01 drug development process
TRANSCRIPT
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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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Economical Environment
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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Economical Environment
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.
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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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Pre-Clinical Testing
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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Pre-Clinical Testing
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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Pre-Clinical Testing
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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Clinical Development
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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Clinical Development
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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Clinical Development
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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Clinical Development
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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Clinical Development
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