This document discusses various clinical trial designs including parallel, crossover, factorial, and adaptive designs. It describes key elements of clinical trial methodology such as randomization, blinding, placebos, and controls. The document also outlines how clinical trial designs are applied differently in each phase of drug development from Phase 0 microdosing to Phase III confirmatory trials. Key challenges in clinical trial design like controlling bias and complex statistical analysis of factorial designs are also summarized.

1. Clinical Trials Design
Dr Ritu Budania
MBBS , MD

2. Overview
•Introduction
• Clinical Trial Designs
•Challenges
•Application in different phases of trial
•Summary

3. Clinical Research
All scientific approaches to evaluate medical
disease in terms
Prevention
Diagnosis
Treatment
Humans

4. Clinical research design
No intervention Intervention
Observational Experimental
Comparison group
NoYes
Analytical study
(case control,
cohort)
Descriptive
study
Random allocation
Yes No
Randomized
controlled trial
Non-Randomised

5. Types of Clinical trials
Treatment trials
Prevention trials
Quality of life
trials
Diagnostic trials

6. Drug development

7. Clinical Trial Designs

8. Designs
 Parallel
 Cross over
 Factorial
 Randomized withdrawal approach
 Adaptive
 Superiority
 Non-inferiority

9. Parallel
• Subjects are randomised to one of two or
more arms
• Each arm being allocated a different
treatment
• Most commonly used design

10. Eligibilty
assessed
Consent
Control
Test drug
Randomised

11. Controls in Clinical Trials
1. Placebo
2.No-treatment
3.Active
4. Dose Response
5. External Controls
5 mg

12. 1. Placebo Control
• Placebo- inert substance – looks exactly
like test drug but contains no drug
• In trials testing efficacy
• Double blinded

13. Advantages of Placebo control
• Minimizes bias
• Ability to demonstrate efficacy

14. When to use placebo?
1.In disease in which no prior drug has been
established as - standard therapy
2. Minimal risk, short term study
3.Add-on design

15. Disadvantages of Placebo Control:
1.Ethical Issues
- Lack of treatment -Serious harm( such as
death or irreversible morbidity)
-Declaration of Helsinki – use of standard
treatment as control
-Used where minimal risk
2.Patient and physician concerns:
-Patients may not enroll
-Withdraw

16. 2. No treatment control
• Subjects are randomly assigned to test
treatment or to no treatment
• Subjects, investigators are not blind to
treatment
• Bias

17. 3.Active control
Standard treatment exists
phase III study designs
compare “new drug” to standard or
compare standard to combination therapy that
involves the standard + “new drug”

18. • 4.Dose response control
• 5.External control
Comparability ?
Baseline characteristics?
No randomization, blinding
Bias

19. Uncontrolled trials
• No controls
• When-
- Determine pharmacokinetic properties of a
new drug (phase 1 trial)
• Limitation- Bias , as no randomization, less
validity than RCT

20. Run-In Design
• Non-compliance

21. Run-In Design
Screen &
Consent
Placebo
Run-In
Period
R
A
N
D
O
M
I
Z
ECompliance Unsatisfactory
Dropped
B
A
compliance
Satisfactory c

22. 2.Cross over
• Each patient gets both drugs
• the order in which the patient gets each drug is
randomized
• Each patient serves as his own control
• Avoids between participant variation in estimating
intervention effect
• Requires a small sample size
• Assumptions:
–The effects of intervention during first period does not
carry over into second period.
–Internal and external factors are constant over time

23. A A
B B
A followed by B
B followed by A
ABA
BAB
ABAB
BABA
Cross over design with switch-back
C.O. design with double switch-back
Run in
Wash out
period

24. Prerequisites for crossover design
• Disease – chronic (asthma, osteoarthritis)
stable
• Effects of drug should develop fully within
treatment period (not for Hit and run type
drugs)
• Washout periods -sufficiently long for
complete reversibility of drug effect
• Wash out period- five half lives of drug

25. Crossover designs- problems
1.Carryover effect
2.Period effect- patients vary from 1 period to another
3.Not useful for acute disease
4.Difficulties in assigning adverse events which occur in
later treatment periods to appropriate treatment
5.generally not used in vaccine trials because immune
system is permanently affected (or at least affected for a
long time)

