new drug dev elopement
TRANSCRIPT
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NEW DRUG DEVELOPMENT
by
Rahul A. Bhalerao (B.pharm)
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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
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GOALS AND OBJECTIVES
Clinical pharmacology and pharmacometrics
Safety
Activity
Effectiveness
Differentiation
Successful FDA submission
Market expansion and post marketingsurveillance
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IS THIS A COSTLY AFFAIR
� Very much so .
� 99% failures
� 500 million $� 15 long years� May fail at any stage
?????
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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
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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
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NATURAL LIGANDS
Examples:
Dopamine- Parkinson- L-dopa
Insulin diabetes exogenous insulin
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Target centered approach
Use biochemical or molecular targetAdv :
� pharmacological activity
� system assay
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STRUCTURE BASED APPROACH
Use 3-D structure of the target obtained through x-raycrystallography or NMR.
Adv :
-potency
-limited number of drugs
Disadv :
-synthesis
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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.
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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.
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REASONS Failure to demonstrate Efficacy Low bioavailability
Extensive metabolism
Low solubility
Toxic effects
Cost effectiveness in synthesis
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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
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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
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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
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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
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TOXICOLOGICAL STUDY
Objectives :
Acute study
Method
Aim : to provide safety/therapeutic index
Observation
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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
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SPECIAL STUDY
Effect on reproductive system and Teratogenicity
Mutagenicity- ames test
Carcinogenicity
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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.
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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
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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.
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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
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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.
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Clinical Trials & Research 26
INFORMED CONSENT
Purpose
Medicine to be
studied
Procedures andschedule
Risks
Potential benefits
Alternatives toparticipation
Confidentiality
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Clinical Trials & Research 27
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.
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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
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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
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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
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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
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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
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PHASE 2A
Pilot study
Dose defining and dose form
Safety and efficacy
PK/PD data Risk benefit ratio
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PHASE 2B
Controlled pivotal study
Placebo
Double blind
Safety and efficacy
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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
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� No fixed time and population
The purpose is usually to support the marketingcampaign
� Rare ADR¶s
� Drug interaction
� New clinical indication (Phase 5)
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Is it safe? Does it work?
Does it
work in
double
blind
trials?
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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)
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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
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Thank you