Phases of Clinical Trials

Dr Hemant Mittal

What are Clinical Trials
Systematic study of new drug therapy or medical
intervention
Performed in humans
To discover or verify:
Pharmacodynamics (how it works)
Pharmacokinetics (what happens to it)
Therapeutic effects (efficacy)
Adverse reactions (safety)
Form the basis of changing current medical practice
Pre-clinical to human studies - the
transition
On completion of pre-clinical studies,
fewer useful candidate drugs.
Advance to involving testing in
humans.
Registration of compound as an
investigational drug.
Permission obtained for undertaking
studies in humans
 DRUG DISCOVERY & DEVELOPMENT
 Can be divided into two broad classes having
subclasses of their own
1. Drug Discovery
a. Target based design
b. Compound based design
c. Lead optimization
2. Drug Development
a. Preclinical Phase
• Pharmacokinetics in animals
• Pharmacodynamics in animals (Animal models of diseases)
• GLP Toxicology and Safety studies, Calculation of 1st Human
dose
a. Clinical Phase
• Phase I Clinical Trials
• Phase II Clinical Trials
• Phase III Clinical Trials
• Phase IV Studies/Trials
 SEQUENCE OF PHASES OF DRUG DISCOVERY &
DEVELOPMENT
Drug discovery Drug development
Phase Target-based / Lead Pre-clinical Phase I Phase II Phase III
Compound-based optimization develop-
ment

Discovery
Chemistry
Discovery Target Assay Animal models of disease
Biology identificati develop-
on ment and
screening

ADME In vitro meta- Pharmaco- Metabolism

bolism kinetics (human) Drug-drug interactions
(animal)
Toxicology Screening Preclinical GLP Effect on Reproduction and Embryo-fetal
toxico-logy Development,
carcinogenesis
Development
chemistry
Medical Safety Efficacy dose Registration trials
exposure selection

IND NDA
 LIFE CYCLE OF DRUG DISCOVERY,
DEVELOPMENT
Drug discovery & APPROVAL
Drug development Post-
(2-5 years) (5-9 years) approval
regulation

Chem & Compound Biological

End of Phase II meeting

Biol identification & characterization

NDA filed: Regulatory

ANDA filed
optimization

Aprvl for Marketing

Toxicolog Toxicology
y studies

Clinical IND Ph. I Ph. II Ph. III Ph. IV Ph. IV

filed trials trials trials

Manufact Develop manufacturing Manufac- Pharmaco-

uring Develop QA/QC program, turing vigilance
GMP practices begins activity/
Patent
Legal Patent Patent granted expires/
application Generics
available
Phases of Clinical Trials

Clinical trials divided into four phases:

Phase I → Safety & Early Clinical Pharmacology
Phase II → Initial Efficacy & Safety
Phase III → Comprehensive Efficacy & Safety
Phase IV → Post-marketing Studies

Each phase:
Cumulatively exposes greater numbers of
human subjects to the drug
Collects increasing amounts of safety and
efficacy data
 Human Pharmacology or Phase I
Clinical trials

Tests take about a year.

Involve about 20 to 80 normal healthy volunteers
Not included:
Children
Women of child –bearing age – unless nature of
IND necessitates their inclusion e.g. oral
contraceptive study
Elderly
Phase I Clinical trials
Place
• Special testing facilities
• Monitored closely
Physician
• Trained investigator
Criteria for selection of volunteers needs to be
carefully laid down in protocol & strictly adhered to.
To document :
 Determine a safe tolerated dose
 Dose level at which signs of toxicity first appear
in humans
Phase I Clinical Trials

Single or multiple doses.

Dose range and route of administration
established.
Pharmacokinetic data.
Pharmacodynamic data.
Maximum tolerated dose.
Other parameters as necessary.
Determination of Maximum
Recommended Starting Dose (MRSD)
NOEL – No Observed Effect Level
NOAEL – No Observed Adverse Effect
Level
 Preferred by FDA
HED - Human equivalent Dose

HED (mg/Kg) = animal NOAEL x

(weight animal/ weight human)1-b

b=0.67
Maximum Recommended Starting Dose
(MRSD)
Margin of safety = HED x safety factor
(=10)
Differences in toxicity in animals
Unexpected toxicities
Interspecies difference in ADME
Differences in receptor densities or affinities
MRSD
Phase I Clinical trials

Start with low dose

Fraction of the “clean” or “no-effect”
dose – observed in toxicologic studies
Unwritten rule is dose should be 1/25 to
1/100 of the no effect dose in mg/kg. or
(1/3 to 1/5 that which is lethal to 10% of
the animals(LD10) expressed as mg/m2 for
oncology drugs
Patient monitored for adverse drug reactions
Use of PK/PD in early Clinical
Development
In Phase I studies: PK/PD is important in :
Understanding dose–concentration–effect
(pharmacological and toxicological)-relationship
Initial determination of dosing regimens to be
used in Phase II studies
Phase I - Clinical trial

 types of subjects enrolled:

