1_Review of Drug Discovery and Development Process

Drug Discovery and Development Activities

Basic research, preclinical development, clinical trials, FDA filling/ approval

Basic Research involves the ff:

lead identifcation, synthesis scale-up, and in-vitro pharmacology

Develop into an appropriate dosage form

■ Because most drugs came from a natural product, so it’s more of an extraction.

■ Developing a way to synthesize it inside the laboratory.

■ Scale-up–manufacturing and production of the active on a large scale.

Synthesis Scale-up

Preclinical Development involves the ff:

mutagenicity, in vitro toxicity, metabolic stability, and pharmacokinetics (ADME).

dito iniintindi kung ano yung magiging effect ng compound/drug that is being developed. we also check the safety of our drug before we commence our clinical trials

Preclinical Development

Different responses from different subjects based on genetic factors.

• Very important since the effects of drugs are not applicable to all patients

Genomic Biomarker Analysis

A test to evaluate the metabolism of drugs by cytochrome P450 enzymes.

• What enzymes are responsible for the metabolism of drugs

CYP Screen

Clinical Trials involves the ff:

ethics review, regulatory reviews, IND, Phase I, long-term toxicity & reproductive toxicity, in vivo metabolism, phase II, phase III

Ethics board (different from regulatory authority)

Ethics review

Regulatory Review IND (Investigational New Drug application) is needed when?

Before clinical trials

Regulatory review process for New Drug Application (NDA).

FDA Filing & Approval

FDA Filing & Approval is needed when?

Before commercialization

Monitoring drug safety after it has been marketed.

Pharmacovigilance

Pharmacovigilance is needed when?

after commercialization

Timeline of GLP during the Drug Discovery and Development as a Quality Assurance Guide

From basic research to preclinical development.

Timeline of GMP during the Drug Discovery and Development as a Quality Assurance Guide

From basic research to FDA filing/approval

(As long as you are making drugs, you should be GMP compliant.)

Quality Assurance Guide involved during clinical trials (applicable to human beings) in the Drug Discovery and Development Process:

GCP

Compounds showing an effect in a biological screen (e.g. binding assay).

Active Compounds

A molecule that shows the desired type of activity in a screening assay.

Hit Compound

Selected from a collection of hits by refining the screening criteria.

Lead Compound (molecule)

Prototype moiety with desired pharmacologic activity

• Undergoes further optimization untilyou reach the final compound that you will develop

Lead Compound (molecule)

Automated technology for rapid data collection in drug discovery.

High Throughput Screening (HTS)

Uses technologies of automation to collect a large amount of experimental data in a relative short time

includes the ff: > Robots, Detectors, Softwares

High Throughput Screening (HTS)

The Echo 650: Liquid Handling Device dispenses a minimum ___ nanoliters through __ waves

2.5, acoustic

Basic Research Steps

many compounds, small amounts in DMSO solution

Early Discovery

some compounds, several mg solid state

Lead Optimization

few compounds, approx 100 mg solid state

Late Discovery

1 compound gram quantity crystalline

Early Development

final form in kilogram quantity

Full Development

in between early discovery & lead optimization

Lead series

in between lead optimization & late discovery

Super qualifiers

in between late discovery & early development

development compound

• To identify compounds with properties that are acceptable for a drug

• Compounds are grouped into:

  • good

  • acceptable

  • bad

  • unacceptable

• Large number of compounds are ranked from a physicochemical point of view

  • Acid/base properties

  • solubility

  • lipophilicity

Early Discovery

In Early Discovery, large number of compounds are ranked from a _____ point of view

physicochemical

Factors that affect the product during early discovery (physicochemical point)

acid/base properties, solubility, lipophilicity

Compounds in early discovery are grouped into: ?

good, acceptable, bad, or unacceptable

• Improvement of target specificity, selectivity, pharmacokinetics (PK), and safety profiles

• done by medicinal chemists using advanced organic synthesis methods or by biotechnological methods

• if the structure of the drug target is known, computational in silico methods is used

in silico = performed in computer

Lead Optimization

Lead compound has 2 parts:

Pharmacophore & Auxophore

The part of a drug's structure responsible for its activity.

Pharmacophore

The part of a drug's structure that modifies physicochemical properties.

