01 drug development process

7/28/2019 01 Drug Development Process

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Drug Development

Process


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Drug Discovery Process

Drugs - & the improved quality of healththey bring to the people are truly

miracles of modern science.

(1)


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What is Clinical Research?

Multidisciplinary, multibillion,

multinational, industry governed by

many complex & interrelatedregulations and guidelines.


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Historical Overview

Thalidomide disaster of the 1960s led topharmaceutical legislation for testing of drugsfor efficacy and safety

Process of clinical testing of drugs hascontinuously evolved, till its present globalharmonization

Emergence of CROs since 1990s has resultedin a shift away from permanent in-house CRstaff to out-sourcing studies or wholedevelopment projects.


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Economical Environment

Governments, the world over, are concernedabout healthcare costs

Growing geriatric population Introduction of modern pharmaceuticals &high technology procedures has an impact onclinical practice, from hospital-based to out-

patient management e.g. peptic ulcers Shortening hospital stay time, e.g. treatment

for myocardial infarction


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Role of Pharmacoeconomics (PE) &improvements in Quality of Life (QoL)

Introduction of complex surgical techniques &diagnostic procedures e.g. MRI haveincreased healthcare costs

Continuing AIDS epidemic, introduction ofnew expensive medicines have increasedstrain on limited financial resources


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Government reaction is to explore waysto either increase revenue or minimize

costs, or both Modern pharmaceutical industry

operates within this environment of cost

control


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Drug Discovery Process

The research process is a complicated,time-consuming,and costly one whose end result is

never known at the outset.Discovering a new drug has been likened tosearching for the proverbial needle in ahaystack.

(3)


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PHASE 1

PHASE 2

PHASE 3

ACCELERATED DEVELOPMENT/REVIEW

TREATMENT IND

PARALLEL TRACKSHORT-TERM

LONG -TERM

PRE-CLINICAL RESEARCH

INDUSTRY TIME

FDA TIME IND SUBMITTED

SPONSER/FDA MEETINGS ENCOURAGED EARLY ACCESS

ADVISORY COMMITTEES E SUBPART E

NDA SUBMITTEDREVIEW

DECISION

SPONSER ANSWERS ANY

QUESTIONS FROM

REVIEW

E

E

E

CLINICAL STUDIES NDA REVIEW

SYNTHESIS ANDPURIFICATION

ANIMAL

TESTING

INSTITUTIONAL

REVIEW BOARDS


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(3)

Literally hundreds, and sometimes thousands, ofchemical compounds must be made and tested tofind one that can achieve that desirable resultwithout too serious side effects.The complexity of the process can be gauged, inpart, by the diversity if scientific disciplines engagedin finding new drugs. Traditional organic and

statisticians have been joined in recent years by newkinds of specialists. Biochemists study the chemistryof life processes. Molecular biologists study themolecules that make up living matter. Toxicologists

investigate chemicals potential for harm.Pharmacologists look at how drugs work. Andcomputer scientists apply the power of theirsophisticated machines to analyze and assess newchemicals. Each provides a different way of looking

for that needle.


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Drug Discovery

The Process

Drug development is a lengthy andexpensive process

It is highly regulated

It is fraught with risks

It brings together people from manydisparate backgrounds & disciplines, allworking towards the same goal


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Drug Discovery

The Goal

To develop a drug that will benefit

patients, satisfy prescribers & earn profits for the company

Drug development is not always

successful, but when it does lead to anew drug available to patients anddoctors, it is a very satisfying endeavor.


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Drug Discovery

A pyramid of uncertainty For over 10000 chemicals screened only

1000 have biological activity

Of these 1000, only 10 will/mayadvance so far as to be administered tohumans

Only 1 will/may reach the market place


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Drug Discovery

A pyramid of uncertaintyApproximate cost to develop a new

drug from concept to market is US$ 350

million Therefore process of drug discovery is

fraught with great uncertainty &

financial burden


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Risk & Reward

The patent life for any new compoundbegins to tick as soon as it is registered

Patent is available fro 20 years fromdate of registration

By the time, the drug is launched only 5

to 10 years of patent life remains tomaximize the return on investment


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Risk & Reward

Therefore the need to complete allactivities within the shortest possible

time, without compromising on quality,rules and regulations


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Legal Environment

Rules & Regulations Pharmaceutical industry is highly regulated

by local country laws, Declaration of Helsinki

(DoH), ICH GCP guidelines & regulatoryauthorities

DoH defines biomedical research in humansubjects

European Agency for Evaluation of MedicinalProducts (EMEA) provides for pan-Europeanregistration