Normal, male volunteers
Patients who are severely ill with disease –
when it is unethical to expose normal volunteer
to test drug
Patients with target disease who are stable and
generally healthy – to evaluate PKs or safety
Data needed to Start efficacy
Study

Determination of primary
efficacy parameter
Clinical endpoint
Surrogate
 Clinical and Surrogate Endpoints

Indication Clinical Surrogate

Endpoint
Hypertension Strokes Decrease blood
Renal damage pressure
Mortality
Diabetes type II Neuropathies Decreased glucose
Nephropathies Decreased HbA1c
Retinopathies

Osteoporosis Fractures Increased bone density

Therapeutic exploratory trial or

Phase II Clinical Trial

Pre requisite – pre clinical data and
phase 1 safety report
Supervised administration
Randomized study comparing new drug
with proto-type drug for the intended
disorder.
Therapeutic exploratory trial or
Phase II Clinical Trial

First opportunity to observe the effect of

long-term administration of the drug to
humans.
Participants should have no health
problems other than the intended disorder.
 Phase II Clinical trial
Purpose
To determine an optimal dose – response range
for the new drug
To verify its efficacy for the intended disorders
Participants also monitored for adverse effects
Phase crucial
 Data used to determine whether to proceed with extensive
studies in large populations
Phase II- Clinical trial

A. Phase II a
Pilot clinical trial
B. Phase II b
Pivotal clinical trial
PHASE II a
PILOT CLINICAL TRIAL
Feasibility trial
Small scale
Often un-blind and open label
Intended to provide experience to
investigator
PILOT CLINICAL TRIAL
OBJECTIVES
 To confirm that trial medicine, procedure
are safe, suitable, and operational.
 Dose range of new drug
 Initial efficacy evaluation of a new drug,
or for new indication
 Determine the duration required
PILOT CLINICAL TRIAL
OBJECTIVES 2

 Evaluation of variables related to clinical

pharmacology
 Estimation of required sample size
 For evaluation of methodology
 Determination of availability of patient
 Exploration of ethical questions
PHASE II b
PIVOTAL CLINICAL TRIAL
Well planned, well controlled trial,
Rigorous demonstration of drug efficacy
Conducted in units with specialist
investigators with experience of particular
indication
Adequate investigational facilities to
monitor safety and efficacy
Doses are usually less than the highest
doses used in phase I
PHASE II b 2

Usually, only 3-4 centers are included

Normally, 10-12 patients should be
studied at each dose-level
May or may not randomized
Open or double blinded trial
Placebo or comparator controlled
Further evaluation of safety,
pharmacokinetic data
Therapeutic confirmatory trial or
Phase III trials
Confirmatory phase
Trials are done to obtain sufficient evidence
about efficacy and safety
Conducted in larger number of patients
In comparison with standard drug/placebo
Phase III
After Phase II studies are completed
Decision of the sponsor to go ahead
Drug evaluted in much larger group of patients
(1000 – 3000)
Randomized, Double blind studies
Comparing new drugs with alternatives
Extremely costly
Difficult to organize
Time consuming (several years)
Phase III
Using data of phase I and II, phase III trials are
designed to minimize errors in placebo effects,
variable disease course, etc.
Double blind, cross over design commonly used
Settings are similar to that associated with the
ultimate use of the drug
Investigators usually clinical specialists
Some toxic effects (immunological) may first
become apparent in Phase III
Phase III
Phase III may also be used to do
pharmacoeconomic analysis

GCP guidelines need to be followed :

- patient group
- data collection methods
- recording information
- statistical analysis
- documentation
Phase III…details
All documents (IB, protocol, CRF, etc.) need
to be approved by regulator/Ethics
Committee

Clinical trial site and clinical investigator

selected, and trained on procedures

Confidentiality statement and financial

agreement worked out and finalized
Phase III
At the end of Phase III, or if results meet
expectations, drug submitted to regulatory
authority for licencing
The dossier needed is a massive . Detailed
compilationof all preclinical and clinical data
obtained
Evaluation by the regulatory authority may take
a year or more
Aspects of submission may have to be clarified
66 % of submissions gain marketing approval
Phase III

New Drug Application (NDA)

Runs in several volumes
All precilinical and clinical data on drug
Priority given to drugs that represent
significant improvements over standard
available drugs
In case of urgency (eg. Anti-cancer drug)
the process may be accelerated
Phase III : objectives

To test the comparative safety, efficacy

and special properties (if any) of new drug
with reference to the old drug/placebo
To determine dosage schedule ( it should
as close as possible to the clinical use)
Interests of regulator and sponsor
Data obtained very component of NDA
application
Phase III studies…
Clinical Trial Co-ordinator

From Clinical Research Unit of Sponsor

Authorized for all clinical trial related activities,

viz :
- Organization
- Management
- Financial aspects
- Study report
Phase III ..requirements
Randomized, Controlled trials (RCT)
Gold Standard in clinical research
Parallel or Crossover design
Investigators meeting : to decide and
ensure uniformity
As multicentric study and data has to be
pooled, designing of CRF and other
related documents must be similar
Phase III…
Large sample size : 1000 – 3000

