New Drug Dev Elopement

8/6/2019 New Drug Dev Elopement

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NEW DRUG DEVELOPMENT

by

Rahul A. Bhalerao (B.pharm)



A process which applies to drugs, products andprotocols to be used on human subjects.

New Drug development is divided into 4 phases1.Drug discovery

2.Pre clinical development

3.Clinical trial

4.Post approval



GOALS AND OBJECTIVES

Clinical pharmacology and pharmacometrics

Safety

Activity

Effectiveness

Differentiation

Successful FDA submission

Market expansion and post marketingsurveillance





IS THIS A COSTLY AFFAIR

� Very much so .

� 99% failures

� 500 million $� 15 long years� May fail at any stage

?????



DRUG DISCOVERY PROCESS

Screening consists of testing many compounds inassays relevant to the disease in questionHIT

If the compound or its structural derivatives continue

to show promise after further biological and chemicalcharacters.LEAD



Two basic strategy are applied

1. Compound centered

2. Target centered

Compound centered approach

Natural products: isolated from plants, animals andmicroorganisms.

ex. Morphine, Quinine, Atropine

Adrenaline, Thyroxine

Penicillin



NATURAL LIGANDS

Examples:

Dopamine- Parkinson- L-dopa

Insulin diabetes exogenous insulin



Target centered approach

Use biochemical or molecular targetAdv :

� pharmacological activity

� system assay



STRUCTURE BASED APPROACH

Use 3-D structure of the target obtained through x-raycrystallography or NMR.

Adv :

-potency

-limited number of drugs

Disadv :

-synthesis



Chemical synthesis:

Based on SAR - ex. Histamine blockers

Based on enantiomers - ex. dopa Rational approach:

ex. Proton Pump Inhibitors.

Molecular modelling:

ex. COX 2 inhibitors Combinatorial chemistry:

Biotechnology:

ex. Growth factors, cytokines.



LEAD OPTIMIZATION

Is the stage where physical, chemical, biological andpharmacological properties are characterized andrefined with the ultimate goal of selecting a singlemolecule to enter into clinical testing and formal drugdevelopment.



REASONS Failure to demonstrate Efficacy Low bioavailability

Extensive metabolism

Low solubility

Toxic effects

Cost effectiveness in synthesis



DRUG DISCOVERY

Identifies interesting drug compounds, drug targets and

delivery mechanisms with the potential fordevelopment into products.

Characterize compounds and their targets

Are proof of concept in nature

Provide fundamental information on target biologicalsystem

Identify lead compounds for further development



PRE CLINICAL DRUG DEVELOPMENT

Space the gap between drug discovery and clinical trials. Provide data on the safety and efficacy of the product

Includes In vitro study, drug manufacturing,formulation and packaging, In vivo studies



IN VITRO STUDY

Intact cell lines

assess drug effects on cells with specific DNAmutation

Cell free systemassay of enzyme activity, receptor binding, proteininteraction with signal transduction



DRUG MANUFACTURING AND FORMULATION

Conducted under current good manufacturing practices(CGMP) guidelines

IN-VIVO STUDIES

PK study ADME study

PD study Therapeutic index

Toxicological study



TOXICOLOGICAL STUDY

Objectives :

Acute study

Method

Aim : to provide safety/therapeutic index

Observation



SUB ACUTE STUDY

aim :

To identify the target organ To determine the clinical parameters

To estimate the safety marginMethod:

Evaluation:

Chronic studySimilar to sub acute study except for the duration



SPECIAL STUDY

Effect on reproductive system and Teratogenicity

Mutagenicity- ames test

Carcinogenicity



CLINICAL DRUG EVALUATION

AUTHORIZATION

Investigational new drug (IND) submission

-the rationale for the drug and patient group to be treated

-all pre clinical safety and efficacy data

-detailed plan for clinical development

-CIB( clinical investigators brochure)

Submitted to FDA for review and permission to proceed.



ETHICS

Declaration of Helsinki-1964

The clinical trial must minimize the risk forparticipants

Provision for care of the patients

Terminate the trial when the risk becomesincompatible with the goals of the trial

Adverse events to be reported immediately to anethical committee



ETHICS COMMITTEES

The ethics committee reviews a protocol beforethe study is allowed to start. Their job is to ensurethat the risks of being in the study are not greaterthan the potential benefit.



IRB( INSTITUTIONAL REVIEW BOARD) IEC

(INDEPENDENT ETHICAL COMMITTEE)

To ensure the rights and welfare of the participants

FDA regulations mandates to review the clinical trialprotocols for ethical and legal issues

Also has the authority to approve, modify or disapproveit



Clinical Trials & Research 25

INFORMED CONSENT

Participation in clinical trials is always

voluntary.

No, thank you, I¶drather not participate.

Yes, I wouldlike to

participate.




INFORMED CONSENT

Purpose

Medicine to be

studied

Procedures andschedule

Risks

Potential benefits

Alternatives toparticipation

Confidentiality




WHAT IS A CLINICAL TRIAL?

Identify a health question.

Develop a plan.

Enroll volunteers and f ollow the plan.

Study the inf ormation collected.

Share the results with others.

Improve treatment.



Clinical trials have a long history even if not

acknowledged as Clinical trials

Formal record of clinical trials dates back to thetime of the Trialists:� Dr. Van Helmonts proposal for a therapeutic trial of

bloodletting for fevers [1628]

� Dr. Linds, a ship surgeon, trial of oranges & limes for scurvy

[1747]

NY/VI AETC





Review of scientific background

Written hypothesis/hypotheses to betested

Study design-type-study population-statistical analysis-enrollment of subjects-intervention-follow up of subjects

Organization

PROTOCOL





PHASE 0

Recent designation FDA-2006 guidelines

First in humans

100th of the pharmacological dose

Early PK and PD data Minimal pre clinical study

Adv : unreliable in vitro and animal study

Disadv : safety/efficacy



PHASE 1

ParticipantsDose

Determines safety of the drug

Involve dose ranging studies to determine toxicityand major adverse effects

May provide early evidence of efficacy

End point- toxicity



PHASE 2Evaluate efficacy and therapeutic benefit

Involve 80-100 Patients

Identify common short term side effects

Establish dosing regimen and dose optimization

Validate the design of phase 3

Duration : 1-2year



PHASE 2A

Pilot study

Dose defining and dose form

Safety and efficacy

PK/PD data Risk benefit ratio



PHASE 2B

Controlled pivotal study

Placebo

Double blind

Safety and efficacy



PHASE 3Large multi-center Randomized study

Involve 1000-3000 patient volunteers

Placebo controlled blind studies to clearly demonstrate

efficacy, safety and therapeutic benefit

Package insertion and labeling

Adverse drug reactions

Duration: 2-3 years



� No fixed time and population

The purpose is usually to support the marketingcampaign

� Rare ADR¶s

� Drug interaction

� New clinical indication (Phase 5)



Is it safe? Does it work?

Does it

work in

double

blind

trials?



THE IMPACT OF CLINICAL TRIALS-UNSUCCESSFUL

Medications did not work as in pre clinical study

Loss of Follow-Up

Harmful substance Unethical & poorly conducted study (Ex: Gene

Replacement Study)



APPROVAL

Once all clinical data has been submitted, reviewed andapproval is granted to license in market

Post marketing surveillance

Approval takes 6 months to 2 years



Thank you

Documents

New Drug Dev Elopement