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Legal Environment

Rules & Regulations US FDA controls licensing of new

medicines in the US

Schedule Y of the Drug and CosmeticAct of India is applicable in India

ICH began as an attempt to harmonize

requirements between the US, Europeand Japan


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Legal Environment

Guidelines & SOPs ICH-GCP guideline sets out the obligations of

sponsors, investigators and monitors

All pharma companies and CROs have theirown SOPs based on GCP guidelines

GCP has brought great improvement to theCR process, resulted in greater acceptance

and credibility of data generated GCP is a vital factor contributing to successfuldrug registration


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Evolution of a Drug

Rational drug design (exceptionsildenafil)

Generation of lead compounds

In-vitrotests

Pre-clinical studies

Pharmaceutics (dosage forms)


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Evolution of a Drug

Analytical method development

Clinical Studies/Development

Registration for Marketing Authorization

Post-launch studies and activities


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Pre-Clinical Testing

Carried out to assess safety and biologicalactivity so as to understand therapeutic ratio

of the compound Various types of studies exist: in-vitromodels

to in-vivoanimal studies

For registration purposes a battery of tests is

specified, covering genotoxicity, acute, sub-acute and chronic toxicity, oncogenecity, &fertility and reproduction


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Genotoxicity Potentially harmful effects of the compound

upon genetic material occurring in the DNA

within cells Mutagenic properties may represent a

potential hazard in terms of carcinogenicpotential of the compound

Drugs for topical use are tested for irritation& sensitization potential to the skin


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Toxicity Performed to assess the possible risks of

exposing humans to the compound

Toxic effects caused by drugs in animals areoften predictive of adverse reactions inhumans

Pre-clinical safety aims to establish whether

potential drugs have side effects that mightpreclude or limit their therapeutic use

Provides an indication of potential safetymargins


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Reproductive Toxicology Developmental effects are investigated

to detect abnormalities in the

developing offspring Reproductive toxicology examines

Fertility & general reproductive

performance Teratogenecity study

Perinatal and postnatal study


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Clinical Development

Phase I First administration in humans occurs in

young healthy volunteers Specialist clinical pharmacology units with panels

of volunteers are availableVolunteers are carefully screened to avoid

exposing them to any major risk

Volunteers are paid a reasonable sum for their

participation Other populations may be involved later e.g.

patients with hepatic or renal impairment, orelderly


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Phase I Such studies provide information on

tolerability of a range of doses, PK, &

early dose-response relationshipfindings

Data will also be generated on plasma

concentrations & on PD activity, BA ofthe drug, its clearance mechanisms,metabolites


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Phase II It is the first time that patients are

exposed to the drug

Such studies are conducted in unitswith specialist investigators

Require prior regulatory & ethics

approval


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Phase II Identification of the optimum dose is crucial

These studies attempt to identify the dosethat produces efficacy with minimal side-effects

Short term exposure of the drug, usuallyinclude a placebo control, specialist

investigators will measure surrogateendpoints (disease markers) by blood tests,scans or other means rather than conductstudies for long period of time


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Phase III To assess the real outcome in a variety

of patients who will receive the drug

once launched Regulatory & ethics committee approval

is mandatory

Safety and efficacy determined


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Phase IIIb Conducted for marketing purposes

Studies start pre-launch but are not

intended to form part of regulatorydossier

Typically use market leader ascomparator, hoping to achieve a benefitover the existing drug in order tomaximize performance after launch


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Pharmacoeconomics

QoL scales are included in pivotalstudies to quantify other benefits of the

drug, apart from simple efficacy E.g. Does lowering of BP matter per se,

or should one measure effect of

lowering BP on mortality due to strokeand heart disease?


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Post-launch studies

Drug development program does not ceaseafter the drug has been launched

Pharma companies must have a strategy todevelop new formulations, expand patientpopulation, to seek new indications & to workwith prescribers optimum patient profile.

Case control studies or classical PMS studies

01 drug development process

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