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Process of new drug development & approval
1. Process of New Drug
Development & Approval
Dr. Marya Ahsan (MBBS, MD)
2. Introduction
ā¢ Drug development is a highly complex, tedious, competitive and
costly process
From the synthesis/identification of a candidate molecule, a new drug
development takes at least 10 years and costs 500-1000 million US$
3. Phases in the development of new drug
Synthesis/Isolation
of new compound
Pre-clinical studies
in animals: screening,
evaluation,
pharmacokinetic and
short-term toxicity testing
Scrutiny and grant
of permission for
clinical trials
Pharmaceutical
formulation,
standardization of
the compound
Clinical studies:
Phase I, Phase II,
Phase III
Review and grant
of marketing
permission
Post marketing
surveillance (Phase
IV studies)
(1 ā 2 yrs) (2 ā 4 yrs) (3 ā 6 months) (0.5 ā 1 year)
(3 ā 10 years)(0.5 ā 2 yrs)
5. Approach to drug discovery
The usual approach to drug discovery is to screen a collection of
chemicals (library) for compounds with desired features or to
synthesize new compounds
Computer analysis is used for identifying āhitsā and āleadsā
6. Discovery of potential drug molecule
ā¢ Exploration of natural sources (plants, animals, minerals, micro-organisms)
ā¢ Chemical synthesis of congeners of compounds with known
pharmacological property
ā¢ New classes of drugs can be developed after identification of novel
target of drug
ā¢ Molecular modelling
ā¢ Computational chemistry
ā¢ Recombinant DNA technology
7. Pre-clinical studies
ā¢ Before being administered to people, potential drugs are tested in
two species of animals:
ļ¼One rodent (usually, mouse)
ļ¼One non-rodent (often rabbit)
8. Pre-clinical studies
ā¢ Screening tests
ā¢ Tests on isolated organs, bacterial cultures
ā¢ Tests on animal models of human disease
ā¢ Confirmatory tests and analogous activity
ā¢ Systemic pharmacology
ā¢ Quantitative tests
ā¢ Pharmacokinetics
ā¢ Toxicity tests
Toxicity test include:
ļ¼ Acute toxicity
ļ¼ Subacute toxicity
ļ¼ Chronic toxicity
ļ¼ Reproduction &
teratogenicity
ļ¼ Mutagenicity
ļ¼ Carcinogenicity
9. IND license
ā¢ Before the drug candidate is administered in human subjects in a
clinical trial, the sponsor must file an āInvestigational New Drugā or
IND application with the drug regulatory authority
IND describes in detail the following:
ļ¼Preliminary evidence for efficacy in experiments
ļ¼Complete pharmacology and toxicology of drug
ļ¼Plan for investigating the drug in human subjects
10. Drug Regulatory Authority
ā¢ FDA (Food & Drug Authority) is the drug regulatory authority in the
US.
ā¢ It is established under the Food, Drug & Cosmetics Act
ā¢ It ensures the safety and efficacy of human and veterinary drugs,
biological products, medical devices, food supply, cosmetics and
products that emit radiation
Saudi Food & Drug Authority (SFDA) is
the government agency that
regulates drugs and medical devices
in Saudi Arabia.
11. Clinical trials
ā¢ Clinical trials of drugs are designed to acquire information about the
pharmacokinetic and pharmacodynamic properties of a candidate
drug IN HUMANS
A drug must be proven to be āefficaciousā and āsafeā before it can be marketed
12. Clinical trials
ā¢ Clinical trials are conducted in four phases:
ā¢ Phase I
ā¢ Phase II Establish safety and efficacy
ā¢ Phase III
ā¢ Phase IV Gives additional information
āNDAā application
13. Phase I clinical trials
ā¢ Drug is administered to āhealthy volunteersā
ā¢ Small number of subjects are involved (usually < 100)
ā¢ Emphasis is on safety, tolerability and to detect any potentially
dangerous effects on vital functions
ā¢ Human pharmacokinetic parameters of the drug are measured for the
1st time
14. Phase II clinical trials
ā¢ Drug is administered to āpatientsā
ā¢ Usually 100-500 patients are selected (based on inclusion and exclusion
criteria)
ļ¼Aim is to establish therapeutic efficacy, dose range and ceiling effect
ļ¼Pharmacokinetic data is also collected
15. Phase III clinical trials
ā¢ Randomized double blind comparative trials are conducted in larger
number of patients (500 ā 3000)
ļ¼Safety and tolerability are assessed on a wider scale
ļ¼Pharmacokinetic data is collected
ļ¼Indications are finalized
ļ¼Guidelines for therapeutic use are formulated
16. NDA application
ā¢ After completion of Phase III clinical trials, a āNew Drug Applicationā is
submitted to the licensing authority
ā¢ If the licensing authority is convinced, permission is granted for
marketing the drug
17. Phase IV clinical trials
ā¢ After the drug is marketed, data is collected about efficacy,
acceptability and adverse effects of the drug in the real field situation
ā¢ Very large number of patients are involved including special
populations (children, elderly, pregnant/lactating women and disease
conditions)
Also called Post-marketing surveillance
ļ¼Uncommon/idiosyncratic adverse effects and adverse events on
long-term use are identified
ļ¼Unsuspected drug-interactions are detected
ļ¼Patterns of drug-utilization and additional indications may emerge
21. References
ā¢ Goodman & Gillmanās: The Pharmacological Basis of Therapeutics,
13th edition. New York: McGraw-Hill, 2018
Editor's Notes
Molecular modelling: Computer programmes are used for optimization of structure of candidate molecule
The FDA has 30 days to review the IND application, by which time the agency may disapprove it, ask for more data, or allow initial clinical testing to proceed