Crossover study design

CROSS-OVER STUDY DESIGNS
PRESENTED BY
DURGADEVI.G
M. PHARM 2ND SEM
DEPT. OF PHARMACEUTICAL ANALYSIS
PSG COLLEGE OF PHARMACY

DESIGN OF PHARMACOKINETIC
STUDIES
 The main object of the experimental design is to minimize
the experimental variables and to avoid a bias.
 In vivo bioavailability study is determined by taking into
consideration of the following points:
 The nature of the reference drug and the dosage form to be
tested
 Benefit risk ratio considerations in regard to testing in
humans
 The availability of analytical methods
 What is the scientific questions to be answered?

FACTORS INFLUENCING
BIOAVAILABILITYSTUDIES
Bioavailability studies are influenced by various factors such as
 Age
 Sex
 disease state
 food habits
 physical and mental health condition
 body weight human volunteer
 experimental design
 time of administration
 time of sampling
 analytical method used
 Compartment model used in estimating pharmacokinetic parameters or
bioavailability that contribute to the observed blood concentration time
profile.

STUDY DESIGN
 The bioavailability study should be designed in such a
way that the formulation effect can be distinguished from
other effects.
 If two formulations are to be compared, a two-period,
two-sequence crossover design is the design of choice
which should ideally be equal to or more than five half-
lives that have to be measured
 Alternative study designs include the parallel design for
very long half-life substances with highly variable
disposition.

PARALLEL DESIGN
 In a parallel design, two formulations are administered to two groups
of volunteers.
 To avoid a bias, formulations may be administered randomly to the
volunteers.
 The major disadvantage of this design is that the intersubject variation
is not being corrected.
 It has been proved beyond doubt that most of the times intersubject
variation is greater than the variation between any formulation.
 Therefore, a cross over design is preferred in bioavailability or
bioequivalence trails to avoid influence of a intersubject variation.
 This design is used mainly for drug, and its metabolites have long
elimination half-life.
 The carryover effects or dropouts were less in parallel studies
compared to crossover studies.

C0NTI...
 A parallel study is also referred to as “between patient” or “non-
crossover” study.
 It is defined as a type of clinical study, in which two separate
treatment arms, A and B, are given so that one group receives only
treatment arm A while another group receives only treatment arm B.
 The two treatment groups of a parallel study can either be composed
of two completely separate treatments (i.e. different drugs), or simply
different doses of the same drug.
 A major characteristic of a parallel study is randomization, which
ensures accuracy of the results and lower risk of being biased.
 Generally, a placebo or active control are used as control groups in
parallel studies.

CROSS-OVER STUDIES
 In crossover studies, the study participants will be switched
throughout to all the treatment groups (both test and reference
formulations) after a washout period.
 Being the same set of the population the advantage of crossover
studies is that patients act as their own controls.
 Bioavailability (BA)/BE studies are usually conducted as
crossover studies.
 BE studies can be conducted under fasting and fed conditions.
 The sampling time points and the duration of BE studies
depend on the half-life of the drug of interest.
 In the case of a feeding study, a high-fat, high-calorie breakfast
would be provided to the subjects before administration of
investigational product (IP).

CONTI…
 As recommended by the USFDA, in most bioequivalence
studies, a test drug is compared with the standard
reference drug in a group of normal healthy subjects of
age 18–55 years, each receives both the treatments
alternately, in a crossover fashion (two-period, two-
treatment crossover design), with the two phases of
treatment separated by a washout period of generally a
week’s duration and it mainly depends on the half-life of
the drug.
 If elimination half-life of the drug increases, the washout
period also increases.

CONTI…
 The drug formulation either test or reference is given to each human
volunteer randomly but an equal number of subjects receives each
treatment in each period.
 In case of two treatments, groups 1 and 2, one group receives the
treatment in the order A and B, and the second group receives in the
reverse order B and A.
 A similar allocation is done in case of a three-treatment crossover
design (three-period, three-treatment crossover design)
 Intersubject variability is observed for several drugs in clearance.
 The intrasubject coefficient of variation (approximately 15%) is
usually substantially smaller than that between subjects
(approximately 30%), and therefore crossover designs are generally
recommended for bioequivalence studies.

CONTI…
 In crossover design, the treatments are compared on the same human
subject, and the intersubject variability is reduced.
 Both the designs depend on the three fundamental statistical concepts
of study design, and these are randomization, replication, and error
control.
 Randomization means allocation of treatments to the subjects without
bias.
 Replication involves the application of more than one experimental
subject for reliable estimates than a single observation and also
provides a more precise measurement of treatment effects.
 The number of replicates required mainly depends upon the degree of
differences to be detected and inherent variability of the data.

