1. Introduction of Clinical Trials
Jessie Zhou
Dept.of Clinical Epidemiology and Biostatistics
McMaster University
August 1, 2011

2. Outline Overview of clinical trials History of the clinical trials
Types of the clinical trials
Design of the clinical trials
Phases of the clinical trials
Some issues on clinical trials design

3. Overview of Clinical Trials
What is Clinical Trials
Any form of planned experiment which involves patients and is designed to answer scientific questions and find better ways to prevent, diagnose, or treat disease.
To discover or verify:
Pharmaco dynamics (how it works)
Pharmacokinetics (what happens to it)
Therapeutic effects (Efficacy)
Adverse reactions (Safety)

4. Overview of Clinical Trials

5. Overview of Clinical Trials
General thoughts:
Study must examine valuable and important biomedical research questions.
It must be based on rigorous methodology & It must follow strong ethical principles.
The probability and magnitude of risk – benefit to the participants.
The population to be studied – its Size, Availability and Accessibility.

6. Overview of Clinical Trials
Some examples:
Assess the safety and effectiveness of a new medication or device on a specific kind of patient (e.g., patients who have been diagnosed with Alzheimer's disease)
Assess the safety and effectiveness of a different dose of a medication than is commonly used (e.g., 10 mg dose instead of 5 mg dose)
Assess whether the new medication or device is more effective for the patient's condition than the already used, standard medication or device ("the gold standard" or "standard therapy“)

7. History of Clinical Trials
The history of clinical trials before 1750 is brief
The first reference - King Nebuchadnezzar II
Persian scientist Ibn Sina wrote Canon of Medicine around the 10th century
One of the most famous clinical trials was James Lind's demonstration in 1747 that citrus fruits cure scurvy
Frederick Akbar Mahomed (1884), made substantial contributions to the process of clinical trials
separated chronic nephritis with secondary hypertension from what we now term essential hypertension
founded "the Collective Investigation Record for the British Medical Association

8. History of Clinical Trials
From 1800 onwards, more attention was paid to study design.
Placebos were first used in 1863.
The idea of randomization was introduced in 1923
In 1930, the US Food and Drug Administration (FDA) was found.
The first trial using properly randomized treatment and control groups was carried out in 1948
Since 1945, the ethical impact of clinical trials has become increasingly important
Clinical trials have thus evolved into a standard procedure, focusing on patient safety and requiring informed consent from all participants.

9. Types of Clinical Trials
By type of products
Pharmaceutical Products (Synthetic “Drugs”)
Biotechnology Products (products made from human cells/tissues for example, such as vaccines, blood products)
Devices (e.g., cardiac stents, pacemakers)

10. Types of Clinical Trials
By purpose of the trials
Treatment trials
Prevention trials
Early-detection trials/screening trials
Diagnostic trials
Quality-of-life studies/supportive care studies

11. Types of Clinical Trials
By the way of research behave
Treatment studies
Randomized controlled trial
Nonrandomized trial (quasi-experiment)
Observational studies
Cohort study
Case-control study
Cross-sectional study
Ecological study

12. Phases of Clinical Trials
Pre-Clinical (in vivo, in vitro)
Phase I - Safety & Early Clinical Pharmacology
Phase II - Initial Efficacy & Safety.
Phase III - Comprehensive Efficacy & Safety
Phase IV - Post Marketing surveillance Studies

13. Phase I Clinical Trials
First time in humans
Objectives
Assess pharmacology/pharmacokinetics
How drug flows through body
How drug is excreted and how long (half-life)
Assess toxicology (safety)
Adverse events, Labs, EKGs, Vital Signs, Physical Exams
Determine maximum tolderated dose (MTD)
Performed usually in subjects
No interest in efficacy
Descriptive Analysis

14. Phase II Clinical Trials
Performed in usually patients
Sample often based on time, cost considerations
Concentrate on safety, but also look at efficacy
Often exploratory in terms of efficacy
Find parameters on which product is efficacious?
Find magnitude of the product’s effect on these parameters?
Contains control group (placebo/active)

