Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions: In Phase I trials, researchers test a new drug or treatment in a small group of healthy people ( 20 -50) for the first time to evaluate its safety, determine a safe dosage range. In Phase II trials, the study drug or treatment is given to a selected group of patients (100 – 300) to see if it is effective and to further evaluate its safety. In Phase III trials, the study drug or treatment is given to a large group of patients ( 1000 – 3000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely. In Phase IV trials, post marketing studies delineate additional information including the drug’s risks, benefits and optimal use.
Before one can initiate testing in human beings, extensive pre- clinical or laboratory research is required. Research usually involves years of experiments in animal and human cells. If this stage of testing is successful, the sponsor then provides this data to the FDA requesting approval to begin testing in humans. This is called an Investigational New Drug (IND) Application If approved by the FDA, testing in humans begins. This is done through a formally written and approved protocol.
These are very early studies of the pharmacodynamic and pharmacokinetic properties of a potential drug in humans. Microdosing approach could‘accelerate’ drug development without compromising clinical safety Microdosing helps researchers select better drug candidates for clinical trials by providing early human PK and bioavailability data.
The aim of a Phase I trial is to determine the maximum tolerated dose (MTD) of the new treatment. The MTD is found by escalating the treatment dose until the dose-limiting toxicity (DLT) is reached. Kinds of Phase I SAD: single ascending dose studies MAD: multiple ascending dose studies Food Effect: investigates differences in absorption caused by food
Randomization Participants are allocated at random to receive on of several clinical interventions. Control It may be standard practice (an active comparator), placebo or no interventions In sum, RCTs are quantitative, comparative, controlled experiments in which investigators study two or more interventions in a series of individuals who receive them in random order. The RCT is one of the simplest and most powerful tools in clinical research
Clinical Trials and Drug Development
Clinical Trial Phases
Dr. Lokendra Sharma
Clinical trial is a systematic
investigation in human subjects for
evaluating the safety & efficacy of
any new drug.
Clinical trials are a set of tests in
medical research and drug
development that generate safety and
efficacy data for health interventions in
What are Clinical Trials?
Research studies involving people
Try to answer scientific questions and find
better ways to prevent, diagnose, or treat
Translate results of basic scientific research
into better ways to prevent, diagnose, or
Clinical Trials Timeline ( 605 BC - 1986
• 605 - 562 BC :
The first clinical trial was carried out
by King Nebuchadnezzar II .
• 1537 :
It was by chance surgeon Ambroise
The Medical Case, U.S.A. (the Doctors' Trial) 1946-47.
Twenty-three German doctors and administrators accused.
War crimes and crimes against humanity.
Medical experiments and medical procedures on prisoners and
>Twelve series of medical experiments concerning
• Emerged the Nuremburg Code - basic
principles to be observed when conducting
research involving human subjects.
• Subsequently formed the basis for
international guidelines on medical research,
such as the Declaration of Helsinki.
Drug Development Process
• Investigational New drug (IND)
• Pre clinical studies (animal studies)
• USFDA- ask for
– Description of drug
– Preclinical information
– Any previous human study
– Investigators Brochure
– Clinical development plan
– Protocol and Investigator submission for first
Different Phases of Clinical Trials
In Phase I trials, small group of healthy people (
20 -50) the first time to evaluate its safety,
determine a safe dosage range.
In Phase II trials, group of patients (100 – 300)
effective and evaluate its safety.
In Phase III trials,large group of patients ( 1000
– 3000)effectiveness, monitor side effects,
compare it to commonly used treatments, and
In Phase IV trials, post marketing studies
drug’s risks, benefits and optimal use.
Before one can initiate testing in human beings,
extensive pre- clinical or laboratory research is
Research usually involves years of experiments in
animal and human cells.
If this stage of testing is successful, the sponsor then
provides this data to the FDA requesting approval
to begin testing in humans.
This is called an Investigational New Drug (IND)
Preclinical evaluation phase ( animal studies)
Pharmacodynamic studies in vivo in animals, in
Absorption, distribution , elimination studies
Acute ,sub acute, chronic toxicity studies (toxicity
Therapeutic index (safety & efficacy evaluation)
A-Preclinical Data Review : Drug Discovery Team
Efficacy Safety Pharmacology
B-Preparation of Investigator’s Brochure
Summaries of Preclinical data with clinical
Prediction of Clinical Effects & Safety
C–Filing of Investigational New Drug Application
Clinical Evaluation needs Prior
Regulatory and IRB Clearance.
Phase-wise clearances have to be
The End Result of Phase I-III studies is
the filing of NDA (New Drug
Application) for obtaining Marketing
Permission from DCGI.
