L1/L2 drug discovery and development pipeline

Podcast Beta

Play an AI-generated podcast conversation about this lesson

Questions and Answers

What are the stages of the drug discovery and development pipeline?

Therapeutic Concept, Target Selection, Target Validation, Lead Finding, Lead Optimisation, Preclinical Development, Clinical Development, Regulatory Approval, Product.

Which stage of the drug development ensures the candidate's safety and therapeutic usefulness in humans?

Lead Optimisation

Preclinical Development

Regulatory Approval

Clinical Development (correct)

What is the typical cost of developing a drug compound?

$1.4 billion

Which phase of clinical trials is primarily concerned with assessing safety and tolerability?

Phase 1 Signup and view all the answers

What does the term 'Lead Optimisation' refer to in drug development?

Enhancing favorable drug-like properties Signup and view all the answers

What are the primary endpoints measured in Phase 1 trials?

Safety and tolerability. Signup and view all the answers

In terms of drug discovery, what does the acronym 'ADME' stand for?

Absorption, Distribution, Metabolism, Excretion Signup and view all the answers

The one and only role of Phase 4 clinical trials is to assess drug effectiveness.

False Signup and view all the answers

What does pharmacovigilance involve?

Monitoring adverse effects and drug interactions after the drug is released to the market. Signup and view all the answers

What is a common issue faced in drug discovery success rates?

Success rate of 0.2% Signup and view all the answers

The therapeutic concept combines research, development, and ______ view.

commercial Signup and view all the answers

List the possible approaches for target selection in drug discovery.

Analysis of disease pathophysiology, mechanism of action of existing drugs, information from gene expression studies. Signup and view all the answers

Match the following drug targets with the associated diseases and example drugs developed:

Reverse transcriptase = AIDS Dihydrofolatereductase = Cancer Acetylcholinesterase = Alzheimers 5HT transporter = Depression Signup and view all the answers

What is the most common drug target in pharmacology?

GPCRs Signup and view all the answers

Preclinical validation can exclusively ensure the drug will be effective in humans.

False Signup and view all the answers

Name a drug developed for the treatment of Alzheimer's disease.

Donepezil Signup and view all the answers

Target validation is primarily established during ______ clinical trials.

phase 2 Signup and view all the answers

Match the disease with its corresponding drug target and developed drug:

AIDS = Reverse transcriptase Cancer = Dihidrofolatereductase Alzheimer’s = Acetylcholinesterase Depression = 5HT transporter Signup and view all the answers

Which of the following is NOT an approach to target selection?

Patient feedback during treatment Signup and view all the answers

Rational drug design prioritizes target identification before understanding disease mechanisms.

False Signup and view all the answers

What type of compounds are evaluated in pharmacological preclinical validation?

Non-selective compounds Signup and view all the answers

What does Log D measure?

Relative concentration of all forms of a drug in different phases Signup and view all the answers

According to 'the rule of 5', a drug with a molecular weight greater than 500 is more likely to have poor absorption.

True Signup and view all the answers

What is the term for the concentration needed in plasma to produce a therapeutic effect?

Minimum effective concentration Signup and view all the answers

The area under the curve (AUC) signifies the ______ of a drug over time.

exposure Signup and view all the answers

Match the pharmacokinetic terms with their definitions:

Cmax = Maximum concentration of a drug after administration Cmin = Minimum concentration between doses tmax = Time at which peak concentration occurs Therapeutic window = Range of doses effective without significant adverse effects Signup and view all the answers

What does pKa indicate in relation to drugs?

Ionisation properties of a drug Signup and view all the answers

Phase 1 metabolism primarily involves processes that reduce drug polarity for excretion.

False Signup and view all the answers

What is the term for the dose at which toxic effects occur?

Toxicity level Signup and view all the answers

What is the primary purpose of the parallel screening cascade in drug development?

To speed up development by assessing multiple properties simultaneously. Signup and view all the answers

Efficacy refers to the maximum effect a drug can achieve.

True Signup and view all the answers

What do the toxicity studies within the preclinical development phase aim to establish?

Maximum tolerated dose and no observable adverse effect level Signup and view all the answers

In pharmacodynamics, ______ refers to the concentration range over which a drug has its effect.

affinity Signup and view all the answers

Which of the following best describes the role of safety pharmacology in drug development?

To assess the drug's safety before clinical trials. Signup and view all the answers

Match the pharmacodynamic property with its description:

Affinity = Range of concentration for effect Efficacy = Maximum achievable drug effect Kinetics = Binding characteristics to receptor Specificity = Effects on other targets and ranges Signup and view all the answers

Metabolism of a drug only produces inactive metabolites.