15. Phase II Clinical Trials
Multiple doses
Find dose with best safety profile and best efficacy profile (not always the highest dose)
Use results to design confirmatory Phase III trials
Not necessarily required to obtain statistical significance (“p<0.05”) in Phase II in order to move to Phase III

16. Phase III Clinical Trials
Objective
Confirm efficacy of new drug seen in Phase II
Determine safety of new drug (especially for uncommon “adverse events”).
Often called “Pivotal” trials

17. Phase III Clinical Trials
Often performed in 2 treatment groups
Study drug vs. Control
Control may be Active or Placebo
Some suggest both Active and Placebo control
If Active-controlled, not necessary to show superiority, but “non-inferiority” or “equivalence”
FDA has no official rules about control group

18. Phase III Clinical Trials
Sample size based heavily on statistics
If treatment works in population, we want a sample large enough to represent population
i.e., Want a high probability treatment works in sample
FDA usually requires 2 phase III studies, with p<0.05 for efficacy (if superiority trial)
For “large simple trials” only one large study may suffice (with, say, p<0.01 or p<0.001).

19. Phase II/III Clinical Trials
Phase IIb, Phase II/III Trials
Exploratory, but less so than Phase II
State a specific analysis; if successful, consider study as one of the Phase IIIs (“pivotal”)
If not successful, then consider as exploratory analysis for planning Phase III

20. Phase IV Clinical Trials
Post Marketing Surveillance Trial
Involve the safety surveillance (pharmacovigilance) and ongoing technical support
Required by regulatory authorities or may be undertaken by the sponsoring company for competitive or other reasons
Detect any rare or long-term adverse effects over a much larger patient population and longer time period
Phase IV trials may result in a drug being no longer sold (Harmful effects)

21. Design of Clinical Trials
Study objective
Study design
Sample size
Randomization
Allocation concealment
Blinding

22. Study objective
Researcher and statistician should jointly articulate the objective of the study.
The objective should be clearly defined.
Ex: While drug “X” was testing for hypertension, the bald head patients reported hair growth. (Minoxidil)
In the above situation, the researcher and statistician may get confusion while collecting the data

23. Study design Descriptive studies Analytical studies Case reports
Case series
Population studies
Analytical studies
Survey
Observational
Experimental

24. Descriptive Studies Case report Case series Population studies
A method designed to give a detailed description of a single case
Case series
A method designed to give a detailed description of more than one case
Population studies
This is the observation of a defined population at a single point in time or time interval. Exposure and outcome are determined simultaneously.

25. Descriptive Studies: Uses
Health care planning
Education or prevention and allocating resources more efficiently.
Hypothesis generation
Searching for determinants or risk factors that can be altered or eliminated to reduce or prevent disease.
Trend Analysis
Suggesting associations

26. Analytical studies Survey
It involves measuring a set of parameters in a population group or in a sample of subjects.
It is usually performed with a carefully developed and pre tested QUESTIONNAIRE.
Most effective for estimation of the frequency of parameters

27. Analytical studies Observational Studies Cross-sectional Case-control
Cohort

28. Analytical studies Observational Studies Cross-sectional A “Snapshot”
Data collected at a single point in time
Describes associations
Prevalence
A “Snapshot”

29. Analytical studies Observational Studies Case-Control Study
Start with people who have disease
Match them with controls that do not
Look back and assess exposures

30. Analytical studies Observational Studies Cohort Study
Begin with disease-free patients
Classify patients as exposed/unexposed
Record outcomes in both groups
Compare outcomes using relative risk

31. Analytical studies Experiment design Simple experiment design
Parallel group design
Repeated measures design.
Crossover designs
Factorial design

32. Analytical studies Experiment design Simple experiment design
Subjects assigned as two groups.
Treatment group & Control (or placebo) group.
Treatment assigned to treatment group and no treatment or placebo assigned to control group.
The outcome measures are compared at the end of experiment.

33. Analytical studies Experiment design Parallel group design
* A homogenous group of subjects is selected then subjects are randomly allocated into treatment & control groups.
Ex: Total population = male + female
Then the male & female subjects were separated as individual/parallel groups.
* Disadvantage: Inter-subject variation is not being correlated.

