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DEVELOPMENT OF NEW DRUGS

KARIM YAR ABBASI

LECTURER

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Introduction

At the end of this presentation the reader will be:

Familiar with the drug development process

Familiar with the protections in place for research volunteers

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DISCOVERY OF NEW DRUGS

THE FIRST PHARMACEUTICAL RESEARCHER

Early man used herbal cures, mineral rubs, and animal products in search for more effective treatments.

Research was by trial and error. What worked continued to be used, what didn’t was abandoned.

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DISCOVERY OF NEW DRUGS

MODERN DAY PHARMACETICAL RESEARCHER

Potential new therapies begin with the identification of new chemical compounds

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METHODS USED TO IDENTIFY NEW COMPOUNDS

Alteration of a Known Compound to act on a selected target.

Computer aided molecular design Synthesis of a plant extract Biologic manipulation Screening large collections of

chemical compounds and natural compounds for desired activity

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New Compounds are First Tested in vitro

Researchers evaluate the new compound for it’s potential effectiveness and

The potential side effects it may cause

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Preclinical Testing

Studies are done in vitro with cell cultures and isolated tissues to determine:Pharmacological effectsToxicological effects

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Preclinical TestingIn Vivo Testing in Animals

Done in at least two species of animals One rodent One non-rodent species

Toxicological effects Mutagenicity / Genotoxicity Teratogenicity Carcinogenicity

LD50 (Lethal Dose) The dose which kills 50% of animals tested

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Animal Testing ADME (Absorption, Distribution, Metabolism

and Excretion) Absorption includes route of administration, dosage form, effects of food, % of absorption, and effect of the first pass through the liver. Distribution includes peak and trough tissue concentrations and accumulation in serum, CSF, urine and bile. Metabolism refers to organs and percentages of toxicity and teratogenicity of metabolites. Excretion pertains to quantities and routes

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Preclinical Testing Lasts 3 to 5 years 1 out of every 1000 compounds

developed goes on to human trials Assess safety and biological activity After preclinical testing the

pharmaceutical company applies to the FDA for an Investigational New Drug (IND) application

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Investigational New Drug Application

Becomes effective if FDA does not disapprove it within 30 days.

Shows results of previous experiments. Tells how, where and by whom the new studies

will be conducted Shows the chemical structure of the compound,

how it is thought to work in the body. Lists toxic effects found in the animal studies. Tells how the compound is manufactured. Progress reports on clinical trials must be sent to

FDA annually

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Safety in Clinical Trials

First consideration is the protection of the rights, safety and well-being of the study subject.

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Phase I Testing Description:

Establishes safety and toxicity in humans Short term (up to 1 month) Few healthy volunteers (20 – 80)

Evaluates: Pharmacodynamics (physiologic effects) Pharmacokinetics Bioavailability Bioequivalence Dose proportionality Metabolism

Last One to Two years.

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Phase I Studies:Participant Issues

Less information for informed consent Generally requires over night stays Frequent blood draws for lab work. Least likely to receive therapeutic

dose. No therapeutic benefit to healthy

volunteers.

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Phase II Studies Description

Well-defined subject eligibility criteria Controlled comparisons with either placebo or

active control Short-medium duration (weeks to months long) Larger number of subjects (100-300) Establishes effectiveness of drug for a specific

population and disease First to use subjects with the disease or

condition (not healthy volunteers)

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Phase II Testing Evaluates:

Safety in patients Efficacy/pharmacologic effects Pharmacokinetics (single and multi dose

optional) Bioavailability Drug-disease interactions Drug-drug interactions Efficacy at different doses

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Phase II StudiesParticipant Issues:

Slightly more information for informed consent

Greater chance of therapeutic dose

Study may be placebo controlled Frequent visits with blood draws

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Phase III Studies Description

Broader patient eligibility criteria than in Phase II studies

Studies may have two or three treatment groups

Longer duration (months to years)

Involves hundreds to thousands of subjects

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Phase III Studies

Evaluates Efficacy and safety evaluation in

population subgroups Dosing intervals Drug-drug interactions Drug-disease interactions Risk/benefit information

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Phase III StudiesParticipant Issues More Information for making

informed consent Visits are less frequent and shorter

in duration May or may not receive active drug

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New Drug Application (NDA)

Filed with the FDA after Phase I thru Phase III trials are completed

Contains all scientific information the company has gathered

Typically runs 100,000 pages or more in length

Average FDA review time is 29.9 months

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FDA Clinical Hold

FDA can stop the study from proceeding or stop a trial that has started: For safety reasons If the company fails to disclose

accurately the risks of the study to the investigators

If protocol design is clearly deficient in meeting stated objectives (Phase II and III)

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Phase IV StudiesDescriptionPost-marketing studiesMay involve additional age or ethnic groupsMonitors continued safety in large groupsMust be conducted if the FDA approves the drug on the “fast track” before all pre marketing data is collectedEvaluatesAdverse eventsOther efficacy or pharmacoeconomic dataEpidemiologic data

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Phase IV StudiesParticipant Issues Most information available for the

informed consent Most likely to receive therapeutic

dosage Less rigid inclusion criteria Study drug may or may not be free May be done at their primary care

providers office

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Cost of Developing New Drugs

It costs $500,000,000

to develop one new medication from the laboratory to FDA approval.

Breakdown of Total Costs by Clinical Development Phase

5%8%

15%

72%

Preclinical

Phase I

Phase II

Phase III

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Drug Development Time LineClinical Trials Early

Research/Preclinical Testing Phase

I Phase

II Phase

III Years 6.5 2 2 3.5 Test Population

Laboratory and animal studies

20 to 80 healthy volunteers

100 to 300 patient volunteers

1000 to 3000 patient volunteers

Purpose Assess Safety and biological activity

Determine safety and dosage

Evaluate effectiveness, look for side effects

Confirm effectiveness, monitor adverse reactions from long-term use

Success Rate

5,000 Compounds Evaluated

File IND at FDA

5 Enter trials

File NDA at FDA

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SCHEMATIC DIAGRAM

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Accelerated Development/ReviewHighly specialized process for speeding the development of drugs that promise significant benefit over existing therapy for serious or life-threatening illnessesCan be used under two special circumstances:

FDA determines that safe use of the product depends on restricting its distribution or useApproval is based on laboratory findings or physical signs of effectiveness

Manufacturers must continue testing after approval to show that the drug indeed provides safe therapeutic benefit to the patient

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Compassionate Use Studies

Available only to patients who have no therapeutic alternatives and who are not eligible for clinical trials conducted under an IND

Protocols have limited detail Still must sign an informed consent Still must have IRB approval for

the study

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Conclusion

Developing new drugs is a long costly process

New drugs are tested extensively in the lab and on animals before being tested on human subjects

New drugs must pass through three phases of testing before approval by the FDA

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Questions

THANKS FOR PATIENCE