Microdosing / Phase 0 study
Early studies of the pharmacodynamic and
pharmacokinetic properties of a potential drug in
Microdosing approach could‘accelerate’ drug
development without compromising clinical safety
Microdosing helps researchers select better drug
candidates for clinical trials by
providing early human PK and bioavailability
Microdosing / Phase 0 study
Advantages: Less chances of adverse effects , Short
Less no. of volunteers
Reduced cost of development
Reduced drug development time
Study mainly based on PK parameters - not efficacy and safety
Agents having different kinetic characteristics between
microdose and full dose are not evaluated by phase 0 trials
Of Limited use for agents having Non linear PKs
The laboratory parameters are very limited and expensive,
researchers have to depend on BA/BE labs
First stage of testing in human subjects
Designed to assess the safety, tolerability,
PK and PD of drug.
20-25 healthy volunteers
Patients: Anticancer drugs, AIDS therapy
Duration: 6-12 months
No blinding / Open labelled
Phase 1 Basic pre-requisites
Approval by the regulatory authority
Protocol approval by the Ethics Committee
Adherence to Declaration of Helsinki /ICH-
GCP guidelines, at the start as well as from
time to time, during the study
Phase I Study/ Clinical trial
The aim of a Phase I trial is to determine the
maximum tolerated dose (MTD) of the new
The MTD is found by escalating the treatment dose
until the dose-limiting toxicity (DLT) is reached.
Kinds of Phase I
SAD: single ascending dose studies
MAD: multiple ascending dose studies
Food Effect: investigates differences in absorption
caused by food
Single ascending dose studies (SAD)
Small groups (3) of subjects are given a single
dose of the drug while they are observed and
tested for a period of time.
If no adverse effects ….dose is escalated with 3
new healthy subjects
If toxicity is observed then ---- 3 more subjects
are given the same dose and
If found toxic….. the dose is considered as max.
tolerated dose (MTD).
Multiple ascending dose studies
Conducted to understand the pharmacokinetics
and pharmacodynamics of multiple doses of
A group of patients receives multiple low doses
of the drug
Samples (of blood, and other fluids) are
collected at various time points
Analyzed: How the drug is processed within the
Phase I studies: Need
To make reliable and rapid Prediction of human
response, from Preclinical Data (PD, PK,
Involves Extrapolation from Animal data to first
Phase I serves as an interface between Preclinical
Research and Clinical Drug development.
Once Phase I is complete, Human beings become
first-choice test species (Human Guinea- pigs).
Phase I study: Objectives
1. Primary :
i. Tolerability and Safety
ii. ii. Pharmacokinetics
Phase I Studies: Subjects
Healthy human volunteers: Most commonly
used. (Non-Therapeutic Research)
Subjects receive no therapeutic benefit by
participation - Ethical issue.
Patient Volunteers: Cytotoxic drugs, AIDS
Patients in advanced stage of disease
Phase I: Reasons for Using Healthy
Large numbers available (vs. Patients)
Rapid recruitment rate
Potential risks are considerably reduced
Results not confounded by presence of disease
More homogenous group
Greater compliance with Protocol
In case of ADR’s Chances of Speedy and Complete
recovery are better Advantages > Disadvantages
Phase I: Patient Volunteers
Whenever Preclinical Toxicity Data
indicates potential risks for subjects &
Ethical Concerns preclude use of healthy
human subjects e.g.
Dose range of interest is appropriate to
determine in patients than in healthy
Phase I: Special Population Healthy
It is now a regulatory requirement to
-Women of child bearing age
-Children, if NCE is proposed to be used
-Elderly (>65 years) of age.
Limitations of Phase I
Trial restricted to homogenous
Performance extrapolated to
heterogeneous market place
Therapeutic Exploratory Trial
To confirm effectiveness, monitor side
effects, & further evaluate safety
First in patients (who have the disease that
the drug is expected to treat)
Duration: 6 months to several years.
Phase II: Objectives
Efficacy in patients (primary objective)
Safety issues (secondary objective)
Optimum dose finding
Dose efficacy relationship :
Therapeutic dose regimen
Duration of therapy
Frequency of administration
Phase II studies : Pre-requisites
Review of Phase I data
Prior approval by IRB and DCGI is Mandatory
For New Actions of a marketed drug, start
with Phase II (Phase I exemption obtained)
Phase II Study/ Clinical trial
Phase II Types:
Phase IIA: Designed to assess
Phases IIB: Designed to study
Therapeutic confirmatory trials.
Large scale, multicentre, Randomised, Controlled
Target population: several 100’s to 3000 patients.
Takes a long time: up to 5 years
To establish efficacy of the drug against existing
therapy in larger number of patients, method of
usage, & to collect safety data etc.
Phase III: Objectives
To assess overall and relative therapeutic value
of the new drug Efficacy, Safety and Special
To determine optimal dosage schedule for use in
The dosage schedule in C.T.’s should be as close
as possible to its anticipated clinical use
Phase III : Prerequisites
Efficacy and dose schedule defined in Phase II
No gross ADR’s
Long term preclinical safety studies completed
- Reproductive toxicity
- Marketing inputs favourable
- IRB and DCGI approval obtained
Phase III studies
Phase IIIA: to get sufficient and significant data.