Adult males (preferably)

Both outpatients and inpatients

Disease criteria to be unifiom

Inclusion / Exclusion criteria very clearly defined

at the outset
Phase III : Statistics…

Inputs from biostatistician

Expected difference in efficacy
Availability of patients
Inclusion/Exclusion Criteria
Expected ; Drop out rate, Withdrawal, Placebo
responders
Interim Analysis: if required
Statistical Analysis
Phase III….Controls

Placebo or standard drug

Placebo : as per regulatory guidelines
Standard drug :
- Registration status
- Current therapeutic status
- PK – PD information
- General marketing inputs (prescriptions..)
Phase III…Efficacy

Changes in subjective and objective parameters

End points :
- Dynamic (primary and surrogate)
- Kinetic
- Biochemical
- Histological

To determine which endpoints are important with

reference to the objective of the study
Phase III…ADRs

Assessment of untoward effects

Common ADRs from symptoms, lab
reports, ECG etc.
Sometimes eliciting information required
Observe : Type, Severity, Duration,
Causality
Report ADR to : Sponsor, Ethics
Committee, Regulator
Phase III..Monitoring
Important component of Phase III trials
To Monitor the following:
- clinical trial supplies
- data entry in the CRF
- collection of completed CRF
- collection of unused rug
- drug supplies inventory check
Regular visits to each of the clinical trial
centres
Phase III…termination
Rescheduling of treatment of trial patients

Collection of CRFs, randomization codes,

unused rug

Storing of CRFs, hospital records, raw

data sheets

Responsibility of clinical trial monitor

Phase III….Audit
Clinical trial audit

Both internal and external

Regulatory authorities (archiving)

Verification of CRFs with raw data

sheets /case records
Phase IV
Begins after approval to market the drug has been
obtained
Monitoring of safety of new drug under actual
condition of use in large numbers
Careful and complete reporting of toxicity
Detect ADR incidences of 1 : 10,000
Also after chronic dosing
Many drugs withdrawn from market during this phase
Phase IV…
Obligatory post-marketing surveillance
May result in limiting drug use or even with –
drawal
Phase IV has no fixed duration
Unsupervised use of the drug in the community
Wider spectrum of use : viz. beyond
inclusion /exclusion criteria, co-morbidities
/drugs, etc.
Phase IV …Objectives
Comparative Benefit-Risk assessment
Drug usage in the community
Quality Of Life assessment
Dose-refinement
Rare ADR’s and long term safety
Benefit-Cost assessment (Pharmaco-
economics)
Improvement in Primary End-points of
disease
Phase IV…Who ?

Pharmaceutical Industry

Specialty Medical Associations

Government organizations

International Agencies
Phase IV…characterstics

Very large sample size

No or little supervision: Physician shopping

Fewer data collected from each patient

Fewer Exclusions (Contraindications only)

Phase IV…charactersrtics
Longer drug administrations

Expensive

Comorbidities and co-medications

Non adherence to treatment: Common

Self-medication common
Types of Phase IV studies
 Prospective studies :
- Extension of Phase III
(Longer drug treatment )

- Comparative Benefit-Risk evaluation

- Comparative Benefit-Cost evaluation

Prospective … Phase IV

- Outcome Studies: Primary End-

points used

- Promotional Trials

- Special Population Groups

Phase IV studies…Types
Observational studies

1. Monitoring Log-term Safety

Prospective and Retrospective

2. Drug Utilization Studies

- Prescribed and Consumption trends
- Impact of National Drug Regulatory
Practices or Treatment
- Guidelines on drug usage
Phase IV…types (contd.)

Observational studies:

3. QOL Assessment Studies

4. Pharmacoeconomic Studies

5. Meta analysis (Statistical inputs based-

Retrospective)
Phase IV…QOL assessment
Impact of the disease or drug on the
quality of life of patients, specially the
elderly
Patients asked about problems,
expectations, improvement
Components of well being assessed :
emotional, social, physical
Questionnaire used to elicit response
(comprehensive method)
Phase IV….Meta analyses

Popular in Phase IV syudies

When results of published clinical trials
are conflicting
Results of similarly conducted clinical
trials are pooled and analysed
Expressed as Odds ration and
Confidence Intervals
Phase IV : ADR reporting
Spontaneous Voluntary Reporting
Case Control Studies
Intensive Hospital Monitoring
Prescription Event Monitoring
Literature Surveys
Prospective population based studies for
rare ADR’s
Automated patient Data Banks
Pharmacovigilance

The science and activities related to ADR

monitoring
National Pharmacovigilance Programme
National, Zonal, Regional and Peripheral
PVig Centres in India
UMC is the international regulatory body
Well structured PVig programme essential
for rational drug use
Summary

Clinical trials are a must for new drug

development
Phase III and IV studies are very crucial
Phase III : focus of sponsor is speedy
delivery to the market
Phase IV : focus is to assess result of
widespread, unsupervised use in the
population