Advanced Pharmacology-I(PHR5001)

Lecture 2:Drug Development

Dr. M G AzamAsstt. Professor

Dept. of Pharmacy, NSU1

Drug Development Process• Discovery and formulation: Synthesis of a potential new drug

molecule and an understanding of its interaction (mechanism) with the

appropriate biologic targets. Repeated application of this approach leads to

compounds with increased potency and selectivity

• Preclinical evaluation: Relevant biologic effects, drug metabolism,

and pharmacokinetic profiles and particularly an assessment of the

relative safety of the drug must be characterized in animals before

human drug trials can be started.

• Clinical evaluation -Phases I-IV: With regulatory approval,

human testing can then go forward in three phases before the drug

can be considered for approval for general use.2

Basic Disciplines of Drug Development• Chemistry, Manufacturing, and Controls– Discovery (serendipity, folk medicine, random

screening, rational drug design)– Chemistry (synthesis, purification, scale-up)– Analytical (chemical structure and activity, excipients,

purity and stability)– Pharmaceutical (dosage form, route of administration,

packaging and labeling)– Good Manufacturing Practice (GMP):• Guidelines related to manufacturing practices and specifications• Focus on impurities• Necessary to ensure quality of drug product (finished dosage form)

and drug substance (bulk ingredients)3

Basic Disciplines of Drug Development• Nonclinical– Testing in laboratory (in vitro) and in animal models

(in vivo) to assess safety and efficacy– Objectives:• To develop the pharmacological profile• To determine the acute toxicity in at least 2 animal species• To assess toxicity with studies ranging from 2 weeks to several

months

– Good Laboratory Practice (GLP):• Guidelines related to studies in animal models• To ensure the quality and integrity of data by establishing basicstandards for the conduct and reporting of nonclinical safety studies4

Basic Disciplines of Drug Development

• Clinical Investigation– Submission of the Investigative New Drug (IND, a request for

permission from FDA to begin testing)

– Conduct of Clinical Studies of the product in humans (in healthy volunteers or in patients)

• Phase 1• Phase 2• Phase 3• Phase 4 (post-marketing studies)

Takes an average of 6 years to complete the first three stages

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Drug Development Process

A view on the process from the idea to the registered pharmaceutical

I. DISCOVERY

Drug discovery is the process by which new candidate medications are discovered. Identification of target and resource

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Target identification- Area of interest in terms of drug indication ?- Relevant cellular or molecular targets ?- Appropriate assays – established or to be developed ?- Available relevant literature ? - Patent situation in the target area ?

I. DISCOVERY

Resource identificationPotential resources for novel drugs:

- Natural organisms (plants, fungi, bacteria, animals)- Combinatorial chemistry- Structure-based drug design

Methods for drug discovery:- High throughput screening (HTS) of random samples : large

libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novel GPCR, compounds will be screened for their ability to inhibit or stimulate that receptor .

- Ethnobiological approach: Traditional use of natural organisms for medicines

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Identification of drug targets

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Resource identification - Natural organisms, in particular plants

- 52% of the drugs approved in the U.S. from 1981-2002 were natural products or derived from them

- 26 plant based drugs were approved during 2000-2006, including novel-molecular based drugs - In the future multicomponent botanical therapeutics will

experience an increasing interest in biomedicine

I. DISCOVERY

Medicinal plants continue to play a significant role as a resource for the discovery of novel drugs.

Method of drug discovery - Ethnobotanical approachSystematic screening of:

- Published literature on traditional medicinal plant use (e.g. documented traditional healers‘ experience)Advantages: - Preselection of potentially active resources

- Promising safety profile (age-long experience)- Cost-efficient and comparatively fast 10

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Process development – in phytopharmacy

Herbal raw material Extraction solvent

Extraction

Miscella (Liquid raw extract)

Encapsulatable massDry extract Liquid extract, tincture

Soft capsulesLiquids, drops, ointments

Tablets, hard capsules

II. HIT GENERATION: RESEARCH AND DEVELOPMENT

Development of the test substance Define: - Active substance (in phytopharmacy: native extract)

- Dosage formEstablish: - Physico-chemical profile (pKa, and solubility; permeability) of active compoundsInvestigate: - Pharmacology, - Mode of action 13

Preclinical development

In vitro profiling:- Biochemical assays (e.g. enzyme activity assays)- Cell culture assays (e.g. cancer cell lines)- Isolated tissue assays (e.g. mucosa model)

In vitro toxicology:Investigate potential toxic effects in bacteria- or cell cultures

II. HIT GENERATION: RESEARCH AND DEVELOPMENT

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What is a Preclinical Trial/Testing?• Preclinical trial - a laboratory test of a new drug or a new

medical device, usually done on animal subjects, to see if the hoped-for treatment really works and if it is safe to test on humans.

• Many preclinical tests include pharmacokinetics - the study of how drugs move through living organisms.

