Clinical trials involve several phases of research to evaluate new drugs and therapies in humans. Phase 1 trials involve small groups of people to determine safety. Phase 2 trials administer the therapy to groups of patients to identify effective doses and further evaluate safety. Phase 3 trials involve large groups of patients and are designed to confirm effectiveness. After approval, Phase 4 trials monitor long-term safety and effectiveness in broader patient populations. Each phase helps researchers and regulators determine whether new therapies should advance in development or be approved for medical use.

1. CLINICAL TRIALS & PHASES
PRESENTED BY : SMRITI THAKUR
M.PHARM (Pharmacology)
Supervisor : Dr. Rahul Deshmukh
Professor

2. INTRODUCTION TO CLINICAL TRIALS
• Definition by WHO: A clinical trial is any research study that
prospectively assigns human participants or groups of humans to one
or more health related interventions to evaluate the effects on health
outcomes.
• Clinical trials may also be referred to as interventional trials.
• Interventions include drugs, cells and other biological products,
surgical procedures, radiologic procedures, devices, behavioural
treatments, process-of-care changes, preventive care, etc. This
definition includes Phase I to Phase IV trials.

3. DRUG APPROVAL PROCESS

4. DRUG REVIEW STEPS
• Preclinical (animal) testing.
• An investigational new drug application (IND) outlines what the sponsor of a new drug proposes for
human testing in clinical trials.
• Phase 1 studies (typically involve 20 to 80 people).
• Phase 2 studies (typically involve a few dozen to about 300 people).
• Phase 3 studies (typically involve several hundred to about 3,000 people).
• Submission of an NDA is the formal step asking the FDA to consider a drug for marketing approval.
• FDA reviewers will approve the application or find it either ‘approvable’ or ‘non-approvable’.
• Phase 4 studies.

5. THE INVESTIGATIONAL NEW DRUG (IND)
APPLICATION
Before a clinical trial can be started, the research must be approved. An investigational new drug or
IND application or request must be filed with the FDA when researchers want to study a drug in
humans. The IND application must contain certain information such as:
• Results from studies so that the FDA can decide whether the treatment is safe for testing in
people.
• How the drug is made, who makes it, what’s in it, how stable it is, and more.
• Detailed outlines for the planned clinical studies, called study protocols, are reviewed to see if
people might be exposed to needless risks.
• Details about the clinical trial team to see if they have the knowledge and skill to run clinical trials.
• The research sponsor must commit to getting informed consent from everyone on the clinical trial.
• They must also commit to having the study reviewed by an institutional review board (IRB) and
following all the rules required for studying investigational new drugs

6. IND REVIEW PROCESS

7. CLINICAL TRIAL PHASES

8. OBJECTIVES OF DIFFERENT PHASES
Objectives of the trials of different phases in the development of drug:
Phase Objective
I The earliest types of studies that are carried out in humans. They are
typically done using small numbers of healthy subjects and are to investigate
pharmacodynamics, pharmacokinetics and toxicity.
II Carried out in patients, usually to find the best dose of drug and to investigate safety
III Generally major trials aimed at conclusively demonstrating efficacy
They are confirmatory trials and, in the context of pharmaceuticals, typically are the
studies on which registration of a new product will be based.
IV Studies carried out after registration of a product. They are often for marketing
purposes as well as to gain broad experience with using the new product

9. PHASE 0 – MICRODOSING PHASE
• Study of new drug in micro-doses to derive pharmacokinetic information in human
before phase 1 trial is called phase 0 .
• Micro-dose: 1/100th of the estimated human dose or maximum of 100 microgram
total dose are administered to healthy volunteers.
• Objective : To obtain preliminary pharmacokinetic data
• The sub-pharmacological doses are not expected to produce any therapeutic or toxic
effects, but yield human pharmacokinetic information.