False Signup and view all the answers

What is the purpose of formal safety testing in drug development?

To establish the safety window before human studies begin Signup and view all the answers

What is the likelihood of an adverse drug reaction (ADR) being classified as 'Very Common'?

1/10 Signup and view all the answers

Phase 1 clinical trials primarily focus on both safety and efficacy of a drug.

False Signup and view all the answers

What is the minimum sample size needed to observe an ADR with a frequency of 1/10?

30 Signup and view all the answers

In clinical trials, a group that does not receive the experimental treatment is known as the ______.

control group Signup and view all the answers

Match the following phases of clinical trials with their primary focus:

Phase 1 = Safety and tolerability Phase 2 = Efficacy and dosage Phase 3 = Comparative effectiveness Phase 4 = Post-marketing surveillance Signup and view all the answers

Which statement about 'Rare' adverse drug reactions (ADRs) is true?

They occur in 1 out of 10,000 patients. Signup and view all the answers

Randomization is essential in clinical trials to avoid bias.

True Signup and view all the answers

What is typically included in the primary endpoints of Phase 1 clinical trials?

Safety and tolerability Signup and view all the answers

What is the primary purpose of a Phase IIb clinical trial?

To confirm if efficacy is statistically significant Signup and view all the answers

Surrogate measures can include survival rates during clinical trials.

False Signup and view all the answers

What does QALY stand for?

Quality-Adjusted Life Years Signup and view all the answers

Phase ___ involves full-scale evaluation of a drug's effectiveness compared to current treatments.

3 Signup and view all the answers

Match the phase of clinical trials with its description:

Phase I = Initial safety and tolerability testing in a small group of healthy volunteers Phase IIa = Exploratory phase focusing on efficacy and safety in a limited patient group Phase III = Large-scale trials to confirm effectiveness against standard treatments Phase IV = Post-market surveillance to monitor long-term effects Signup and view all the answers

What is typically measured during Phase 4 of clinical trials?

Long-term efficacy and side effects Signup and view all the answers

Crossover trials involve patients receiving only one treatment throughout the study.

False Signup and view all the answers

In Phase II trials, how many patients are typically involved?

50-500 patients Signup and view all the answers

Study Notes

Drug Discovery and Development Pipeline

Drug discovery identifies candidate drugs, beginning with a therapeutic concept that hypothesizes drug action.
Drug development transforms a candidate drug into a marketable product.
Stages of the pipeline:
- Therapeutic Concept: Formulate the hypothesis on drug action, integrating research, development, and commercial viability.
- Target Selection: Identify the specific molecular target for the drug.
- Target Validation: Assess the likelihood of target effectiveness for the intended therapeutic effect.
- Lead Finding: Identify potential chemical starting points for the drug.
- Lead Optimization: Enhance desirable drug-like properties.
- Preclinical Development: Evaluate safety and efficacy for human testing.
- Clinical Development: Ascertain safety and therapeutic utility in humans.
- Regulatory Approval: Determine societal value of the drug.
- Product: Ensure commercial attractiveness.

Key Pipeline Statistics

Drug discovery success rate: 0.2%; development success rate: 11.8%.
Average cost per compound: $1.4 billion.
Timeframe from concept to product: 10-15 years.

Therapeutic Concept Considerations

Research: Assess feasibility of development and available technology.
Development: Confirm availability of appropriate assays or models for safety and efficacy.
Commercial: Consider profitability, innovation, and unique targets.

Target Selection Approaches

Pathophysiology Analysis: Investigate impacted receptors or enzymes in disease state.
Existing Drug Mechanism Impact: Utilize insights from existing drugs for new targets.
Genomic Studies: Utilize genetic fault information to identify drug targets.

Target Validation

Critical during Phase 2 clinical trials.
Preclinical Evaluation: Use pharmacological and genetic validation methods to confirm target efficacy.

Lead Finding Strategies

Pathophysiology-based: Enhance potential drug compounds' affinity for targeted action.
Bioassay-based: Refine drug effects without prior target identification.

Lead Optimization Factors

Physicochemical Properties: Ensure the drug's molecular weight is ≤ 500; Log P < 5 for better absorption.
Pharmacokinetic Properties: Predict safety, efficacy, and therapeutic window through metrics like Cmax, Cmin, and Log D.

Preclinical Development Focus

Assess physicochemical properties, safety pharmacology, and toxicology.
Conduct 7-28 day toxicity studies in multiple species to establish safety parameters.

