
Give a clear and concise statement of the research question(s) (eg,
does treatment X have an effect on variable Y in population Z compared with
placebo?). State the type of comparison to be made, ie, whether the goal is
to establish superiority of one treatment over another or non-inferiority of
one treatment with respect to another. State one or more specific null
hypotheses based on the research questions (eg, mean levels of variable Y in
treatment and control groups will not be different xx months after treatment)
and the corresponding alternative hypotheses. The context of the study within
an overall research plan should be given, eg, is this an initial exploratory
study or a confirmatory trial to test a predefined hypothesis?
B. Outcome Variables
Give one or more primary outcome variables. These should be the
variables most relevant to the study objective. Sample size calculations
should be based on the primary outcome variables. If more than one primary
outcome variable is used, explain why no single primary outcome variable could
be selected. If appropriate, define the secondary outcome variables which
are measurements made to provide supporting evidence for the research
question or to provide information on treatment mechanisms.
C. Study Population
Define the specific population from which study subjects will be
selected and give the mechanism for selection (eg, random sampling, clinic
population, recruitment through advertisements). State clearly defined
inclusion and exclusion criteria.
D. Treatment Assignment
State the method of assigning treatments to subjects (or experimental
units such as teeth within subjects). This method should be selected to
minimize bias due to selective assignment of certain treatments to particular
subsets of subjects based on demographic, prognostic, or other information.
Ideally, randomization will be used for assigning treatments. Randomization
involves the deliberate use of an element of chance such as flipping a coin,
computer generated random numbers, or tables of random numbers. The
procedures for generating random treatment assignments should be explicitly
defined, including blocking or stratification as appropriate.
Randomization tends to guard against bias due to selective assignment of
treatments and/or imbalances in prognostic factors, and also serves as the
fundamental basis for the statistical analysis of the results.
If randomization is not proposed, carefully justify why it is not
feasible and what procedures will be used to guard against bias.
State the type of blinding that will be used for subjects, clinicians,
and evaluators. Ideally, double blinding will be used, in which the clinicians
and evaluators, as well as the subjects, do not know the identity of the
treatment used. Blinding is used to minimize bias of clinicians or evaluators
and the placebo effect. If blinding is not to be used state why it is not
feasible and describe the procedures that will be used to guard against bias.
F. Study Design
State the specific type of design to be used. This should be either a
parallel group design or a within-subject design. In a parallel group design,
the group to which a subject is assigned determines the interventions
received. In a within-subject design each subject receives more than one
of the treatments and comparisons of treatments can be made within subjects.
Examples of within-subject designs are split-mouth designs in which different
treatments are assigned to different parts of the mouth, cross-over designs
in which each subject receives two or more treatments in succession.
G. Sample Size
Give a justification of the sample size to be used. Ideally, the
sample size is selected based on calculation of the power of the statistical
tests of the primary hypotheses. The sample size will depend on the
the magnitude of the treatment effect, the level of the type I and type II
errors. Depending on the type of statistical analysis to be used
(comparison of means, proportions, event rates, etc), the sample size
may also depend on the variability of the primary outcome variables
or the baseline disease prevalence or incidence rate in the population.
If the sample size is not based on calculation of power, explain why
this is not feasible, eg, because the study is exploratory in nature
or because sufficient pilot data is not available for power calculations.
H. Data Collection
Describe the procedures for collection, including timing of all
subject visits, personnel for performing data collection, and
instruments/questionnaires to be used in data collection. Describe also
procedures for managing the data, including computer entry of the data.
I. Statistical Analysis
Describe the statistical analysis methods to be used, paying particular
attention to methods for testing the primary hypotheses. Give plans for
evaluating baseline comparability of treatment groups and any statistical
assumptions necessary. Analyses of secondary outcome variables should
also be described.
1. International Conference on Harmonisation; Draft Guideline on Statistical
Principles for Clinical Trials. U.S. Food and Drug Administration,
2. Statistical guidance for clinical trials of non-diagnostic medical devices.
Division of Biostatistics, Center for Devices and Radiological Health,
U.S. Food and Drug Administration, 1996.
3. Page RC, Armitage GC, DeRouen TA, Genco RJ, Hujoel P, Jeffcoat MK,
Kornman KS, Williams RC: Design and Conduct of Clinical Trials of
Products Designed for the Prevention, Diagnosis and Therapy of
Periodontitis. The American Academy of Periodontology, 1995.
4. Friedman LM, Furberg CD, DeMets DL: Fundamentals of clinical trials
(3rd ed.). St. Louis: Mosby-Year Book, 1996.
5. Pocock SJ: Clinical trials: a practical approach. Chichester: Wiley, 1983.