Auxophore

In Lead Optimization, to optimize the series as regards to physicochemical properties:

• pKa

• logP/logD

• aqueous solubility

• stability

Selection of promising compounds (super qualifiers)

• Few promising compounds are selected – super qualifiers

• To characterize them and judge whether they have suitable properties for development, highlight problems, and give input to possible solutions

• Solid state characterization

Late Discovery

Characterizing super qualifiers and judge whether they have suitable properties for development, highlight problems, and give input to possible solutions

Late Discovery

In late discovery, it refers to evaluating the physical form of a drug and its effects on dissolution.

Solid State Characterization

Types of Solid state characterization:

• Effect of crystal form on dissolution

• Characterization of polymorphs

• X-ray diffraction

• To find the best form of the compound for development into a drug

• Evaluate whether the compound may be developed into a stable bioavailable drug

• Whether prodrug formation should be considered

• Compatibility studies

• Best salt for development has to be identified.

Early Development

• polymorphism (XRPD)

• intrinsic dissolution rate

• thermal properties (TGA & DSC)

• solid state stability (light, heat, & humidity); stability is tested under stressed conditions to be able to rank the compounds in a short time

• hygroscopicity (DVS)

Best salt for development has to be identified through the following instructions:

Evaluation of physicochemical properties during scale-up and stability testing of drug compounds.

Full Development

• Bioassays (measures biological activity)

• Biological test system (in vitro, ex vivo, in vivo)

Pre-Clinical Development

Pre-clinical development: Measurement of biological activity of substances in various test systems.

Bioassays

Biological test systems in Pre-clinical Development

in vitro, ex vivo, in vivo

lower organisms, enzymes, cells

in vitro

animals (mice, rat)

in vivo

tissues, organs

ex vivo

Phase 0, Phase I, Phase II, Phase III

Clinical Trials

Focus on relationship of mechanism of action and treatment of disease

Clinical Trial Phase 0

• pharmacokinetics (PK), including biodistribution

• microdoses (1/100th of the dose calculated to yield a pharmacological effect)

• no therapeutic event

• 7-14 days (short-term)

Clinical Trial Phase 0

Prioritizes safety and pharmacokinetics in open studies focusing on ideal dosage range

Clinical Trials Phase I

• Safety

• Pharmacokinetics

• Ideal dosage range

• Non-blind or open studies

Clinical Trials Phase I

• Efficacy

• IIA: Best and most effective dose

• IIB: Drug response to the dose

• Single-blind design, with placebo and established active drug in addition to the investigational agent

Clinical Trials Phase II

Focuses on efficacy and determining the best and effective dose.

Clinical Trials Phase IIA

Focuses on efficacy and determining the drug response to the dose

Clinical Trials Phase IIB

Single-blind design, with placebo and established active drug in addition to the investigational agent

Clinical Trials Phase II

• Safety and Efficacy

• IIIA: done prior to marketing

• IIIB: supplemental/label expansion

• Certain toxic effects may first become apparent

• Double-blind and crossover techniques

Phase III

Prioritizes safety and efficacy with double-blind/ cross-over techniques.

Clinical Trials Phase III

Clinical trial in which certain toxic effects may first become apparent

Clinical Trials Phase III

Clinical Trial: done prior to marketing

Clinical Trials Phase IIIA

Clinical Trial: supplemental/label expansion

Clinical Trials Phase IIIB

Clinical Trial: Phase I participants, duration & purpose

Participants: 20-80 healthy human volunteers

Duration: 1 month

Purpose: • Safety profile • Dose-ranging • Identifying S/E

Participants: Few dozen to 300 patients with the disease

Duration: Several months

Purpose: • Evaluate effectiveness • Further evaluate safety

Clinical Trial: Phase II

Participants: >300 (2000-3000) patients with the disease

Duration: Several years

Purpose: • Confirm effectiveness • Compare treatment drug to standard/ commonly used tre atment

Clinical Trial: Phase III

Done if Phase III results meet expectations

Submission of clinical data for marketing permission.

Regulatory Application and Review

Full reports of all pre-clinical and clinical data

Registration Dossier

Version of Registration Dossier in the US

NDA/ New Drug Application

Version of Registration Dossier in the EU

Marketing Authorization Application

Ongoing monitoring of drug safety and adverse effects, involving:

• Additional pharmacological & toxicological data

• ADR reporting

• Product defect reporting

Post Marketing Surveillance (Phase IV)

Drug Discovery and Development. The discovery and development of new drugs