Overview of Phase Zero Trials

Overview of Phase Zero Trials

  • Introduction to Phase Zero Trials

    • Emerged from concerns regarding the high failure rates and rising costs of drug development.
    • Initial drug success rates declined from 14% (1985) to 8% (2000).
    • Simultaneous cost increases: drug development costs rose by 55% during this period.

  • Regulatory Response

    • In 2006, the FDA proposed new guidelines leading to Phase Zero trials.
    • Officially referred to as exploratory IND studies.

Objectives of Phase Zero Trials

  • Early Failure Identification

    • Emphasis on failing early in the drug development process to minimize financial and time investments.
    • Goal: Provide a "go or no-go" decision early in the process.

  • Dosage and Design

    • Utilizes very low doses (about 1/100th of the therapeutic dose).
    • Conducted on very few patients with no therapeutic intent.
    • Focus: Assess drug interaction with target, metabolism, and stability in vivo without inducing toxicity.

  • Outcome Measurements

    • Gathering information on pharmacokinetics (how the drug is processed in the body) and pharmacodynamics (how the drug affects the body).
    • Allows multiple drug candidates to be compared and ranked.

Advantages of Phase Zero Trials

  • Resource Efficiency

    • Less resource and time-intensive than traditional trial methods.
    • Quick transition to Phase One studies if sufficient data is gathered.

  • Optimal Candidate Selection

    • Ability to progress with several candidates in parallel, reducing the risk of restarting the development phase upon failure of a single candidate.

  • Minimal Risk of Toxicity

    • Low doses and limited patient numbers reduce the risk of adverse effects.

Ethical Considerations of Phase Zero Trials

  • Informed Consent

    • Physicians must communicate clearly that no therapeutic efficacy is expected due to low doses.
    • Patients need awareness that participating may disqualify them from future clinical trials aimed at therapeutic interventions.

  • Transition Assurance

    • Ensuring that patients are seamlessly transitioned to subsequent clinical trials that hold potential therapeutic benefits.

Example of a Phase One Trial

  • Case Study: PARP Inhibitors and BRCA Mutations

    • Focused on patients with hereditary breast cancer, specifically mutations in BRCA1 and BRCA2.
    • PARP inhibitors (e.g., olaparib) were effective for patients with these mutations.
    • PARP inhibitors received FDA approval for ovarian cancer in 2014 and for BRCA-mutated breast cancer subsequently.

  • Trial Design

    • Started dosing at 10 mg/day, escalating to 1200 mg/day.
    • Measurements included maximum tolerated dose and biochemical endpoints for PARP inhibition.

  • Patient Selection

    • Included patients with both BRCA mutations and wild-type tumors to determine efficacy across genetic backgrounds.

Data from the PARP Inhibitor Trial

  • Biochemical Assays

    • Assessed levels of poly ADP ribose, a product of PARP activity.
    • Samples from white blood cells indicated effective PARP inhibition across various doses (40 mg, 200 mg, 400 mg).
    • Example: Patient 8 showed robust poly ADP ribose levels pre-treatment which significantly dropped post-treatment.

  • Clinical Efficacy Observations

    • Anecdotal evidence: tumor size reduction observed in patients (e.g., Patient 20’s tumor reduced from 53 mm to 18 mm).
    • Noted potential limitations in interpreting these results due to small sample sizes and the nature of phase one designs.

  • Primary vs Secondary Endpoints

    • Efficacy considered a secondary endpoint; primary focus on determining appropriate dosing and scheduling based on pharmacokinetics.