Mastering Drug Discovery

Phase I

Phase II

Phase III

To test the drug in a general population

Months to 2 years

Phase II

To evaluate the effectiveness of the drug in a specific target population

Forever

To determine the safety and adverse effects of a drug

To evaluate the effectiveness of the drug in a specific target population

False

True

True

True

True

Phase III

To evaluate the effectiveness of the drug in the general population

Months to 2 years

Phase I

To evaluate the effectiveness of the drug in a specific target population

True

To determine the safety and adverse effects of the drug

Forever

Phase II

False

Clinical need and commercial potential

The number of drug targets in the human genome

To understand the molecular mechanisms of disease

To confirm hits

The re-examination of PD, PK, toxicity, selectivity, etc.

All of the above

Toxicity testing

Nephrotoxicity, hepatotoxicity, immunotoxicity

To evaluate the safety and effectiveness of the drug in a large number of patients with the disease

To evaluate the safety and effectiveness of the drug in a large number of patients with the disease

Target identification and validation

Phenotype-based drug discovery and target-based drug discovery

Rationale drug design

To determine the safety and adverse effects of the drug

Phase I, Phase II, Phase III

Phase III

Unmet medical need and economic viability

To determine the effectiveness of the drug in a specific target population

A few years

To evaluate the safety and adverse effects of the drug in the general population

Drug Discovery, Preclinical development, Clinical trials, Post-marketing surveillance

To determine the safety and adverse effects of a drug

To determine the safety, effectiveness, and dose of a drug in a specific target population

To evaluate the effectiveness of a drug in a large number of patients with the disease

To assess the effectiveness of a drug in the general population and monitor safety and adverse effects

Several months

Months to 2 years

1-3 years

1-2 years

To identify and validate a potential target for the drug

Target identification and validation, phenotype-based drug discovery, target-based drug discovery, lead discovery and optimisation, preclinical assessment of toxicity and safety, clinical assessment of efficacy, toxicity and safety.

Phenotype-based drug discovery involves screening compounds for their ability to produce a desired phenotype, while target-based drug discovery involves identifying and validating a specific target for the drug.

Lead optimisation is the process of refining and improving the properties of a lead compound to make it more effective and safe as a drug candidate.

Unmet medical need, economic viability, size of target population, feasibility of drug development, and information about the disease.

The purpose of preclinical assessment is to evaluate the toxicity and safety of a drug candidate before it is tested in humans.

Phase I, Phase II, and Phase III.

The purpose of Phase I clinical trials is to evaluate the safety and dosage of a drug candidate in a small group of healthy volunteers.

The purpose of Phase II clinical trials is to evaluate the effectiveness and side effects of a drug candidate in a larger group of patients.

The purpose of Phase III clinical trials is to confirm the effectiveness and monitor side effects of a drug candidate in a larger population.

The purpose of Phase IV clinical trials is to monitor the long-term safety and effectiveness of a drug after it has been approved for marketing.

Clinical need and commercial potential, involvement in disease pathophysiology, target-related safety, primarily expressed on tissues of interest, manageable on-target adverse effects, druggable, availability of assays for screening

The subset of the human genome that can be modulated by low molecular weight compounds with 'drug-like' properties

It involves understanding the molecular mechanisms of the disease, which can sometimes be straightforward for monogenic diseases but often complex for polygenic diseases. It can also involve the use of big data and translational relevance.

To identify 'hits' by developing an assay amenable to high-throughput screening and using compound libraries to screen for compounds that elicit a desired phenotype.

Lead optimisation is the process of evaluating and refining leads. It involves medicinal/synthetic chemistry, generating structural analogues, evaluating structure-activity relationships, and re-examining pharmacodynamics, pharmacokinetics, toxicity, and selectivity.

An IND dossier includes information about the drug's toxicity profile, pharmacological profile (in vitro and in vivo), pharmacodynamic and pharmacokinetic data, dose information, chemical/manufacturing information, formulation, proposed clinical plans/protocols, and toxicity testing.

The types of toxicity assessed in preclinical assessments include nephrotoxicity, hepatotoxicity, cell death (necrosis/apoptosis), hypersensitivity/immunosuppression, acute toxicity, genotoxicity, chronic toxicity, immunotoxicity, carcinogenicity, mutagenicity, and teratogenicity.

The factors considered when choosing a disease for drug discovery include clinical need, commercial potential, evidence that the target is involved in disease pathogenesis, and evidence that modifying the target alters the disease state.

Preclinical development involves assay development and screening, hit and lead identification, lead optimisation, and preclinical assessments such as toxicity testing and pharmacological characterisation.

The rationale behind drug design during lead discovery and optimisation is to generate or obtain structural analogues of leads, evaluate their structure-activity relationships, and re-examine their pharmacodynamics, pharmacokinetics, toxicity, and selectivity.