34. Parallel group A B C D 34

35. Analytical studies Experiment design Repeated measures design
* Same as the simple experiment, but the repeated measures were taken in both, the treatment group as well as the control group.
* Here the results are some more accurate than simple experiments.

36. Analytical studies Experiment design Crossover design
* Get two or more treatments successively.
* Time gap - “WASH OUT PERIOD”.
* This method minimizes the “inter-subject variation”; some more accurate than simple experiments.
* Requires less no. of subjects to get meaningful results.
* But the only disadvantage is, increased no. of study periods leads to subject drop outs & longer duration.

37. Analytical studies Experiment design Factorial design A DRUG Level A=0
* To estimate the effect of main treatment & other factors simultaneously.
* In a specific case of 2 treatments A & B,
* The groups taken as:
Given neither A (A=0) nor B (B=0)
Given A alone (A=1) & not B (B=0)
Given B alone (B=1) & not A(A=0)
Given both A (A=1) & B (B=1) A
DRUG
Level
A=0
A=1 B
None
A alone
B alone
A&B both
B=0
B=1

38. Sample Size
If few subjects were chosen, it may not give accurate outcome / the results are not trusty.
If large no. of subjects were taken, then the time span and cost of the study will increases highly.
But “Unfortunately there is no way of guaranteeing an adequate sample size”.
The experienced investigator can only make an educated guess about the suitable adequate sample size.

39. Sample Size How to guess Study objectives and hypothesis
Type I error and Type II error
Precision analysis
Power analysis

40. Randomization
The probability that allows every subject to get equal treatment.
To minimize or avoid bias and errors.
Randomization techniques:
Simple randomization
blocked randomization
Stratified randomization
Factorial randomization

41. Randomization Simple randomization
Like “different color balls drawn from a basket”.
First the subjects satisfying selection criteria are identified.
Later, from the above group subjects are chosen in random manner.

42. SIMPLE RANDOMIZATION
Group.A Group.B 42

43. Randomization Blocked randomization
number of subjects in one group versus the other group are specified, and subjects are allocated randomly within each block..

44. Randomization Stratified randomization
First all the subjects are divided into 2 specific groups (STRATA) on the basis of some predefined factor. So, 2 or more “Stratas” will formed.
Later, from the individual strata, the random samples will be taken& assigned as study groups.

45. STRATIFIED RANDOMIZATION
FEMALE STRATA
MALE-STRATA
Group.A Group.B
Group.A Group.B

46. Randomization Factorial randomization
Ex: Comparison of response pattern with two treatments in depressed as well as non depressed male and female subjects.
Randomize subjects from each type.
Male – Depressed
Male – Non depressed
Female – Depressed
Female – Non depressed

47. FACTORIAL RANDOMIZATIO
SEX
FACTORS
MALE
FEMALE
A B A B D I S E A T
NON DEPRESSED
DEPRESSED

48. Allocation concealment
Protecting the randomization process so that the treatment to be allocated is not known before the patient is entered into the study
sequeBlinding
ntially-numbered
opaque
sealed envelopes (SNOSE)
sequentially-numbered containers
pharmacy controlled randomization
central randomization

49. Blinding Types of studies on the basis of blinding: Open/ No blinding:
Investigator, patient & statistician all are aware of treatment
Single blind
One party, either the patient or the investigator aware of treatment. (Mostly the investigator will be aware.)
Double blind
:Neither the investigator nor the patient are aware of treatment.
Triple blind
Investigator, subject and the statistician is also not aware of treatment

50. Blinding Methods of achieving double blinding:
If two treatments are available in the form of tablets then matching both tablets in terms of colour/shape/size.
If two treatments available in different forms like tablet(A) & capsule(B), then all subjects are given both 1tablet & 1capsule.
Here subjects assigned to treatment “A” will get original drug containing tablet and a placebo capsule.
Subjects assigned to treatment “B” will get original drug containing capsule and a placebo tablet.

51. QUERIES????

52. Thank You!