• Four processes are examined in pharmacokinetic studies: absorption, distribution, metabolism, & excretion• Other tests include chemistry tests on purity, stability, and shelf life of product, as well as development studies on dosing, packaging, & administration (tablet, injection, etc…)

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Preclinical development

In vivo testing Animal model (mouse or rat)

Drug action: - Behaviour and reaction- Physiology- Histopathology

Toxicology: - Acute toxicity- Subchronic toxicity- Tissue specific toxicity- Tolerability

Consider ethical aspects (e.g. number and kind of animals used)

III. LEAD GENERATION: RESEARCH AND DEVELOPMENT

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To develop the pharmacological profile• To determine the acute toxicity in at least 2 animal species• To assess toxicity with studies ranging from 2 weeks to several months

Objectives:

long-term carcinogenic effects or toxic effects on mammalian reproduction

Heart, lungs, brain, kidney, liver and digestive system

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Preclinical development (continued)

Pharmacokinetic studies What does the body to the drug ?Investigate: - Liberation

- Absorption- Distribution- Metabolism- Excretion

Pharmacodynamic studies What does the drug to the body ?Investigate: - Physiological effects

- Drug action- Relationship between drug concentration & effect

III. LEAD GENERATION: RESEARCH AND DEVELOPMENT

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The main goals of pre-clinical studies are to determine a product's ultimate safety profile

Steps in Doing a Pre-Clinical Trial

• Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease.

• Scientists use a variety of techniques to identify and isolate individual targets to learn more about their functions and how they influence disease.

• Compounds are then identified that have various interactions with the drug targets that might be helpful in treatment of a specific disease.

Step One: Get an idea for a drug target.

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Step Two: Develop a BioassayA Bioassay is a “live” system that can be used to measure

drug effect.

• It may be a culture of cells or organs or a whole animal.

For example:– Zebra-fish embryos - you can

see effects of drugs on bone density, blood vessel growth and many other systems of the zebra-fish.

Steps in Doing a Pre-Clinical Trial

• This is the actual test of the drug on the chosen bioassay.

• This will determine if the drug is SAFE and if it is EFFECTIVE in the bioassay (BEFORE it is ever tested on humans!)

Step Three: Screen the drug in the Bioassay.

Steps in Doing a Pre-Clinical Trial

IND must show how the drug:– Is manufactured.– Appears (color, solubility, melting point,

particle size, moisture content).– Formulated (pills, liquid, etc. + inactive ingredients).– Will be analyzed for purity, concentration, stability.– Will be tested for safety (this will be the basis for allowing first

use in humans).

Step Five: Application is made to the Food and Drug Administration (FDA) as an Investigational New Drug (IND).

• Most drugs have a toxic level or an amount at which the drug will becomeharmful instead of helpful.

Step Four: Establish what dosage amount of the drug is safe and what dosage amount of the drug is toxic.

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Preclinical Information Required Before A Preclinical Information Required Before A Selected Drug Candidate Can Be Selected Drug Candidate Can Be

Administered To HumansAdministered To Humans

• Pharmacological activity• Pharmacokinetics and drug

metabolism• Toxicology• Pharmaceutics

Decision to proceed to man only after thorough characterisation of dose/concentration response relationships of candidate compound in vitro and in vivo

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PHARMACOKINETICS AND DRUG METABOLISMPHARMACOKINETICS AND DRUG METABOLISM

– PK of drug in rodents, dogs and primates as predictor of the human situation

– PK in animals is an essential part of drug selection to define the desired kinetic profile for a drug eg. half-life and bioavailability

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Pharmacokinetics in Preclinical SpeciesSingle dose administration, IV & P.O. in safety species and pharmacology model (usually rat, dog, monkey)•Purpose

–Ensure good bioavailability and exposure in safety assessment species to enable further evaluation in safety assessment studies (adequate exposure margins for human studies)

–Utilize data for prediction of human PK–Understand the relationship between PK and efficacy in animals

•Data Obtained–Area under the Curve (AUC, µM·hr): Area under the plasma concentration-time curve – reflects exposure

–Bioavailability (F, %): fraction of drug entering systemic circulation–Clearance (CLp, mL/min): vol of plasma cleared of drug per unit time–Volume of Distribution (Vd, L/Kg): measure of drug distribution in body–Half life (t1/2, hr): time taken for the drug concentration in plasma to be reduced by half.

–Cmax, Tmax: maximum plasma concentration; time to reach maximum plasma concentration

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Challenges and opportunities in Early Clinical Drug Development

Understand the drug in context of;• the disease

– How to measure– The chemistry/pharmacology– What causes the disease– How does the disease evolve

• the patient– What different phenotypes exists– Are there different Genetic profiles

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Preclinical Testing

• Assess primary safety, biological activity, and

therapeutic ratio

• In vivo animal models

• In vitro physiological models

• 1 in 10,000 compounds pass

• 3.5- 4 years to develop compound29

Review: Steps to New Drug DiscoveryPre-Clinical Trials

Get idea for drug target

Develop a bioassay

Screen chemical compounds in assay

Establish effective and toxic amounts

File for approval as an Investigational New Drug (IND) (leads to clinical trials)

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Lecture 3:

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Drug Safety Assessment

Clinical Trials &

PurposeIs drug SAFE AND EFFECTIVE???

