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CLINICAL TRIALS OF DRUGS
DESIGN OF CLINICAL TRIALS
by
Mahender.k
M.Pharm 1st yr,(Pharmacology)
Srikrupa institute of pharmaceutical sciences
Velkatta,kondapak,medak.
Andhra pradesh
Under the guidance of
Mr . CHIRANJIB BHATTACHARJEE
M.Pharm (Ph.D)

DRUG DEVELOPMENT
 Drug development is a term used to define the entire
process of bringing a new drug or device to the
market.
It includes:
 drug discovery
 product development
 pre-clinical research (microorganisms/animals)
 clinical trials (on humans)

WHY ARE CLINICAL STUDIES
PERFORMED?
 No chemical can be certified as completely "safe".
Every chemical is toxic at some dosage.
 It is important to estimate the risk associated with
exposure to the chemical under specified conditions
by performing appropriate tests.
 Clinical trials may be required before the national
regulatory authority approves marketing of the drug
or device, or a new dose of the drug, for use on
patients.

WHEN IS CLINICAL TRIAL NECESSARY?
 Assess safety and efficacy of New Chemical Entity
 Assess safety and effectiveness of a different dose
(e.g., 10 mg dose instead of 5 mg dose)
 Assess safety and efficacy of an already marketed
medication or device for a new indication i.e. a
disease for which the drug is not specifically
approved
 To compare the effectiveness in patients with a
specific disease of two or more already approved or
common interventions for that disease

CORE COMPONENTS OF CLINICAL TRIALS
 Involve human subjects
 Move forward in time
 Most have a comparison CONTROL group
 Must have method to measure intervention
 Focus on unknowns: effect of medication
 Must be done before medication is part of
standard of care
 Conducted early in the development of therapies

NY/VIAETC
TAKING PART IN RESEARCH STUDIES:
QUESTIONS TO ASK
 What is study about?
 What are the goals?
 Study sponsor?
 Participant input into
protocols?
 Inclusion criteria?
 Benefits & risks
 Is there an incentive?
 How protected from harm?
 What is required: # study
visit & what occurs?
 What happens after study is
over?
 How results will be
disseminated?

NY/VIAETC
PARTICIPATION IN CLINICAL TRIALS
Why Some Participate:
 Give back to society
 Health care services
 Payment & incentives
 Support
 Others??
Why Some Do Not?
 Mistrust of studies
 Do not want to be “guinea
pig”
 Do not meet criteria
 Cannot give up time for
study visits
 Barriers: long., distance

ETHICS OF CLINICAL TRIALS:
PROTECTION OF PARTICIPANTS
3 ethical principles guide clinical research:
 Respect for Persons: Treatment of person as
autonomous.
 Beneficence: : potential conflict between good of
society vs. individual.
 Justice: Treatment of all fairly & all equally share
benefits & risks.

CLINICAL TRIALS
I. Phase I – Healthy Volunteers
II. Phase II – Target Patient Volunteers
III. Phase III – Larger Number of Patients
IV. Phase IV – After marketing

PHASE 1
 Phase 1 clinical trials are done to see if an
experimental medication or treatment is safe.
 After a treatment is tested in the lab or on animals, it
enters a phase 1 clinical trial that is done with
humans.
 A phase 1 clinical trial usually involves only a small
number of people to determine if a drug or treatment
is safe, and to determine the best dose of a drug and
how it should be given (whether orally or
intravenously).

 It includes:
 1a.single ascending dose
 1b.multiple ascending dose

 SAD : Single Ascending Dose
 small groups of subjects are given a single dose of the
drug while they are observed and tested for a period
of time.
 If they do not exhibit any adverse side effects, and the
pharmacokinetic data is roughly in line with
predicted safe values, the dose is escalated, and a new
group of subjects is then given a higher dose.
 This is continued until pre-calculated
pharmacokinetic safety levels are reached, or
intolerable side effects start showing up
 At this point the drug is said to have reached the
Maximum tolerated dose (MTD).

