Drug Discovery and Development Lecture Notes

Drug Discovery and Development

Overview of Clinical Drug Development

  • Clinical drug development is divided into four phases (Phases I-IV).

    • Phase I revolves around investigations into the safety and pharmacokinetic (PK) profiles in healthy controls (HC).

Stages of Drug Development

  • Phase I Clinical Trials

    • Objective: Confirm drug administration safety to humans.

    • Population: Healthy human volunteers or patients in relatively stable condition with their disease.

    • Participant Count: Typically involves 20-80 volunteers.

    • Duration: Lasting from 6 to 12 months.

    • Evaluation: Maximum tolerated dose (MTD) for the drug must be established.

    • MTD must be higher than the expected therapeutic dose for study continuation.

    • Study Designs:

    • Multiple rising dose (MRD) or multiple ascending dose (MAD) studies.

    • ADME (Absorption, Distribution, Metabolism, and Excretion) studies often involve radioactive labeled compounds.

    • Common Findings: Side effects are prevalent during Phase I trials.

    • Regulation: Drugs for Phase I clinical trials must be manufactured under Good Manufacturing Practices (GMP).

Drug Development Flowchart

  • Preclinical Stage: High-throughput screening of thousands of compounds leads to the following stages:

    • Hit to Lead: Reduction to hundreds of compounds;

    • Lead Optimization: Narrowing down to dozens of compounds;

    • Candidate Seeking: Selection of 1-3 compounds;

  • Phases of Clinical Development:

    • Phase I: Safety and tolerability in healthy volunteers.

    • Phase II: Safety and efficacy in patients (early clinical proof of principle).

    • Phase III: Definitive clinical proof of principle with larger populations.

    • Postmarketing Surveillance: Ongoing safety monitoring post-approval.

Detailed Phases of Clinical Development

  • Phase I Trials

    • General Aim: Exploratory focus on safety and tolerability.

    • Subjects/Design: Healthy subjects; single dose, placebo-controlled, randomized, double-blind.

    • Data Collected: Adverse events and pharmacokinetic parameters.

    • Number of Subjects: 40-60.

    • Time Required: Approximately 6 months.

  • Phase II Trials

    • Phase IIa: Exploratory trials in small groups to indicate safety and efficacy.

    • Phase IIb: Conducted in larger cohorts to confirm efficacy and determine optimal dosage.

    • Transition: Phase IIa to IIb is termed proof of concept (POC) or proof of principle (POP).

  • Phase IIa Specifics

    • Established criteria in advance for halting or advancing development.

    • PK profiles may differ in various disease states (e.g., drug absorption in HIV).

    • Dose Regimen: Guides will depend on PK profiles from Phase I and the drug's mechanism of action (MOA).

    • Duration varies; for instance, post-operative pain efficacy can be shown quickly compared to chronic conditions like osteoporosis or Alzheimer’s.

    • Drug Classification:

      • First in class: POC must encompass the entire new class.

      • Follower drugs: Require at least equivalent efficacy to show improvement.

  • Phase IIb Trial Specifics

    • Examines the dose-response relationship and selects dosages for Phase III.

    • Sufficient patient numbers to provide statistically confident inferences.

    • Standard design includes parallel-group, randomized, double-blind, and placebo-controlled trials.

    • Open Label Use: Often in cancer chemotherapy trials due to ethical considerations regarding placebos.

    • Outcome Measures: Protocol must specify a change from baseline response to qualify.

  • Phase III Trials

    • Must be placebo-controlled; potential demonstration of quantifiable advantages over standard treatments (e.g., efficacy, safety).

    • Often comprises multiple studies across various centers (multicenter trials).

    • Bridging Studies: Necessary to account for genetic and dietary differences affecting drug safety and efficacy (e.g., polymorphisms in cytochrome P450).

Key Ethical Considerations in Clinical Trials

  • Historical References:

    • Nuremberg Code (1947)

    • Declaration of Helsinki (1975-2008)

    • Belmont Report (1978): Outlines three core ethical principles:

    • Respect for Persons: Treat individuals as autonomous agents.

    • Beneficence: Maximize possible benefits while minimizing harms.

    • Fairness in Distribution: Ensure equal opportunity in trial participation.

    • Three Recommendations:

    • Avoiding bias.

    • Mandatory publication of findings.

    • Securing informed patient consent.

Randomization in Trials

  • Definition: Assignment of trial participants to treatment groups at random.

    • Ensures:

    • Each participant stands an equal chance of group assignment.

    • Elimination of bias, affirming significant results.

    • Homogeneity in known and unknown group characteristics.

Blinding Techniques in Trials

  • Single Blinding: Patient unaware of the treatment received.

  • Double Blinding: Both patient and clinician unaware of treatment allocation.

  • Triple Blinding: Unawareness extends to statisticians as well.

  • Ethical Aspect: Blinding should not induce harm or undue risk.

Phase III Trial Design

  • Must target quantifiable treatment advantages encompassing various metrics (safety, compliance, cost-effectiveness).

  • Characteristics include multicenter setups to boost patient accrual and ensure broader population representation.

  • Challenges: Complexity in planning, increased costs, and the need for standardized training.

Pediatric Clinical Trials

  • Regulatory pressure encourages testing drugs on children instead of relying on adult data.

  • Acknowledgement of different pharmacokinetics and pharmacodynamics in children necessitates ethical consideration.

  • FDA Modernization Act (1997): Introduced incentives for drug testing on pediatric populations, including patent extensions.

Quality Assurance Mechanisms

  • Trial centers selected based on thorough facility inspections and investigators' qualifications.

  • Companies bear the responsibility to train personnel in protocols, adhere to ICH GMP standards, and oversee sites.

  • Data auditing acts as a safeguard for quality maintenances, albeit with associated costs.

Information Disclosure Requirements

  • Approved trials must be recorded publicly through databases (e.g., ClinicalTrials.gov).

    • Accessible listings include trial purposes, study centers, investigators, and phases.

  • Each trial receives an International Standardized Randomized Controlled Trial Number (ISRCTN).

  • Publication of trial results is discretionary; a significant portion remains unpublished, leading to safety and efficacy information gaps.

Drug Approvals and Statistics

  • Graphical Data: Novel FDA approvals since 1994 illustrating annual numbers of New Molecular Entities (NMEs) and Biologics License Applications (BLAs).

  • Distribution of approvals across therapeutic areas includes cardiovascular, dermatology, hematology, etc.

Attrition Rates in Clinical Phases

  • Attrition statistics between phases reveal a notable decline from Phase I to approval, with various reasons cited:

    • Phase 1 to Phase 2 attrition rate: 15.3%.

    • Phase 2 to Phase 3 attrition rate: 10.4%.

    • Adverse effects commonly lead to discontinuation, alongside pharmacokinetics and toxicity evaluations.

Reasons for Phase Attrition

  • Various influences, including:

    • Pharmacokinetics: Drug behaviors in the body.

    • Animal Toxicity: Adverse effects seen in animal models.

    • Miscellaneous Factors: Including commercial reasons.

    • Lack of Efficacy: In human trials compared to expectations.