Overview

• History • Definition • Regulatory bodies• In silico and in vitro trials• Pre clinical trials• Phases of clinical trials • Types of clinical trials

History

• James Lind, Scottish physician• First ever clinical trial• Group of sailors – suffering

from Scurvy• Vinegar to cider• Citrus fruits• Discovered Vitamin C can cure scurvy

Definition

• Clinical trials mean a systematic study of a new drug ( therapy protocols, devices ) in human subjects to generate data for discovering or verifying the clinical claims or pharmacological and adverse effects with an aim to determine the safety and efficacy of drugs in question

Regulatory bodies

• U.S.A – Food and drug administration• U.K – Committee on safety of medicine• Japan – Ministry of health labor and welfare• India – Drugs controller general, Govt.of India

FDA 1906 – Interstate transport of adulterated

food and drugs 1938 – Elixir sulfanilamide 1960 – Thalidomide

Safety

Efficacy

Drug development steps

In silico

• Simulator software available• Predict mechanism, metabolism, distribution• Expected to contribute in reduction of animal

use• Disadvantage: applicable only to those areas

which are well understood. Also hepatotoxicity neurotoxicity can not be predicted

In vitro

• Isolated cells, tissues and organs• The National disease research institute- 130

types of tissues for >50 types of disease• E.g.: monoclonal antibodies – cultured cells• Limitation: not available for all the tissues

Normal systemic pharmacokinetic profile (ADME) is absent.

PRE CLINICAL Non human• - Lab• - Animal (rats, rabbits, etc.) Pharmacological studies: to know Biological activity Mechanism of action Selectivity and specificity Drug metabolism

• Toxicity – Acute toxicity Sub acute toxicity Chronic toxicity Including effects on

reproduction, teratogenicity,

carcinogenicity and mutagenicity.

PHASES Phase 0: Pharmacodynamic (PD) and

pharmacokinetics (PK) Phase 1: Screening for safety Phase 2: Efficacy of the drug Phase 3: Final confirmation of safety and

efficacy Phase 4: Post marketing surveillance Phase 5: Translational research

• U.S FDA in 2006• Speed up development of promising drugs• Go / no go decision

Thalidomidetests in pregnant mice, rats, and

guinea pigs were negative.

Cerivastatinsubstantial risk for

severe or fatal rhabdomyolysis.

16

FenclofenacNo animal toxicity in 10 species. Severe

liver toxicity in humans

CisaprideHeart rhythm disturbances in trials, but not in animal studies

5 2

34

TroglitazoneSafe in rats, severe

liver failure in humans.

PhenylbutazoneBone marrow toxicity, phototox & liver tox

only in humans

PenicillinDiscovered in 1929

Not used till 1939 because of its ineffectiveness in curing infected rabbits

Furosemide

Experiments in mice: extensive liver damage

Aspirin

Causes teratogenic malformation in mice, rats, dogs, cats, rabbits and monkeys

Phase 0 or microdose

• Microdosing :• Less than 1/100th of the dose calculated to

yield a pharmacological effect of the test substance based on primary pharmacodynamic data obtained from in vitro and in vivo (typically doses in or below the low microgram range) and at a maximum dose of <100microgram

Objectives of microdosing study To clarify bioavailability and PK profiles To clarify metabolic profiles To obtain information on tissue distribution

18

Basic features First-in-human trial conducted prior to

traditional Phase 1 study Small number of subjects (≈10-15) Limited drug exposure Low, non-toxic doses (<100mcg) Short duration (≈ ≤7 days) No therapeutic intent Eliminate bad agents early (rapid clearance,

poor bioavailability, fails to reach target)

Microdosing trials are not definitive studies

Drug candidates (NME/NCEs)

AnimalmodelsIn-vitroIn-silico

Limited toxicology studies

Human microdose study(Phase 0)

PROCEDURE

• Plasma / urine / biopsy sample serially collected

• Sample analyzed for parent drug and metabolite

• Microdose -> micro plasma drug concentration• Extremely sensitive analytical methods

required

21

POSITRON EMISSION TOMOGRAPHY (PET)

Drug specific receptor ligand labeled with a short lived positron emitting isotope

Distribution of drug and relative concentration at target area over time can be visualized

Info: mostly PD data through real time imaging and limited PK data

Liquid chromatography mass spectrometry

Generate drug concentration data from samples(plasma/ urine) overtime.

Accelerator mass spectrometry AMS works on isotope ratio

method Measures total 14C content As well as 14 C content ratio

of parent drug to metabolite after separation by HPLC

Info: Extent of metabolism measure of first pass effect

10.0

Oral microdose (100 ug)

1.0

0.1 0 1 2 3 4 5 6 7 8 9

Time (h)

ng/m

L pe

r 1 m

g do

semidazolam

Oral 7.5 mg dose midazolam

Parameter Oral dose

t½ 4.0 3.0%F 22 23

0.1 mg 7.5 mg

PK prediction

Study in sensitive population

• Inherent low risk of toxicity: PK studies can be undertaken

34 82% were scalableOrally

administered drugs 11 100% were

scalableIV administereddrugs

LITERATURE REVIEWThere are 45 drugs with data (in peered reviewed literature ) comparing microdose PK to therapeutic dose PK

PHASE 1

Volunteers ( healthy and unhealthy) (10-100) Safety , tolerance Types• - Single ascending dose studies• - Multiple ascending dose studies• - Food effect assessments

Single ascending dose studies (SAD)

• SAD those in which 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 previous

dose is considered as max. tolerated dose (MTD).

Multiple ascending dose (MAD)• MAD are 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

How the drug is processed within the body- analyzed

Food effect studies

• Volunteers are given 2 identical doses of the drug

on different occasion, one while fasting and

another after being fed

PHASE 2 First time in patients with target disease 100-300 subjects Phase 2A (IIA)• - Assess dosing requirements Phase 2B (IIB)• - Study efficacy Study design – case series, RCT

PHASE 3 Compare new treatments with the best

currently available treatment - Confirms its effectiveness - Monitor side effects Randomized controlled multicenter

trials Drug licensing studies (pre-marketing phase) Large study groups (300-3000 subjects)

• Phase IIIA- conducted prior to regulatory

submission of a new drug application.

• Phase IIIB- after submission, but before approval

the new drug.

PHASE 4

Post marketing surveillance Safety surveillance Rare or long term adverse effects over a

much larger patient population Harmful effects discovered by phase IV

trials may result in a drug being no longer sold, or restricted to certain rules.

• E.g.: Rofecoxib

Phase 5

• Used to signify the integration of a new clinical treatment into widespread public health• It is a survey without administration of drug

• Focus is to determine whether or not the therapeutic effect is realized in day to day

clinicalpractice

• To seek additional marketing claims for-new formulation-new indication-new combination

Some example• Phenytoin sodium / lactose• Phenytoin uses• Methyldopa + diuretic combination

Basic features

• No dosing• No patient monitoring• Main focus – new therapy• All reported use• Research on data collected

Phases Dosing Number of subjects

Main goal

0 Sub therapeutic

About 10 PK and PD

IA/IB/IC Ascending dose

20-100 Safety

IIA/IIB Therapeutic dose

100-300 Efficacy

IIIA/IIIB Therapeutic dose

300-3000 Therapeutic use

IV Therapeutic dose

Anyone seeking treatment

Long term effect

V No dosing All reported use

Research on data collected

• Treatment Trials- test experimental treatments, new combinations of drugs, or new approaches to surgery or radiology/radiation therapy.

• Prevention Trials- look for better ways to prevent disease in people who have never had them or prevent them from returning.

• Diagnostic Trials- conducted to find better tests or procedures for diagnosing a particular disease or condition.

• Screening Trials- test the best way to detect certain diseases or health conditions.

• Quality of Life- explore ways to improve comfort and the quality of life for individuals with chronic illness

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