26. Use of cross over design:
• Bioequivalence studies
• Phase I

27. Parallel Crossover
Groups assigned different
treatments
Each patient receives both
treatments
Shorter duration Longer
Sample size- large Smaller
No carryover effect Carryover effect
Acute cases Not in acute,
Chronic,stable

28. Latin Square Design
A  B  C
B  C  A
C  A  B
I II III
1
2
3
Subjects
Period

29. Greco-Latin Squares
Effect of treatment & effect of another factor (eg.
ancillary Treatment, diet etc)
A  B  C
B  C  A
C  A  B
I II III
1
2
3
Subjects

30. Intensive Design: Comparing 2 Tts.(A & B) each subject
receives same Tt. several times.
Period I II III IV V VI
Treatment A B B A A
B
- For short period of Rx/single dose
- For testing efficacy of new compound

31. 3.Factorial design
- two or more interventions
- Allows study of interactive effects

32. 2×2 factorial design
B only Neither A nor B
A onlyBoth A and B
Advantages
-Two drugs
studied at same
time
-Discover
interactions
-Test FDC
Disadvantages
1.Complexity of trial
design
2. Complexity of
statistical analysis

33. 33
Incomplete Factorial Design
Eg. depression; if unethical to
do nothing
• A – Desipramine
• B – Congnitive therapy
• C – Combination of A & B
3 n
eligible
A no, B yes
A yes, B no
A yes, B yes

34. 4.Randomized withdrawal approach
Third, the design is particularly useful in
determining how long a therapy should be
continued (e.g., post-infarction treatments
with a beta-blocker

36. Group 1 Group II
Pt Sex Age IQ Pt Sex Age IQ
1. m 25 95 4 m 25 95
2. f 35 100 5 f 35 100
3. m 45 105 6 m 45 105
5. Matched pairs
- Pts. With same characteristics
- Expected to respond similarly
Group characteristics
2 males 1 female 2 males 1 female
Average age 35 yrs. 35 yrs.
Average IQ 100 100
Pt 1. matches with Pt 4
2. ‫״‬ ‫״‬ ‫״‬ 5
3. ‫״‬ ‫״‬ ‫״‬ 6 Advantage- Less Variability
Group -I Group-II

37. Clinical trial design innovations
• Adaptive Design
- allows adaptations or modifications to trial
design after its initiation without undermining
validity and integrity of trial

38. 1.Maximum Information Design
• interim analyses until the target or maximum
information level reached.
• Whenever the pre-specified target
information level is reached, the patient
recruitment is stopped.
2.N-Adjustable Design

39. 3. Group sequential design
prematurely terminating trial based on the
results of interim analyses
• Early-efficacy stopping
• Early futility stopping

40. (4) Drop-Losers Design
- allows dropping of treatment arm(s) during
study based on interim analysis results
-trial starts with several treatment groups; at
each stage, interim analyses are performed
- losers (inferior groups) are dropped based on
prespecified criteria.
-best arm(s) will be retained.
-used in a phase-II/III combined trial

41. 5.Adaptive Randomization Design
• Response-adaptive randomization (RAR) -
allocation probability is based on response of
previous patients.
• The purpose is to provide the patients with a
better chance of being assigned to the
better/best treatment

42. 42
Superiority Trials
Show that new treatment is better than control or standard
(maybe a placebo)
• Examples:
Placebo-controlled efficacy trials
Active controlled

43. Non-Inferiority Trials
-Show that new treatment
Is not worse that the standard by more than
some margin
-Active control equivalence trial
-Placebo not used
-Better tolerated,
less dosing

44. X is non inferior
Placebo
Active Control
DELTA

45. Multicentric trials
1. Large sample size needed- in less time
2. Availability of eligible patients is a constraint
3. Role of Racial/ Ethnic factors to be studied
• Strict protocol compliance by Investigators at
all centres
• Central monitoring committee
• Phase III trials

46. Challenges in Design:
Control of bias (Randomization, Blinding )

47. Bias
 Prejudice
 Deviation from truth
 Selection/Allocation bias
 Observer bias
Good study design - minimizing all possible
sources of bias

48. Randomization
-Assigns patients to treatment arms by chance
-Eliminates selection bias
Pseudo randomization

49. Randomization methods
1. Simple randomization
2. Block Randomization
3. Stratified Randomization ( age, gender, stage, severity)
Tossing coin
Dice
Random number table
Computer generated

