Clinical
studies & Pharmacovigilance
Content
•
Stages
of clinical studies
•
Pharmacodynamic
studies
•
Toxicity
studies
•
Assessment
of safety index
At the
end of this lecture, student will be able to
•
Explain
the stages of clinical studies
•
Describe
Post marketing studies
•
Discuss
the assessment of safety index
Clinical Studies
Clinical trial is a
systemic research of investigating the safety and efficacy of a new drug in
human subjects
•
Establishing
new drugs
•
comparing
with standard treatments trying in different population
•
To study
the pharmacological properties of drugs i.e. pharmacokinetic &
pharmacodynemic
•
To study
toxicological properties of drugs
•
It
represent the scientific way to test individual agents to ensure safety &
effectiveness, as well as compare two or more methods.
•
It can
give information about appropriate route & frequency of administration of
drug in human.
Phases of clinical trial
Phase 0
•
Phase 0
is a recent designation for exploratory, first-in-human trials conducted in
accordance with the U.S. Food and Drug Administration’s (FDA) 2006 Guidance on
Exploratory Investigational New Drug (IND) Studies
•
Also
known as human microdosing studies
•
Administration
of single sub-therapeutic dose of the study drug to a small number of subjects
(10 to 15) to gather preliminary data on the drug’s :
ü
pharmacokinetics
(how the body processes the drug)
ü
pharmacodynamics
(how the drug works in the body)
It gives no data on
safety/efficacy, as the dose is too low to cause any therapeutic effect
Phase-1
•
First time testing
•
In a small group of 20-100
•
Duration
: 6-9 months
Purpose
•
To evaluate
safety & tolerability with the initial administration of investigational
new drug into human.
•
Conducted
in healthy volunteers
•
Drugs
with significant potential toxicity e.g.
Cytotoxic drugs are usually studies.
Studies conducted in
phase-1, usually intended to involve one or a combination of following
objectives:
•
Maximum
tolerated dose: to determine
the tolerability of the dose range expected to be needed, nature of adverse reaction
that can be expectd, in this included both single & multiple dose
•
Pharmacokinetics
: i.e. characterization of
drug’s absorption, disteibution, metabolism, excretion
•
Pharmacodynamics: depending on the drug & endpoint
studies, studies related to drug blood levels may be conducted into healthy
patient or patient with target disease
Phase-2 Therapeutic exploratory trials
Tested
in large group of people
•
100-300
Duration
•
6 month
to 3 year
Purpose
is to further evaluate
•
Effectiveness
of a drug for a particular indication in patients with the condition under
study to determine the common short term side effects & risk associated
with the drug.
•
Additional objectives of phase 2 studies can include
evaluation of potential study endpoints, therapeutic regimens for further study
Classification
•
Phase IIA – to assess dosing requirements (how much drug should be given)
•
Phase IIB – to study efficacy (how well the drug works at the prescribed dose)
Phase 3 Therapeutic
confirmatory trial
Objective
ü
to
gather additional information about efficacy and safety to evaluate overall benefit-risk ratio of the drug
Sample size
•
several
hundred to several thousand(1000 to 3000/more)
•
Duration
: 1 to 4 year
Design
•
randomized
controlled multicenter (can be multinational also)trials
•
sometimes
crossover design is also used
Phase-4 Post marketing trial
•
Post
marketing trial are studies performed after drug approval
•
These
trials go beyond the prior demonstration of drug’s safety, efficacy.
•
These
trials may not be considered necessary at the time of new drug approval but may
be required by licensing authority for optimizing drug’s use
•
Certain rare ADRs/low frequency effects not manifest
in earlier clinical trials because of small study population
•
To study
increase in frequency or severity of known adverse reactions as population of
users expand after drug approval.
•
Study
population in clinical trial not always representative of normal clinical
practices i.e. age, gender, race etc
•
To study
modifiers of efficacy-concurrent drugs, disease severity, pregnancy, lactation,
renal impairment etc.
•
To
compare the incidence of ADRs in humans treated and not treated with the drug
•
Harmful
effects discovered by Phase IV trials may result in a drug being no longer
sold, or restricted to certain uses.
Post marketing surveillance
After the approval of the product, new drugs should
be closely monitored for their clinical safety once they are in marketed, as
per revised Schedule Y, the applicant is required Periodic Safety Update
Report(PSURs) every 6 months for the first 2 years after approval of drug.
Structure of PSURs:
•
Title
page(applicant name data of approval etc)
•
Introduction
•
Current
worldwide market authorization status
•
Update
of actions taken for safety reasons
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Changes
to reference safety reasons
•
Estimated
patient exposure
•
Presentation
of individual case history
•
Studies
•
Other
information
•
Overall
safety evaluation
•
Conclusion
•
appendix
Phase 5
•
new uses for drugs
Summary
•
Clinical trials are experiments or observations
done in clinical research
•
Such prospective biomedical or
behavioural research studies on human participants are designed to
answer specific questions about biomedical or behavioural interventions,
including new treatments
•
Clinical trials generate data on safety
and efficacy
•
They are conducted only after they have
received health authority/ethics committee approval in the country
where approval of the therapy is sought.