 MAD: Multiple Ascending Dose studies
 In these studies, a group of patients receives multiple low
doses of the drug
 Samples of blood and other fluids are collected at
various time points and analyzed to understand how the
drug is processed within the body.
 The dose is subsequently escalated for further groups, up
to a predetermined level.

 Parameters known by this
 Cmax
 Tmax
 T1/2
 AUC
 Vd
 Cl
 MRT(Mean Residence Time)

PHASE2
 Mainly used to study
 Safety efficacy and
 Dose fixing
 It includes
Phase2a and
Phase2b

 Phase2a
 Single blind study
 Only 10-15 patients
 GO/NO GO concept
i.e taking /not taking of
drugs
 It takes 9months-2yrs.
 Phase2b
 Double blind study
 200-800 patients
 Similar to phase3
 Determines dose response
relationship
 Conformation of clinic
dose and regimen.
 To find out exact
mechanism of action of
individual drugs.
 It takes 2-3 yrs.

PHASE 3
 Deals mainly about pharmacoeconomics.
 Most of the ADR and D-D interactions are studied.
 Combination testing of the drugs are carried out at
last stages of phase 3.
 In phase III, the drug is evaluated in much larger
numbers of patients—sometimes thousands—to
further establish safety and efficacy.
 Using information gathered in phases I and II, phase
III trials are designed to minimize errors caused by
placebo effects, variable course of the disease, etc.

 Therefore, double-blind and crossover techniques are
frequently used
 Phase III studies can be difficult to design and
execute and are usually expensive because of the large
numbers of patients involved and the masses of data
that must be collected and analyzed.
 The investigators are usually specialists in the disease
being treated.
 Certain toxic effects—especially those caused by
immunologic processes—may first become apparent
in phase III.

PHASE IV
 Phase IV trial is also known as Post Marketing
Surveillance Trial.
 Phase IV studies may be required by regulatory
authorities or may be undertaken by the sponsoring
company for
1. competitive (finding a new market for the drug)
2. To check for drug interactions with other drugs
3. certain population groups such as pregnant women,
who are unlikely to subject themselves to trials

• Careful and complete reporting of toxicity by
physicians after marketing begins is very important.
• Low incidence drug effects will not generally be
detected before phase 4 no matter how carefully the
studies are executed.
• Phase 4 has no fixed duration.
• Adverse effects detected by Phase IV trials may result
in withdrawal or restriction of a drug.

THE IMPACT OF STUDIES
o Some clinical trials have been critical to patient
health & provision of health care.
Other clinical trials have not been as
successful for a variety of reasons:
 Medications did not work as in laboratory
 Loss to Follow-Up of too many patients
 Harmful substance
 Unethical & poorly conducted study

LIST OF WITHDRAWN DRUGS:
 Rofecoxib (Vioxx) 2004 Withdrawn because of risk of
myocardial infarction.
 Thioridazine (Melleril) 2005 Withdrawn from U.K.
market because of cardiotoxicity.
 Pergolide (Permax) 2007 Voluntarily withdrawn in
the U.S. because of the risk of heart valve damage.
Still available elsewhere.
 Cisapride (Propulsid) 2000s Withdrawn in many
countries because of risk of cardiac arrhythmias.
 Thalidomide 1950s–1960s Withdrawn because of risk
of teratogenicity; returned to market for use in
leprosy and multiple myeloma under FDA orphan
drug rules.

RECENT DATA:
 Drug : Teri flunomide {Aubajo}
• Used in the treatment of multiple schlerosis in adults
causes the side effects like
Nausea
Dizziness
Hair loss
Abnormal liver tests
 Reserpidine like binding profile and potential
antipsychotic efficacy include
ZIPRASIDONE,SERTINDOLE are removed recently
from clinical trials due to cardiac depression.

CONCLUSIONS :
 Clinical trials often yield important results that
affect health and well being
 Must follow guidelines & protocol
 Must ensure well-being of participant
 Clinical trials are susceptible to human error
either on part of investigator or patient
 Research is soft science

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