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CLINICAL TRIALSPRESENTED BY
DR.PALLAVI BHAILUMEPG STUDENT
Clinical research design
No intervention InterventionObservational ExperimentalComparison
group
NoYes
Analytical study (case
control, cohort)
Descriptive study
Random allocation
Yes NoRandomize
d controlled
trial
Non-Randomised
Type
s of
exp
erim
enta
l stu
dies
Preventive or prophylactic study –e.g. Study of vaccines or risk
factor
Therapeutic or clinical trials
Community (field) trial -Community wide basis e.g.
fluoridation trial for prevention of tooth decay.
Clinical Trials are the best way to test whether a treatment is effective and better than other treatments (or no treatment).
Randomized controlled trials are best suited for testing new treatments.
STEPS OF A RCT1.Preparing a protocol.
a)The medicine to be researched , selection of patients , diagnostic criteria , dose of drug , duration of treatment , method of randomization , method of blinding , etc.b)Developed and approved before enrollment of subjects from the institutional ethics committee
2.Selection of reference & experimental populations:
Reference population –the population / group to whom an
investigator expects the result to be applicable.
all human beings or subgroups women , smokers etc
Experimental population- actual population in which the study
will be carried out.
INFORMED CONSENT- Legally and ethically to inform
• Medicine its cost , possible toxic effects and benefits.
• By accepting to participate in the study he is willing to subjects himself for new treatment that is under trial.
• He can withdraw from trial without giving any reason and without any fear of loosing the benefits he has received till that time.
3.Randomization –
Statistical procedure by which the participants are allocated in
to groups usually called ‘study’ and ‘control’ group.
Types
A]Simple randomization
B]Systematic randomization
C]Stratified randomization
4.Intervention
Deliberate application or withdrawal or reduction of a suspected
causal factor.
5.Follow up
The period of follow up is predetermined and documented in
the protocol.
6.Assessment
Positive results-benefits –reduced incidence or severity.
Negative results –severity & frequency of side effects and
complication including death.
Bias Selection bias
Bias due to subject variation
Observer bias
Investigator bias
Attrition bias
Good study design - minimizing all possible sources of bias
Blinding Single blind
Double blind
Triple blinding
Open label
Types of study designs Randomized controlled trials
Non randomized controlled trials
Concurrent parallel design
Group getting new medicine continues to get the new medicine and
control group continues to get standard treatment
this is the usual format of rct.
Eligibilit
y assesse
dConsent Randomize
d
Test drug
Control
Cross over type design
a.Each patient gets both drugs the order in which the patient gets
each drug is randomized
b.Each patient serves as his own control
c.Avoids between participant variation in estimating intervention
effect
• Requires a small sample size
A(NEW MEDICINE)
A
B(STANDARD MEDICINE) BA followed by BB followed by A
Run in
Wash out period
Factorial design-
- two or more interventions.
- Allows study of interactive effects.
Disadvantages1. Complexity of trial design2. Complexity of statistical analysis
Clinical trial using historical controls
A new intervention is used in a series of participants and results
are compared to the outcome in a previous series of
comparable population , the historical controls.
Withdrawal study
Participant on particular treatment are taken off therapy or have
dosage reduced.
The study is used to assess response to discontinuation or
reduction.
Group allocation design
Also called cluster randomisation design.
A group of individual , a clinic or community.
Hybrid design
if substantial data is available from historical controls.
Smaller proportion of participants is allocated to either group and
study is conducted to see the effect of medicine.
Double dummy technique
Randomize
Placebo
Placebo
-refers to type of placebo -drugs are adminstered by different routes (e.g.injection nd pills)-In order to keep participants from knowing which treatment arm they are in
Clinical trial is an organized research , conducted on human beings to investigate the safety and efficacy of a drug.
Clinical trial may be done for various purposes.
Common types
• 1.prophylactic trial e.g immunization• Safety trials e.g.side effects of oral
contraceptics & injectacbles
• Therapeutic trials e.g drug treatment , surgical procedure
• Risk –factor trials ,e.g proving the etiology of a disease by inducing it with the agent in animals / withdrawing the agent
NEW DRUG DEVELOPMENT PROCESS
Drug discovery requires two basic steps , i.e. RESEARCH & DEVELOPMENT.
