Drug Development

process

mohD AjmAl
Dep. oF phArmAcY
 Phases of Clinical Trials
Phase I:
Safety
(15–30 people)

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Phase II:
Safety and Effectiveness
(Fewer than 100 people)

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Phase III:
Effectiveness compared to standard of care; Safety
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(More than 100 to a few thousand)
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Clinical Trials & Research 30

Does it
work in
double
Is it safe? Does it work? blind
trials?
DRUG DEVELOPMENT PROCESS

INTRODUCTION

 A process which applies to drugs, products and protocols to be used on human subjects

 New Drug development is divided into 4 phases

1. 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 marketing surveillance

• Very much so ….

• 99% failures

• 500 million $

• 15 long years

• May fail at any stage

 DRUG DISCOVERY PROCESS…

 Screening consists of testing many compounds in assays relevant to the disease in

 If the compound or its structural derivatives continue to show promise after further biological
and chemical characters….LEAD

 Two basic strategy are applied

1. Compound centered

2. Target centered

Compound centered approach

 Natural products: isolated from plants, animals and microorganisms.

e.g. : Morphine, Quinine, Atropine , Adrenaline, Thyroxin, Penicillin

 NATURAL LIGANDS

Examples:

• Dopamine- Parkinson- L-dopa

• Insulin – diabetes – exogenous insulin

Target centered approach

 Use biochemical or molecular target

 Advantages :

 Pharmacological activity

 System assay

 Structure based approach

 Use 3-D structure of the target obtained through x-ray crystallography or NMR

 Advantages :

-potency
 -limited number of drugs

• Disadvantages :

-synthesis

 Chemical synthesis:

Based on SAR - e.g.: Histamine blockers

Based on enantiomers - e.g:. dopa

• Rational approach:

e.g.: Proton Pump Inhibitors.

• Molecular modeling:

e.g.: COX 2 inhibitors

• Combinatorial chemistry:

• Biotechnology:

ex. Growth factors, cytokines.

 Lead optimization

 Is the stage where physical, chemical, biological and pharmacological properties are
characterized and refined with the ultimate goal of selecting a single molecule to enter into
clinical testing and formal drug development?

 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
for development into products.

 Characterize compounds and their targets

 Are “proof of concept” in nature

 Provide fundamental information on target biological system

 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 DNA mutation:

• Cell free system

Assay of enzyme activity, receptor binding, protein interaction 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

Objectives :

Acute study

 Method

 Aim : to provide safety/therapeutic index

 Sub acute study

aim :

 To identify the target organ

 To determine the clinical parameters

 To estimate the safety margin

Method:

Evaluation:

Chronic study

Similar to sub acute study except for the duration

 Special study

 Effect on reproductive system and Teratogenicity

 Mutagenicity- ame’s test

 Carcinogenicity

 Clinical drug evaluation

 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 for participants

 Terminate the trial when the risk becomes incompatible with the goals of the trial

 Adverse events to be reported immediately to an ethical committee

 Ethics Committees

 The ethics committee reviews a protocol before the study is allowed to start. Their job is to
ensure that the risks of being in the study are not greater than 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 trial protocols for ethical and legal issues

 Also has the authority to approve, modify or disapprove it

 Informed Consent

 Participation in clinical trials is always voluntary.

 Informed Consent

 Purpose

 Medicine to be studied

 Procedures and schedule

 Risks

 Potential benefits

 Alternatives to participation

 Confidentiality

 What is a Clinical Trial?

 Historical Minute
First “Clinical Trials”

 Clinical trials have a long history – even if not acknowledged as Clinical trials

 Formal record of clinical trials dates back to the time of the “Trialists”:

• Dr. Van Helmont’s proposal for a therapeutic trial of bloodletting for fevers [1628]
 • Dr. Lind’s, a ship surgeon, trial of oranges & limes for scurvy [1747]

 COMPONENTS OF A CLINICAL TRIAL

 Review of scientific background

 Written hypothesis/hypotheses to be tested

 Study design

-type

-study population

-statistical analysis

-enrollment of subjects

-intervention

-follow up of subjects

 Organization

 Phases of Clinical Trials

 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

 Participants

 Dose
 Determines safety of the drug

 Involve dose ranging studies to determine toxicity and major adverse effects

 May provide early evidence of efficacy

 End point- toxicity

 Phase 2

 Evaluate 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 3
  Large 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

 Phase 1V (Postmarketing surveillance)

• No fixed time and population

 The purpose is usually to support the marketing campaign

• Rare ADR’s

• Drug interaction

• New clinical indication (Phase 5)

 The Impact of Clinical Trials-Successful

 Some clinical trials have been critical to patient health & provision of health care

 For instance:

o Protocol 076:  HIV perinatal transmission

1st trial of AZT

o Various cancer treatments

o Development of other HIV related medications like PIs

 The Impact of Clinical Trials-Unsuccessful

 Medications did not work as in pre clinical study

 Harmful substance

 Unethical & poorly conducted study (Ex: Gene Replacement Study)

 APPROVAL

 Once all clinical data has been submitted, reviewed and approval is granted to license in market

 Post marketing surveillance

 Approval takes 6 months to 2 years

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