•Predict Toxic Effects•Determine Safe Dosage•Determine efficacy (effectiveness)

Clinical Trials

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Clinical trials are a process of testing products prior to approval of a drug or treatment plan for widespread use in humans.

Phase I Clinical Trials

• Determine primary safety and the maximum-tolerated

dose in humans

• Usually involve a single administration of the product or

a placebo

• Normal, healthy volunteers (20-100)

• identify side effects

• Usually last 6 months to 1 year (30% of drugs fail Phase

1 testing)

33Determine ADME and pharmacological action of drug in humans

FINDINGS LIKELY TO LEAD TO PROJECT TERMINATIONFINDINGS LIKELY TO LEAD TO PROJECT TERMINATION• Poor tolerability at therapeutic concentrations• Unsatisfactory kinetics/metabolism• Low potency• Absence of efficacy

PK REASONS FOR STOPPING DRUG DEVELOPMENTPK REASONS FOR STOPPING DRUG DEVELOPMENT

• Half-life (t ½) too short or too long• Poor bioavailability• Inconsistent bioavailability with low therapeutic index34

FACTORS TO BE CONSIDERED IN DECIDING THE STARTING DOSEFACTORS TO BE CONSIDERED IN DECIDING THE STARTING DOSE• Maximum no effect dose/exposure in toxicity studies using

most sensitive species• Nature & severity of toxicity seen in animals• Slope of dose-response curve

Phase II Clinical Trials

• Evaluate effectiveness, examine adverse effects,

and select optimal dose• Involve patients who have the indicated disease

or condition• – Small patient population (100-300)• – Usually last 2 years (37% of drugs fail Phase 2

testing)

Study design: - Dosage comparison

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Phase III Clinical Trials• Large-scale studies aimed at verifying efficacy establishing long-

term safety & establish optimal dose and establishing the optimum dosage

• monitor side effects• compare it to commonly used treatments• Interactions (with other meds)

– Involve a larger number of patients (500-2000)

– Usually last 3 years (6% fail Phase 3 testing)

- Apply for a New Drug Application (NDA): 80% of an NDA is clinical data. About 80% of drugs that make it to Phase III studies get approved

Overall aim of Phase III: Risk-benefit evaluation

Study design: Comparison to placebo or to standard therapy36

Phase IV Clinical Trials

• Post-marketing surveillance

• Long-term safety and efficacy in large patient

populations

• New indications for use

• Special disease-state and populations

• Drug interaction studies

• Pharmacoeconomic studies

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Phase IV•after the drug or treatment has been marketed•collect information about their effect in various populations •side effects associated with long-term use. •New indications: important for company to extend its patent protection. •Eg. Prozac – antianxiety, approved recently for PMDD (premenstrual dysorphic disorder)

Pharmacovigilance is the science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medicines, biological products, herbals and traditional medicines with a view to:Identifying information about potential new hazards Preventing harm to patients.

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Timeline for Discovery and Development

A. Laboratory and animal studies 6 yrs

B. File Investigational New Drug (IND) to FDA

C. Phases I- III 7 years

D. File New Drug Application (NDA) at FDA: 1.5 years

E. Phase IV (post approval) 6 years

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Allocation of time (in years)

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The development and testing process required to bring a drug to market

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Drug Safety Assessment• Drug safety assessment is an important goal in the

drug development and Post Marketing Surveillance (PMS)

• It contributes to the balance of benefits and risks of the product

• It consists generally in anticipating, assessing and minimizing the cases of adverse drug reactions.

• At each step of the drug development– Pre clinical – Phase 1, 2-3

• PMS (Post Marketing Surveillance)– Mainly based on Spontaneous Reporting Systems

Drug Safety Assessment

• Objective : to assess toxicity in animal– Acute toxicity (LD50, …) – Subchronic toxicity (13 / 26 weeks)– Chronic toxicity and cancerogenesis– Reproductive testing

Pre clinical studies

• Objective– Assess safety or toxicity (depending on compound)– Define therapeutic window / Maximum Tolerated Dose

• Available data– Few volunteers (or patients) / dose escalating process– Thorough clinical assessment

Phase 1 clinical studies

Drug Safety AssessmentPhase 2-3

• Objective : to assess safety of study drug in larger studies in patients vs. placebo or reference drug

• General safety parameters– Adverse events (AE) / serious adverse events (SAE)– Biology / Biochemistry / ECG / Vital signs, …

• Disease / class specific safety parameters– e.g. CV safety in diabetes

• Statistical analysis (adverse events)– Descriptive tables (counts, crude incidence, incidence rate, …)

• Number of AE (NAE) in a given primary system organ class• Number of patients (n) with at least one AE in a given

preferred term or a given primary system organ class• Number Needed To Harm (NNTH)

The End