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1. CLINICAL TRIALS
Ravish Yadav

2. • Drug Review Steps
• 1. Preclinical (animal) testing.
• 2. An investigational new drug application (IND) : outlines what the sponsor of a
new drug proposes for human testing in clinical trials.
• 3. Phase 1 studies
• 4. Phase 2 studies
• 5. Phase 3 studies
• 6. Submission of New Drug Application (NDA) is the formal step asking the FDA
to consider a drug for marketing approval.
• 7. FDA reviewers will approve the application or find it either
"approvable" or "not approvable.“
• 8. Phase 4 studies

3. • Micro dosing / Phase 0 study / Preclinical
• These are very early studies of the pharmacodynamic and
pharmacokinetic properties of a potential drug in humans.
• Micro dosing approach could ‘accelerate’ drug development without
compromising clinical safety
• Micro dosing helps researchers select better drug candidates for clinical
trials by providing early human PK and bioavailability data

4. • Identifying a Drug Target: Identifying the appropriate target step in the
biochemical pathway is critical and can determine the chances of
success of the prospective drug molecule.
• Developing a Bioassay: A bioassay is a “live” system that is devised to
measure the effects of a drug. It varies from a cell or tissue culture
system to organs or even a whole living being. For example, a zebra fish
embryo can be used to observe the effects of drugs on bone density,
blood vessel growth, among other systems.
• Screening the drug in the Bioassay: This is a screening test done with
the bioassay to determine the safety and effectiveness of the molecule.
The drug must clear this step.
• Establishing effective and toxic doses: This step involves establishing
the safe and toxic dose ranges. Future studies take cues from here about
the dose ranges to be tested in human
• Filing for an approval as an IND (Investigational New Drug): After all
these steps are cleared the drug is fit for an application to the FDA .

5. • IND Application Filing
• Once preclinical studies have indicated the safety and efficacy of a drug an
IND application has to be filed with the regulatory authorities
• for obtaining regulatory Approval for Phase I, phase II and Phase III clinical
evaluation.
• Contents of IND application
• Preclinical Data (All data from animal studies)
• Information on composition and source of drug
• Chemical and manufacturing information
• Proposed clinical plans and protocol
• Ethical Committee Clearance

6. • Phase I
• First stage of testing in human subjects
• Designed to assess the safety, tolerability, PK and PD of drug.
• 20-25 healthy volunteers
• Duration: 6-12 months
• No blinding / Open labelled

7. • Phase I Study/ Clinical trial
• 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.
• Two types of Phase I Trials
• • SAD: single ascending dose studies
• • MAD: multiple ascending dose studies

8. • 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).

9. • Multiple ascending dose studies (MAD)
• conducted to understand the pharmacokinetics and pharmacodynamics
of multiple doses of the drug.
• 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 body.

10. • Phase I study: Objectives
• i. Tolerability and Safety
• ii. Pharmacokinetics
• iii. Pharmacodynamics

11. • Phase II • Therapeutic Exploratory Trial
• 20-300 Subjects
• 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.

12. • Phase II: Objectives
• Efficacy in patients (primary objective)
• Safety issues
• Therapeutic dose regimen
• Duration of therapy
• Frequency of administration
• Therapeutic window

13. • Phase III • Therapeutic confirmatory trials.
• Large scale, multicentre, Randomized, Controlled trials .
• 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

14. • Phase III: Objectives
• To assess overall and relative therapeutic value of the new drug Efficacy,
Safety and Special Properties
• To determine optimal dosage schedule for use in general .
• The dosage schedule in C.T.’s should be as close as possible to its
anticipated clinical use

15. • NDA: New Drug Application
• NDA Refers to New Drug Application
• Formal proposal for the FDA to approve a new drug for sale
• Sufficient evidences provided to FDA 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
• Can take 2-3 years for FDA to review

16. • Phase IV
• Done after drug has been marketed
• Post Marketing Surveillance (PMS).
• No fixed duration / patient population
• studies continue to collect data about effects in various populations &
side effects from long term use.

17. • Phase IV: Objectives
• Confirm the efficacy and safety profile in large populations during
practice
• Detect the unknown/rare adverse drug reaction
• Evaluation of over-dosage
• Identifications of new indications
• Dose refinement: Evaluation of new formulations, dosages, durations of
treatment

19. Pharmacovigilance
• Pharmacovigilance :is the study of the safety of marketed drugs under
the practical conditions of clinical use in large communities
• Pharmacovigilance: is concerned with the development of science and
regulation in the area of drug safety.
• Pharmacovigilance aims at the detection, assessment and prevention of
adverse effects and other problems related to the use of medicines

20. Aim
• To improve patient care and safety
• To improve public health and safety
• To contribute to the assessment of benefit, harm ,effectiveness and
risk of medicines
• To promote education and clinical training
• To promote rational and safe use of medicines

21. Responsibility
• Aim And Objectives of Pharmacovigilance Aim:- To identifying new
information about hazards as associated with medicines Objective:-
Improve patient care and safety Improve public health and safety
Encourage safe, rational and appropriate use of drugs Promote
understanding, education and clinical training in pharmacovigilance

22. • Adverse event: Any untoward medical occurrence that may present
during treatment with a pharmaceutical product but which does not
necessarily have relationship with the treatment.
• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious
ADR): Any untoward medical occurrence that at any dose:
•Results in death
•Is life-threatening,
•Requires inpatient hospitalization or prolongation of
existing hospitalization,
•Results in persistent or significant disability/incapacity,
or
•Is a congenital anomaly/birth defect.