CLINICAL TRIAL

Definition
According to international conference on harmonization
(ICH):

“Any investigation in human subjects intended to discover

or verify for clinical, pharmacological &/or pharmaco-
dynamic effects of an investigational product &/or to study
“ADME” of an investigational product with the object of
ascertaining its safety &/or efficacy”
 ETHICAL CONSIDERATIONS

In order to protect human subjects, minimize trial misuse &

maximize favorable risk benefit ratio, United States
National Institutes Of Health (NIH) provided 7 ethical
requirements:

1. Social value
2. Scientific validity
3. Fair subject selection
4. Informed consent
5. Favorable risk benefit ratio
6. Independent review
7. Respect for human subjects
1. SOCIAL VALUE

• Before starting CT, make sure they are justified based on

scientific research
• Outcomes of trial will benefit health sciences
• Bring improvement in scientific research
• Resources used to conduct Ct, are all directed towards
meaningful clinical research rather than human
misuse/exploitation

2. SCIENTIFIC VALIDITY
• People should plan methodology which should be
scientifically evaluated or clearly defined
• As expected results & outputs should be statistically
verified
• Before conducting a CT, pre-clinical data should be three
especially toxic studies
• Trial should not be biased

3. FAIR SUBJECT SELECTION

• Subject selection should be based on scientific reasons

rather than convenience like before study design
inclusion/exclusion criteria of subjects
• Only diagnosis of inclusion/exclusion is not important
documentation is also very much important (with reference
of research publication for inclusion/exclusion of subject)
• Exploitation of human is also important
4. FAVORABLE RISK/BENEFIT RATIO (RBR)

• Before trials, RBR should be evaluated

• Some scientific data is require to evaluate our study of
RBR for quotation
• CT subjects Should be subjected to minimal risk &
maximal benefits
• In pre-clinical studies, if doubt is there in RBR, CT can not
initiated

5. INDEPENDENT REVIEW BOARD/INDEPENDENT

ETHICS COMMITTEE (IRB/IEC)

• Also called 3rd party analysis

• It is independent, unbiased analysis
• It is important for trial subject welfare
• This committee has the right if during study they see
some unethical practice or misuse, they can stop the trial &
can change the methodology
• Members of committee have d/f view points for protects
the rights of the subjects
• Constitution of board
1. Clinicians
2. Scientists related with study design
3. Lawyers
4. Layman
5. Religious leaders
7. RESPECT FOR HUMAN SUBJECTS

• Results should be delivered to the subjects as it is

unchanged form

• Protection should be provided to them

• Progress should be closely monitored

• Throughout the study period, if minor damages occur,

don’t overlook but provide tx
 PHASES OF CLINICAL TRIAL
4 phases
PHASE 1

• Phase 1 CT is the 1st experiment in which a drug is tested

on the human being
• The primary aim of the trial is to assess the safety &
efficacy of the new drug
• Other areas of study include pharmacokinetics &
pharmaco-dynamics
• Should take healthy volunteers sometimes may use
critically ill pt when we have to determine RBR
• In phase 1, stipends & financial support is given to the
volunteers
• Phase 1 studies are usually open label study i-e; aims,
objectives & type of study both pt & physician knows
• Range of subjects could be 10-100
• Need to administer drug to pt
• A safe dose of drug is given. Quantity based on pre-
clinical studies of toxicology
• After giving drug, d/f body fluids & specimens ( blood &
urine sample) are checked or taken from pt to evaluate the
kinetics of drug in body
• Physical state of pt should also be determined periodically
like pain, irritability, malaise etc in order to develop good
relationship b/w drug & body behavior
• vital signs like BP, body temp, pulse rate, heart rate should
also be determined
•Phase 1 may take 1-2 yrs
phase 11

• Aim of phase 11 is to determine the safety & efficacy of

drug in targeted disease gps safety & efficacy may alter in
pts
• Drug given in d/f dose range in order to determine
effective & safe dose range of the new drug
• This study needs to have control gp also
• Phase 11 studies could be single blind or double blind
depending upon the type & nature of the study
• Phase 11 gives information about effective dose, dosing
regimen, duration estimation, frequency of dosing
• Clinical markers are reqd which is also called clinical end
points
• 2 types of markers are;
1. Definitive marker
2. Surrogate marker
• Statistically analyzed trial
• # of pts are 50-500
• Take 1-2 yrs or more to complete
Phase 111
• Phase 111 is an extension of phase 11
• Also called multi-site trials like d/f hospitals, d/f
institution, d/f demographic location & d/f ethnic gps
• Additional information about d/f ethnic gps with d/f race,
habits, diet etc
• Phase 111 also referred to as pivotal trial
• Useful for pharma industries to develop new drugs, d/f
strengths, d/f dosage, formulations, tx frequency etc
• # of pts 100-1000 or more
• Industry submit all data to regulatory authority
• Phase 3 duration may be 3-5 yrs
Phase 1v

• Also called post marketing surveillance trials

• Sample population is ↑ed
• Confirmation of all parameters as well as determination
of rare ADR
• Additional info i-e; cost effectiveness, effect of drug on
life style
• If serious events are reported, the drug is recalled or
doctors & pts are notified
 REGULATORY REQUIREMENTS OF CLINICAL TRIAL
1. SPONSORS
• This is the organization or individual that initiates the
clinical trial & finance the study, the organization may
be Govt. dept, pharmaceutical company, university or
individual. Normally, the sponsor is a pharmaceutical
company
• Sponsor’s job is to select the investigator & to prepare an
investigator’s brochure
• Through mutual efforts, they design protocol of
trial/study
• After designing of protocol submit data to review board
for their approval after that it is submitted to regulatory
authority
• There are 13 regulatory issues which should be fulfilled
by both sponsor & investigator
2. INVESTIGATOR

• Investigator is a person who conduct the trial.

• If there is a team in the investigation then there is a

principle investigator and co –investigator.

• Responsibilities
1. To ensure that trial should be according to GCP
guideline.
2. Subject welfare should be respected.
3. He should not be partial.
3. INVESTIGATOR BROCHURE (IB)

• IB is a collection of information prepared and updated by

the sponsor for the investigator .

• Information consist of all relevant data like

physiochemical and biological properties, dosage form,
storage condition ,kinetics' and dynamic etc.

4. INFORMED CONSENT

It is the right of subject to withdraw at any time without

reason without any penalty
5. Protocol

• It is the documents for the conduction of CT

• It contains methodology, # of subjects to be protected, the
markers & end points, statistical methods, protection of
subjects & his managements, frequency of monitoring
Information on protocol
1. Protocol title
2. Names & address of sponsor
3. Name of authorized person ( coordinator)
4. Name of investigator responsible for trial
5. Name of sponsor’s medical expert
6. Name of physician responsible for trial related medical
decision
7. Name of clinical lab & other institution involved in CT
8. Name & description of CT protocol
9. Summary of results from non-clinical study
10. Potential risks & benefits
11. Description & justification of route of administration,
dosage & tx plan

Compliance to GCP

• Description of the population to be studied

• Reference literature & related data
• SOPs
6. INCLUSION & EXCLUSION CRITERIA
• There must be a definitive criteria important to set criteria
to assure uniformity in selection
• Screening of subjects so that to confirm the subjects lab
findings → uniformity → to finalize inclusion

7. Case report form (CRF)

• Subjects related information is gathered in CRF

• Start from pt’s baseline information
• Results of markers, vital signs of pts, hormonal changes,
enzyme conc/level all should be documented
• Comments of pt a/f getting tx
• Comments of investigator observing pt
 PART OF CRF

a) Personal data → name, address

b) Study data → age, gender, race
c) Clinical data → ht, wt, BP, history
d) Lab analysis → lab findings, Hb, cholesterol
e) Other details → comments of pts, physician name etc

8. RANDOMIZATION
A) Randomized Parallel Gp Fixed Dose

Subjects are divided into several gps such as placebo 10 mg,

20mg, & 40mg. Subjects continue with this regimen for the
duration of the trial
B) RPG forced Titration

Subjects are divided into placebo & active gps. Active gps all
start with the same dose for eg 10mg. One gp continue with
10 mg, another gp later ↑es to 20mg, & stays at this dose.
A third active gp than ↑es from 10mg to 20mg & finally to
40mg progressively

C) RPG Optimal Titration

Subjects are divided into placebo & active gps. Active gps all
start with the same dose i-e 10mg. Depending upon the
response & safety assessment, dose can be ↑ed to 20 mg &
then 40mg for selected subjects
D) Randomized Cross Over Design
Subjects are divided into placebo & test
A gp → placebo
B gp → tx
After wash out
A gp →tx
B gp → placebo

E) Randomized Latin Square Design

Tx given in even & odd
Placebo, 10mg, 20mg
Placebo, 20mg, 10mg
10mg, 20mg, placebo
20mg, 10mg, placebo
10mg, placebo, 20mg
20mg, placebo, 10mg
9. MONITORING

Throughout study, pt physical examination effects of drug

& placebo, adverse events, etc are recorded in CRF

10. ADVERSE EVENTS

• Unintended rxns as taking placebo or tx

• Subjects may be removed temporarily
• If AE persists, subjects may be withdrawn from the study
• Randomization code may be opened to determine
whether the subject has been given drug or placebo

11. STATISTICS
Effectiveness can be measured by markers, lab findings,
endpoints all are statically analyzed
12. CLINICAL RESEARCH ORGANIZATION(CRO)
Sponsors contract with organization to monitor the trial
that enhances the validity of trial results

13. SURROGATE MARKERS

Used to predict/monitor the kinetic & dynamic of the drug

GENE THERAPY CT

• FDA requires IND for normal drug trials

• It should be approved by regulatory authority
• Regulations require guidelines that are more strict in this
case b/c rectified gene is incorporated in pt to cure a disease