Commonly used cross over designs
 Commonly used cross over designs in
bioavailability trails are
 Latin square cross over design
 Balanced incomplete block design
 Replicate Crossover-study design

LATIN SQUARE DESIN
 The Latin-square design plans the clinical trial so that each subject
receives each drug product only once, with adequate time between
medications for the elimination of the drug from the body.
 In this design, each subject is his own control, and subject-to-subject
variation is reduced.
 Moreover, variation due to sequence, period, and treatment
(formulation) are reduced, so that all patients do not receive the same
drug product on the same day and in the same order.
 Possible carryover effects from any particular drug product are
minimized by changing the sequence or order in which the drug
products are given to the subject.
 Thus, drug product B may be followed by drug product A, D, or C .
 After each subject receives a drug product, blood samples are
collected at appropriate time intervals so that a valid blood drug level–
time curve is obtained.

CONTI…
 The time intervals should be spaced so that the peak blood
concentration, the total area under the curve, and the absorption
and elimination phases of the curve may be well described.
 The crossover design is a type of Latin square. In a Latin square
the number of treatments equals the number of patients.
 In addition, another factor, such as order of treatment, is
included in the experiment in a balanced way.
 The net result is an N X N array (where N is the number of
treatments or patients) of N letters such that a given letter
appears only once in a given row or column. This is most easily
shown pictorially.

Two-Period Crossover Design
 For randomizations of treatments in Latin squares, For the comparison
of two formulations, a 2 X 2 Latin square (N = 2) consists of two
patients each taking two formulations (A and B) on two different
occasions in two “orders”.
 The balancing of order (A-B or B-A) takes care of time trends or other
‘‘period’’ effects, if present. (A period effect is a difference in response
due to the occasion on which the treatment is given, independent of
the effect due to the treatment).
 The 2 X 2 Latin square shown above is familiar to all who have been
involved in bioavailability/bioequivalence studies. In these studies, the
2 X 2 Latin square is repeated several times to include a sufficient
number of patients. Thus the crossover design can be thought of as a
repetition of the 2 X 2 Latin square.

CONTI...
 2 formulations, even number of subjects, randomly
divided into 2 equal groups.
 First period , each member of one group receive a single
dose of the test formulation; each member of the other
group receive the standard formulation.
 After a wash period (5 half lives), in second period , each
member of the respective groups will receive an
alternative formulation & experiment will be repeated.

Incomplete block design (BIBD)
 More than 3 formulations, Latin square design will not be ethically
advisable. Because each volunteer may require drawing of too many
blood samples. If each volunteer expected to receive at least two
formulation, then such a study can be carried out using BIBD.
 It eliminates many of the difficulties encountered with the Latin
square design.
 In this, each subject receives not more than two formulations, each
formulation is administered the same number of times and each pair of
formulations occurs together in the same number of subjects.
 In this design, as discussed above, each subject receives two
formulations, each formulation is administered six times and each pair
of formulations occurs together in two subjects (the pairs are AB, AC,
AD, BC, BD, and CD).

Balanced incomplete block design
(BIBD) for four formulations

Replicate Crossover-study design
 For highly variable drugs.
 It allows comparisons of within-subject variances.
 It reduces the number of subjects needed.
 Four-period, two-sequence, two-formulation design
(recommended) or Three-sequence, three-period, single-
dose, partially replicated.
 Replicated crossover designs are used for the
determination of individual bioequivalence, to estimate
within-subject variance for both the Test and Reference
drug products, and to provide an estimate of the subject-
by-formulation interaction variance.
 Generally, a four-period, two-sequence, two-formulation
design is recommended by the FDA.

PERIOD 1 2 3 4
GROUP 1 T R T R
GROUP 2 R T R T
Where,
R = reference
T = treatment
The same reference and the same test are each given twice to the same
subject. Other sequences are possible. In this design, Reference-to-
Reference and Test-to-Test comparisons may also be made.

DIFFERENCE BETWEEN PARALLEL
AND CROSSOVER STUDY DESIGN
PARALLEL STUDY DESIGN CROSSOVER STUDY DESIGN
Groups assigned different treatments Each patient receives both treatments
Shorter duration Longer duration
Sample size is large Sample size is smaller
No carryover effect Carryover effect
Acute cases Not in acute cases
Doesn’t require stable disease and
similar baseline
Requires stable disease and similar
baseline

PARALLELVS CROSS-OVER DESIGN
PARALLEL DESIGN CROSS-OVER DESIGN
 ADVANTAGES
 Easy to organize
 Easy to analyze
 Easy to interpret
 DISADVANTAGES
 Comparison is carried out between
subjects: Not very powerful
 ADVANTAGES
 Comparison is carried out within and
between subjects: Much powerful
 Each cross-over patient serves as his
or her own control.
 DISADVANTAGES
 Unsuitable for long half life drugs
 Carry-over effect due to
inappropriate wash-out.
 Order effects the results.
 Difficult to analyze
 Takes long time to complete
 Not optimal for study in patients

Crossover study design

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