Clinical Development Phases

Phase 1: Safety and tolerability assessment in 40-60 healthy volunteers; single and multiple ascending doses.
Phase 2: Efficacy assessment with 50-500 patients; randomized, placebo-controlled.
- Phase IIa (exploratory) and IIb (confirmatory) focus on dose confirmation and statistical significance.
Phase 3: Large-scale efficacy and safety evaluation (2,000-10,000 patients) against standard or placebo; multi-center studies.
Phase 4: Post-market surveillance to monitor long-term safety and adverse effects.

Outcome Measures in Clinical Trials

Primary Outcomes: Assess direct efficacy, safety, or tolerability.
Secondary Outcomes: Evaluate additional benefits, quality of life measures like QALY.

Regulatory Approval Process

Involves health authority assessment for safety, quality, and efficacy.
Requires detailed documentation on chemistry, pharmacology, pharmacokinetics, toxicology, and human efficacy studies.

Reasons for Drug Failure

Safety issues often arise in early-phase trials (Phase 1 or 2).
Poor absorption or permeation indicated by the "rule of 5": More than 5 hydrogen bond donors, 10 acceptors, >500 molecular weight, or Log P > 5 increases failure risk.### Adverse Drug Reactions (ADRs)
Detection of events influenced by exposure and frequency of ADRs.
Exposure involves the number of patients and study duration.
Frequency is determined by event likelihood and the event threshold.
ADR classifications:
- Very Common: ~1 in 10
- Common: ~1 in 100
- Uncommon: ~1 in 1,000
- Rare: ~1 in 10,000
- Very Rare: < 1 in 10,000

Power of Detecting ADRs

To achieve 95% likelihood of observing an ADR at 1/n frequency, approximately 3n patients are needed.
For a 1 in 10 frequency, 30 subjects must be tested.

Clinical Trial Phases

Phase 1:
- First in human studies with prior animal testing for safety.
- Focuses on safety and tolerability with primary endpoints.
- Involves 40-60 healthy volunteers, often placebo-controlled and double-blind.
- Includes pharmacokinetics and proof of mechanism evaluations.
Phase 2 and 3:
- Involve patients with the disease, organized into treatment arms.
- Randomization is crucial; may include stratification by characteristics.
- One group acts as the control, receiving existing treatments or placebos.
- Primarily double-blind to reduce bias; crossover trials may be considered.
- Outcomes must be relevant, often leading to clinical efficacy or quality of life assessments.

Phase 2 Specifics

Focuses on efficacy, proof of concept, and safety.
Involves small patient samples (50-200) and controlled studies.
Phase IIa is exploratory, lasting about a year with results based on Phase 1.
Phase IIb confirms efficacy and dosing for larger trials with 200-500 patients over two years.

Phase 3 Specifics

Comprehensive evaluation of effectiveness and safety compared to standard treatments.
Includes a large population (2,000-10,000) over several years.
Data generated supports drug registration for a specific condition.

Phase 4

Involves post-market surveillance to monitor long-term effects and rare adverse reactions.
Reports are gathered from healthcare providers and patients.

Pharmacokinetic and Pharmacodynamic Properties

Drug metabolism includes active and inactive metabolites.
Key pharmacodynamic aspects:
- Mechanism of action: enzyme inhibition, receptor antagonist/agonist.
- Affinity: concentration ranges affecting the drug's impact.
- Efficacy: maximum drug effect.
- Kinetics: binding properties to the target receptor.
- Specificity: effects on other targets and potential off-target impacts.

Preclinical Development

Focus on physical properties, safety pharmacology, and toxicology.
Metabolite identification and toxicokinetics are studied.
Safety testing precedes human trials to define safety window.

Clinical Trial Purposes

Gain authorization from regulatory bodies (FDA, MHRA, EMEA).
Evaluate clinical benefits and improvements to standard care.
Assess risks including on-target and off-target effects.

Target Selection Approaches

Basis for early target validation involves understanding disease mechanisms.
Mechanism of action of current drugs aids in new drug development.
Structural studies enhance target identification and rational drug design.

Target Validation

Validated across trial phases, strongest in Phase 2.
Preclinical validation checks binding to receptors and clinical effects in models.
Approaches include both pharmacological and compound classes with similar effects.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

This quiz covers the key stages of the drug discovery and development pipeline, detailing the purpose of each stage. It also explores the phases of clinical trials, including typical primary and secondary outcome measures. Test your knowledge on the intricacies of getting a candidate drug to market.