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.
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
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
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
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
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
35.
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
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
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
61.
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
63.
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
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
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
Editor's Notes
Placebo : test treatment or an identical-appearing treatment that does not contain the test drug
No treatment : subjects are assigned to the test treatment or to no study treatment
Dose-response: subjects are randomized to one of several fixed dose groups
Active: subjects are assigned to the test treatment or to an active control treatment
External(including historical): compares a group of subjects receiving the test treatment with a group of patients external to the study. Can be historical, i.e, group of patients treated at an earlier time