50. Randomized controlled trials
• Gold standard
• Minimize bias
• Costly, time consuming

51. Allocation Concealment
• Preventing next assignment in clinical trial
from being known
• procedure for protecting randomization
process so that treatment to be allocated is
not known before the patient is entered into
the study

52. Methods of Allocation concealement
• Sequentially numbered, opaque, sealed
envelopes,
• Pharmacy-controlled allocations
• Coded identical containers or kits
• Central randomisation systems

53. Blinding
• ensuring that neither patients, healthcare
providers, nor researchers know to which
group specific patients are assigned

54. Reasons for blinding
-Patients on active treatment - adhere
Placebo- do not adhere
- Observer’s bias- Principal investigator-more
vigorously examine active group

55. Blinding types
• Open label
• Single blind
• Double blind
• Triple blind
• PROBE (Prospective Randomized Open with
Blinded End point Assessment)
No standard definition
Should be specified who is blinded and
how

56. Double dummy technique
Randomise
Placebo
Placebo

57. Blinding not possible when
• Surgery with non–surgical treatment
• Types of dialysis [hemodialysis versus
peritoneal dialysis]

58. Application of various designs
in phases of clinical trial

59. Phase I (Human Pharmacology)
Aims:
– To find safe dose range
– Pharmacokinetics of drug
– Drug food interaction
– First in man study
Sample:
• Healthy volunteers
• Drug -too toxic (cancer, HIV): patients
Sample size- 20-50

60. Phase I contd
Design
Open label
Non-randomized
Dose escalation
Uncontrolled
Randomized 2 way crossover study of one dose level of
drug under fasting and fed conditions
6010/21/2016

62. Phase II (Therapeutic exploratory)
IIa IIb
II a- Proof of concept
Sample – Patients
Sample size- 40-100 subjects
Placebo control preferred
not- multi centered

64. Phase II b- Dose range finding
• To find optimal dose response range
• 300-400 patients
• Placebo/ active control
• Multicentric

65. Phase III
Confirmatory trials- confirm drug is safe and effective
• Sample- 1000-3000 patients
• Active controlled
• Randomized
• Double blinded
• Parallel
• Non-inferiority
• Multicentric

66. Phase IV
Post- marketing surveillance
• Detect long term ,rare side effects
• Pharmacoeconomics
• New indication
Uncontrolled
ObservationalNew drug status-
4 years

67. Bioequivalence studies
• For generic drug submission
• ANDA- Abbreviated new drug application
• RLD- Reference listed drug
• Parallel-Group Design
•Even number of subjects in two groups
•Each receive a different formulation

68. Single dose,two
way crossover
fasting
Single dose,two
way crossover
fed
Single dose
parallel fasting
Multiple dose,
crossover
fasting

69. Microdosing (Phase 0)
• Candidate drugs fail- suboptimal human
pharmacokinetics
• FDA- 100 mcg drug or
< 1/100 th of pharmacological dose
determined from animal models
• LCMS

70. Hierarchy of Evidence

71. Summary
Success of clinical trial- appropriate clinical
design, control group
RCT – gold standard
Blinding, randomization- minimize bias

72. References
1.ICH E8 ,9,10 Guidelines : General consideration for clinical
trials, Current Step 4 version, 1997
2. Lawrence J. Appel. Primer on the Design, Conduct, and
Interpretation of Clinical Trials. Clin J Am Soc Nephrol 1:
1360–1367, 2006
3.Shein-Chung Chow and Mark Chang. Adaptive design
methods in clinical trials – a review .Orphanet Journal of
Rare Diseases 2008, 3:11
4.Kenneth F Schulz, David A Grimes. Blinding in randomised
trials: hiding who got what. THE LANCET 2002 ,359:2
5.New Movement in Drug Development Technology –
Micro-dosing and its challenges, QUARTERL REVIEW
No.40 / July 2011

73. 6.Thereasa A , Clinical pharmacology ; Goodman and
Gilmans, Pharmacological basis of therapeutics; 12;1731-50;
2010.
7.HL Sharma and KK Sharma, Clinical pharmacology ,
Principles of Pharmacology;2;871-91;2010