RESEARCH -3 Sequential activities –Target selection , drug selection & product development.
Target selection –a disease to treat and then developing a model for that disease.
Drug selection – finding a drug or group of drugs that work within that model system.
When the compounds with the desired activity are
discovered , the most promising among them are
optimized to produce one or two final compounds that may
eventually become drugs.
DEVELOPMENT –
-Preclinical & Clinical development (clinical trial)
Preclinical development. Performed in the laboratory , using a wide array of
chemical and biochemical assays, cell culture models and animal models of human disease.
Develops -
Pharmacological profile
Acute toxicity
Short-term toxicity studies
Phase -4 years. Investigational New drug application-test –human If regulatory body does not disapprove it within 30days ,
then this application becomes effective and at this stage clinical trial can be initiated.
Phases of clinical trials Clinical trials on patients in different countries are
approved and monitored by different regulatory agencies , which in India , is monitored by Drug Controller of India (DCGI) under Central Drug Standard Control Organization(CDSCO).
Duration – 8-9years
Phases of Clinical Trial
PHASE l
PHASE ll
PHASE lll
PHASE lV
Phase I
First stage of testing in human subjects (20-100).
Designed to assess the initial safety ,maximum tolerance ,
Pharmacokinetics of the drug.
Time period – 3 -6months
Phase II Therapeutic Exploratory Trial. (20-300 Subjects). Efficacy in patients (primary objective) Safety issues (secondary objective) Dose and adverse reaction of drug. 6months to 2years. Phase II
› Phase IIA: Designed to assess dosing requirements› Phase IIB: Designed to study efficacy
Phase III Therapeutic confirmatory trials. (300-3000 subjects). To establish efficacy of the drug against existing
therapy in larger number of patients, method of usage etc.,.
Subtypes› Phase IIIA: to get sufficient and significant data.› Phase IIIB: allows patients to continue the
treatment, Label expansion, additional safety data.
Phase IV
Post Marketing Studies (PMS). Involves safety surveillance. Determine behavior of drug in real life situations. Evaluate action of drug in a situation of missed
dosage or over dosage.
5,000-10,000 compounds
250
5
1 Approved by FDA
Preclinical testing
Clinical testing
REGULATORY FRAMEWORK International ethical and scientific quality standard for
designing , conducting , recording and reporting of clinical trials
International conference on harmonization of technical requirement for registration of pharmaceuticals for human use – good clinical practice : consolidated guidance (ICH-GCP , 1997)
Local regulatory requirements (DCGI) Indian council of medical research (ICMR code , 2000 ) Local ethics review boards (ERBs)
Good Clinical Practice International ethical and scientific quality standard for
designing , conducting , recording and reporting of clinical trials
Rationale Of Good Clinical Practice Legal requirement for conduction of the trial. Protects the rights , integrity and confidentiality of research
subjects. Provides assurance that the data and results are credible and
accurate. Global acceptance of the data.
Ethics Review Board No clinical trial is initiated at any investigator site without
obtaining a written permission by the review board.
Sponsor / CRO
Investigator
Study subjects
REGULATORY AUTHORITY
ERB
Protocol of proposed study.
Informed consent document and its translation in vernacular language
All clinical and non clinical data of investigational product
Study advertisement an investigator’s qualification
Trial permission by DCGI/FDA
Clinical Trial Stakeholder
Conduction of clinical trial Different pharmaceutical companies , Biotechnology
companies , contract research organisation (CRO) , Research/ Academic Institutions and Cooperative Groups.
Sponsor / CRO
Investigator
Regulators
Registry of clinical trial
The Clinical Trials Registry- India (CTRI), hosted at the ICMR's National Institute of
Medical Statistics (http://nims-icmr.nic.in), is a free and online public record system
for registration of clinical trials being conducted in India that was launched on
20th July 2007 (www.ctri.nic.in).
Initiated as a voluntary measure, since 15th June 2009, trial registration in the CTRI
has been made mandatory by the Drugs Controller General (India) (DCGI) (
www.cdsco.nic.in).
References
Park’s textbook of preventive and social medicine Essentials of preventive and commuity dentistry –Soben
Peter. Principles and practice of medical research by dr.J.v.Dixit Mahajan & gupta textbook of preventive and social
medicine Online sources
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