10. ADVANTAGES
• Less chances of adverse effects.
• Short duration
• Less no. of volunteers
• Reduce cost of development
• Reduce drug development time

11. PHASE I:HUMAN PHARMACOLOGY AND
SAFETY
• First human administration of the drug.
• Designed to access the safety , tolerability , PK and PD of drug.
• 20-28 healthy volunteers
• Dose: lowest estimated dose
• Duration: 6-12 months
• No blinding is done ; study is open label.

12. AIM OF PHASE 1
• The aim of phase 1 is to determine the maximum tolerated dose (MTD) of the new
treatment
• Kinds of phase 1:
SAD-Single ascending dose studies
MAD-Multiple ascending dose studies
Food effect-Investigates differences in absorption by food
LIMITATIONS : Trial restricted to homogeneous subjects.
Performance extrapolated to heterogeneous market place.

13. PHASE II : THERAPEUTIC MONITORING AND
DOSE RANGING
• Therapeutic exploratory trial
• Conducted by physicians who are trained clinical investigators
• 100-500 subjects
• First in patients (who have the disease that drug is expected to treat)
• Aim is establishment of therapeutic efficacy , dose range and ceiling effect
• Duration – 6 months to several years
• Study maybe controlled and randomized and maybe blinded or open label

14. PHASE II STUDY TYPES
• PHASE II –A : Designed to
access dosing requirements.
• PHASE II –B : Designed
to study efficacy.

15. PHASE III : THERAPEUTIC CONFIRMATION
• It is therapeutic confirmatory trial
• These are randomized double blind trials conducted on large population
• Multi-centric trials
• Target population-500 to 3000 patients
• Takes a long time – upto 5 years
• To aim to establish the value of drug in relation to existing therapy.
• Safety and tolerability are assessed on larger scale

16. PHASE III SUBTYPES
• PHASE IIIA : To get sufficient and significant data.
• PHASE IIIB: Allows patients to continue treatment ,label expansion ,additional
safety data.
• PHASE IIIB are also known as ‘label expansion’ to show drug works for additional
types of patients/ diseases beyond the original use for which the drug was approved
for marketing.

17. NDA-NEW DRUG APPLICATION
• A new drug application(NDA) is submitted to the licensing authority(like FDA), who
if convinced give marketing permission.
• Sufficient evidences provided to FDA/DCGI to establish:
i. Drug is safe and effective.
ii. Benefits outweigh the risk.
iii. Proposed labeling is appropriate.
• NDA contains all the information gathered during preclinical to phase1.

18. PHASE IV : POST MARKETING
SURVEILLANCE
• This is post marketing surveillance of a drug to know the rare adverse effects or
those occurring with prolonged use of the drug.
• It provides more information on the drug’s effectiveness and safety in more real life
conditions and either confirm or add indications to a drug’ s label.
• No fixed duration/patient population.
• Helps to detect the rare ADRs ,drug interactions , and also to explore new uses of
drugs.
• Such studies can look at different drug doses and study populations ( e.g varying
ages , ethnic groups )

19. OBJECTIVES OF PHASE IV
• Confirm the efficacy and safety profile.
• Detect the unknown and rare adverse drug reactions.
• Evaluation of over dosage and new formulations.
• Identifications of new indications.
• Reporting of ADR : ADR can be reported to a formal reporting system as:
• WHO International System
• USFDA- Medwatch
• UK-Yellow Card System
• INDIA-National Pharmacovigilance Programme (CDSCO)

20. CONCLUSION
• Clinical trial is a human experiment designed to study the efficacy and safety of
new drug
• Involves phase1-4 with specific objectives and end results.
• Application to regulatory authority:
IND-Permission to conduct CT
NDA-Permission to market new drug
CT must follow guidelines and protocol to ensure well being of participants.
Ultimate goal of drug development.

21. CLINICAL TRIALS DATABASES
WHO: International Clinical Trials Registry Platform
(ICTRP)
ISRCTN registry
clinicaltrials.gov
EU Clinical Trials Register
Pan African Clinical Trail Registry
Links: