EXPLORATORY DRUG RESEARCH

:Presented by : Nitisha ThakurClinical Research Unit, Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, SAS Nagar, Punjab

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Exploratory research

Ligand or target

structural informatio

n

Lead developm

ent

Assay development/HTS

Lead modificatio

n/candidate screening

Preclinical

testing

Regulatory drug approval

Clinical trials start

Exlporatory researchPhase I/ Phase II

What is exploratory research…….Exploratory research is research

conducted for a problem that has not been clearly defined.

It often occurs before we know enough to make conceptual decision.

It helps to determine the best  research design, data collection method and selection of subjects

Need for exploratory research in drug development……As it is the first part of clinical drug

development so it helps to defined the hypothesis like tolerability, pk/pd activity in human in which an early indication of therapeutic efficacy is obtained

Main purpose of this research is to formulate problem for more precise investigation or to develop working hypothesis from operational point of view

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• With the help of this study selecting the wrong compound for development can be minimised

Role of exploratory research in drug research The purpose of exploratory

research is to generate data on the base of which decision about future development strategy of drug is well defined.

Target finding:Before any drug discovery and its development , first step is to identify disease , its pathophysiology.

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Target identification: identify the target in that pathway ( gene, enzyme, receptor, ion channel nuclear receptor) Target validation:Test the target and confirm its role in disease studied through complicated experiments

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Identify a lead compound……• Lead compounds are found by

characterizing natural products, employing combinatorial chemistry, or by molecular modelling ..

• Average time to bring a drug to market takes around 12-15 years.

From 20,000 compounds evaluated in animals, 10 make it to human clinical trials, of which 1 goes to market after

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Preclinical studies………..klkkkkinn

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It is a stage of research that begins before clinical trials (testing in humans) can begin, and during which important feasibility, iterative testing and drug safety profile i.e toxicity & efficacy determined in animal model

the main goals of pre-clinical studies are to determine the safe dose for First in human studies and start to assess product's safety profile

both in vitro and in vivo  tests will be performed..

Development process…...• Before any clinical trial begin, sponsor

must file an Investigational New Drug (IND) application with the FDA.

• The application includes the results of the preclinical work, genotoxicity, as well as investigation on drug absorption & metabolism, toxicity of drugs metabolite & the speed with which drug & its metabolites are excreted from body

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• Pharmacological profile of drug• Based on pre-clinical trials, No

Observable Adverse Effect Levels (NOAEL) on drugs are established, which are used to determine initial starting dose in phase 1 clinical trial 

• Animal NOAEL converted to human dose & apply to 10 field margin using formula

HEDmg/kg= animal NOAELmg/kg * (Wanimal/Whuman)1-0.67

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Maximum tolerated dose:

1) The highest dose of a drug or treatment that does not cause unacceptable side effects. The maximum tolerated dose is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found.

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Phase I study/ First in human studies….

Objectives1. To assess a safe & tolerated dose 2. To see if pharmacokinetics differ

much from animal to man 3. To detect effects unrelated to the

expected action4. To detect any predictable toxicity

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Small number of healthy volunteersFirst in a small group of 20 to 25

volunteers Slowly increase the dose to find a safe

tolerated dose

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Goal

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Phase I design:

Ruled based design a) (convential 3+3 design) Model based design

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1)Ruled based design: The rule-based designs assign patients to

dose levels according to prespecified rules based on actual observations of target events from the clinical data. 

the MTD or recommended dose for phase II trials is determined by the prespecified rules as well. 

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2) Conventional 3+3 design This rule-based design proceeds with

cohorts of three patients; the first cohort is treated at a starting dose that is considered to be safe based on extrapolation from animal toxicological data, and the subsequent cohorts are treated at increasing dose levels that have been fixed in advance

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Advantages of 3+3 design:The main advantages of the

traditional 3+3 design are that it is simple to implement and safe

the three patients per dose level provides additional information about pharmacokinetic interpatient variability.

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Model based design:It is statistical models that actively seek a dose level that produces a prespecified probability of dose-limiting toxicity by using toxicity data from all enrolled patients to compute a more precise dose–toxicity curve. 

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Phase II clinical trial:Phase II trials are performed on

larger groups (100-300) with relevant disease and are designed to assess how well the drug works,Therapeutic benefits & ADRs evaluated

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Phase II studies are sometimes divided into Phase IIA and Phase IIB.:

Phase IIA is specifically designed to assess dosing requirements (how much drug should be given).

Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).

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POC: proof of concept: Proof of Principle studies are an

early stage of clinical drug development when a compound has shown potential in animal models and early safety testing.

This step links between phase I phase II studies

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Conclusion : Exploratory research give clear indication

that drug is serious candidate or not Possible to design better molecule with

help of exploratory research Tolerability, pk/pd activity are defined in

man in which an early indication of therapeutic efficacy is often obtained

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These are designed to detect a signal that the drug is active on a pathophysiologically relevant mechanism, as well as evidence of efficacy in a clinically relevant endpoint. 

Used to reduce drug faliure ,drug cost and faliure.

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References : Exploratory research http://

www.ncbi.nlm.nih.gov/pubmed/19601827 accessed on 05/09/2015

Griffin john p,o’gradey john The textbook of Pharmaceutical Medicine fifth edition London 2006

Rang H P Drug Discovery And Development First published London 2006

Phase design http://brb.nci.nih.gov/techreport/phaseIctd.pdf accessed on 06/09/2015

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Proof of concept http://onlinelibrary.wiley.com/doi/10.1002/9780470571224.pse251/abstract accesed on 06/09/2015

Proof of concept http://www.ncbi.nlm.nih.gov/pubmed/16377153 accessed on 06/09/2015Oligonucleotide drugs https://en.wikipedia.org/wiki/Antisense_therapyAccesed on 07/09/2015