Phase IIIB: allows patients to continue the
treatment, Label expansion, additional safety data.
Phase III B studies are known as "label expansion”
to show the drug works for additional types of
patients/diseases beyond the original use for
which the drug was approved for marketing
• Prior to NDA
• Generates data on safety
• After the NDA but prior
to the approval and
• These may supplement
or complete the earlier
trials or may be
directed to Phase IV
End of Clinical Trial Activities
Sponsor: Expert Committee review of
Efficacy, safety and potential sales
Go-No Go decision to file new drug
application with DCGI
Expert review by DCGI’s Committee
NCE marketed ….. Phase IV begins
NDA: New Drug Application
NDA Refers to New Drug Application
Formal proposal for the FDA/DCGI to approve a new
drug for sale
Sufficient evidences provided to FDA/DCGI to establish:
-Drug is safe and effective.
-Benefits outweigh the risks.
-Proposed labeling is appropriate.
NDA contains all of the information gathered during
preclinical to phase III
NDA can be thousands of pages long
Can take 2-3 years for FDA to review
Phase IV Study / Clinical trial
Harmful effects discovered may result in a drug
being no longer sold, or restricted to certain uses.
On September 30, 2004, Merck withdrew rofecoxib
from the market because of concerns about
increased risk of heart attack and stroke
associated with long-term, high-dosage use.
Phase IV: Objectives
Confirm the efficacy and safety profile in large
populations during practice
Detect the unknown/rare adverse drug reaction/s
Evaluation of over-dosage
Identifications of new indications
Dose refinement: Evaluation of new
formulations, dosages, durations of treatment
Phase IV: Objectives
Evaluation in different age groups / types of
Comparative Benefit-Risk assessment
Benefit-Cost assessment (Pharmaco- economics)
Drug usage in the community
Quality Of Life assessment
REPORTING of ADR
If Health care personal suspects that a particular
medication is associated with an adverse event
observed during the course of caring for a patient, he
can report the ADR to a formal reporting system.
Various reporting systems are:
WHO International System
UK –Yellow card system
INDIA – National Pharmacovigilance Programme
Unexpected SAE Reporting
timelines in India
Site To sponsor: 24 hrs
Site to EC : 7 working days
Sponsor to DCGI: 14 calendar
Sponsor to Other Investigators:
14 calendar days
• Site To sponsor: 24 hrs
• Sponsor to DCGI: 15
Types of Trials
• Open Label Trial – Both Investigator and
Patients knows the full details of the treatment
• Single Blind- Investigator knows the details of
the treatment but patient does not.
• Double Blind- Neither investigator nor patients
is aware of the treatment details.
• Triple Blind- Investigator, Patients and
statistician are blinded
Randomized Controlled Trials (RCT)
• Participants are allocated at random .
• It may be standard practice (an active
comparator), placebo or no interventions.
• The RCT is one of the simplest and most
powerful tools in clinical research
DCGI : (Drugs Controller General of India)
• Approval for marketing
a new drug in India
requires DCGI approval
• Drug approval process
in India is as per
Schedule Y guidelines
• Process is closely
associated with ICH
The journeyThe journey towards becoming an attractive new destination fortowards becoming an attractive new destination for clinical researchclinical research
1992 1996 2000 2004 2008 2012
registered with US FDA
Growth of Indian Clinical Trial IndustryGrowth of Indian Clinical Trial Industry
2002 - 03 2005 - 06 2006 - 07 2007 - 08 2009 - 2010
Growth of Indian Clinical Trial Industry
As per FICCI - Ernst & Young Survey Report 2008, India can attract between 5 - 10% of the
global contract research outsourced market
(all services including chemistry, toxicology and clinical research) over next 5 years.
Clinical Trial Registry India
• An online register of clinical trials
being conducted in India
• Registration with full disclosure of
clinical trials to be conducted in India
• Registration of trial prior enrollment of
An Overview: Drug DevelopmentAn Overview: Drug Development
Clinical Trials from IndiaClinical Trials from India
(www.clinicaltrials.gov; 15 Apr08)(www.clinicaltrials.gov; 15 Apr08)
Phase of trial
India 32 165 394 63
USA 6324 11305 5683 2474
All 8540 16878 11662 6142
Phase-1 Phase-2 Phase-3 Phase-4
Clinical Trial - Phases
Safety & efficacy
Basis for labeling,
effects & efficacy
21 CFR 312.21
Clinical trial is a human experiment designed to study the
efficacy and safety of a new drug/intervention
involves Phase 1-4 with specific objectives and end
Application to Regulatory authority:
IND – Permission to conduct CT • NDA – Permission to
Market New drug
Well designed and effectively executed clinical trials form
the base of therapeutic decisions
CT must follow guidelines & protocol to ensure well-
being of participants