Download therapeutic / clinical trial

AN INTRODUCTION
TO
CLINICAL PHARMACOLOGY
BEFORE STARTING DRUG THERAPY, DOCTORS CONSIDER
 Whether intervention needed ?
 Objective of treatment ?
 Best suitable drug ?
 How to monitor ?
 How to administer ?
 Side effects ?
 When to discontinue ?
 Risk benefit ratio ?
DRUG THERAPY involves a great deal more than matching
the name of the drug to the name of the disease
Requires:
 Knowledge
 Judgement
 Skill and wisdom
 A SENSE OF RESPONSIBILITY
DRUGS CAN DO GOOD
DRUGS CAN DO HARM
Whenever a drug is given a risk is taken
Reduction of drug risk
Better knowledge of drug and disease process: RESEARCH
Site specific delivery and effect : Drug Delivery Systems
INFORMED, CAREFUL AND RESPONSIBLE PRESCRIBING
STEPS : DISCOVERY AND DEVELOPMENT OF DRUGS
Idea or hypothesis
Design and synthesis of substances
Studies on tissues and whole animals- PRECLINICAL STUDIES
Studies in man- CLINICAL STUDIES (Phase I, II, III)
From lab. to pharmacy : 9-12 years & crores of rupees
Grant of an official licence to make therapeutic claims and to sell
Post-licensing (marketing) Phase IV studies of safety and
comparisons with other medicines
Bioequivalence
• Two pharmaceutically equivalent drug products are
considered to be bioequivalent when the rates &
extents of bioavailability of the active ingredient in the
two products are not significantly different under
suitable test conditions.
• For the products which are already available in the
country, the companies conduct only bioequivalence
studies to get drug license
PRECLINICAL STUDIES
 Pharmacodynamics
 Pharmacokinetics
 Toxicology: acute, subacute and chronic
 Special toxicology:
mutagenicity
carcinogenicity
teratogenicity
Phase I
Phase II
Phase III
Phase IV
Exploratory Confirmatory
PMS
Patients
Patients
Patients
Study
Healthy
Population Volunteers
No. of pts. 20-50
50-300
Conducted Clin.Pharm Clinical
by
acologist
Pharmac. &
Clinical
Investigator
Objective  PK
 PK
 Safety
 Safety
 Efficacy/PD
 Dose Range
Bioavail.
250-1000
10000
Clinical
Investigator
Doctors using
drug
 Efficacy
 Safety
 Safety
 Drug use
 Comparison  Comparison
with existing
with existing
drugs
drugs
 New
indications
Bioequivalence
THERAPEUTIC / CLINICAL TRIAL
It is a carefully, and ethically, designed experiment with
the aim of answering some precisely framed question
Aims:
 Whether a treatment is of value
 How great it’s value is/ comparisons
 What is the best method of applying the treatment
and dose
 What are the disadvantages and dangers of the
treatment
STEPS TO CONDUCT A CLINICAL TRIAL
Protocol generation
Selection of investigator and sites
Permissions of drug regulatory authority and institutional
ethics committee
Initiating the trial: recruitment of subjects
Monitoring and data collection
Closing the trial
Feeding the data in the computer
Statistical analysis
Report generation and submission to regulatory authorities
Proceeding to the next step
Common Terms
Statistics, significance and “p” value:
The probability (p) of incurring false positive results is
expressed as significance
Whenever this probability (of a false positive result) is
less than 5 in 100 observations (p<0.05) it is said to
have reached a level of significance
When this probability is less than 1 in 1000 observations
(p<0.001) it is said to be highly significant
Common Terms
Review article :
A review & analysis of available literature for a
particular drug
Prospective study :
Ongoing study of patients receiving drug
Retrospective study :
Compilation & analysis of the records of the patients
who were treated with the drug during a specific
period
Meta analysis
• Collecting numerous trials in a systematic review and
analysing the results by using appropriate statistical
methods to assess benefits or risks that are
sufficiently uncommon that an individual study lacks
the power to detect them
 Drawback : Publication bias
Placebo
 Pharmacologically inert substance (e.g., starch,
sucrose)
 Used to differentiate pharmacodynamic effects from
psychological effects
 Distinguish drug effects from fluctuations in the
disease
Open label trial
• When the patient as well as doctor is aware of the
treatment given & there is no placebo arm
• E.g., Phase IV (Post-Marketing Surveillance)
• Drawbacks :
– Doctor/ patient bias
– For statistical significance, more pts. required
Blinding
• The purpose is to eliminate any bias in reporting of
results
• Single blind trial :
A blind trial is one in which the participant is not
aware of which arm — experimental or control — of
the clinical trial he or she is on
• Double-blind trial:
A clinical trial in which neither the participants
receiving the treatments nor the researchers
administering the treatments are aware of which
group is receiving the experimental treatment.
Randomization
• A process that reduces the likelihood of bias by
assigning people to treatment groups by chance alone
(randomly).
• When groups are created by random assignment,
individual characteristics are less likely to make the
results inaccurate
Control Group
• A group of clinical trial participants that receives the
placebo (placebo controlled) or standard therapy
(active control or parallel group) for a condition while
another group is given the experimental treatment
• The control group serves as a measuring stick to
gauge the effectiveness of the experimental
treatment.
• It is possible to have a placebo group & parallel group
compared with experimental drug in one trial
Cross-Over Study
Patients
50
Drug A
50
Drug B
Wash-out Period/ No drug (e.g., 1-4 wks)
Drug B
Drug A
Usually used in parallel group study, to reduce the
likelihood of selection bias & to re-confirm drug effects
Cohort
• Follow up study of all the patients receiving a
particular drug for estimation of incidence of adverse
effects
• E.g., Phase IV (PMS) study
• Drawbacks :
– Must have at least 10000 pts.
– Can not discover rare events
– Adverse event could be attributed to drug only if, it
does not occur spontaneously in control group
Case-Control Study
• Follow up of a spontaneously occurring adverse event
with a substantial no. of more patients & controls to
establish the the drug as a cause of the adverse event
• Can discover rare drug-induced events
• Drawbacks
– Difficult to establish appropriate control group
– Can not establish incidence of adverse effect
Clinical Evidence Level
• Level Ia : Review (meta-analysis) of
Randomized Placebo-Controlled Trials (RCTs)
• Level Ib : At least one RCT
• Level IIa : At least one placebo-controlled but
non-randomized trial (CT)
• Level IIb : Well designed quasi-experimental
study
• Level III : Comparative, Cohort, Case report,
Case-series
• Level IV : Expert opinion (letter), Anecdotes
Statistical Tests
• Parametric :
Quantitative analysis of objective parameters
(blood pressure assessment)
e.g., Student’s t-test (Paired/ Unpaired)
• Non-Parametric :
Qualitative analysis of subjective parameters
(pain assessment)
e.g., Wlicoxon, Chi-square