Clinical Pharmacology Deep Dive

Objectives

Tools/Deliverables

Impact on Drug Development

Predict exposure-response relationship in humans.

• Utilize PK/PD data from preclinical models to inform candidate selection and developability to FIH.

• Estimated therapeutic dose range for humans.

Propose relevant dose range and design for FIH.

• Model-predicted human PK.
• Estimation of Minimum Anticipated Biological Effect Level (MABEL) and toxicological coverage for humans.

• Estimate safe starting dose for humans.
• Ensure that the proper dose range is studied.

Assess clinical drug-drug interaction (DDI) potential.

• Preclinical drug metabolism data.
• A qualitative prediction of clinical DDIs.
• A quantitative prediction of clinical DDI magnitude.

• Provide development strategy for clinical DDI studies and inclusion/exclusion of key con-meds in clinical trials.

Benchmark competitor compounds for precedented MOA (through development)

• Meta- or a descriptive-analysis of relative potencies, therapeutic indices, DDI

• Differentiate compound against key competitors.

Objectives

Tools/Deliverables

Impact on Drug Development

Inform dose escalation and repeat dose decisions in human subjects.

• NCA PK analyses.
• Evaluation of systemic exposure and variability.
• Determine steady-state and dose proportionality of systemic exposure.

• Exposure in humans relative to pharmacologic target and toxicological risk informs appropriate dose escalation.
• Estimate variability in systemic exposure.

Characterize the clinical PK in healthy subjects and/or patients

• NCA PK analyses.
• Population-PK-model of exposure and variability.
• Early evaluation of potential inter-ethnic differences.
• Sampling strategies for population PK-PK/PD analyses.

• Determine early sources of variability in exposure.
• Evaluate potential differences between healthy subjects and patients.

Provide rationale for dose regimen(s) for PoC studies.

• Identify relationship between exposure and response to select appropriate dose regimens.
• Estimate key parameters of pharmacological response.
• Conduct model-based analysis of exposure-response, PK and drivers of variability.
• Predictions of therapeutic index.
  

• Enhanced understanding of benefit and risk and increase chances of a successful PoC.

Advocate for innovative trial designs

• Model-based trial simulations including key drivers of outcome.
• Adaptive trial design simulations.
• Exposure-response power estimates
• Non-traditional endpoint evaluations.

• Improved drug development decisions using model-based simulations of the drug- and disease-time course

Initial evaluation of the risk of potential DDIs and Food Effect (FE)

• Rationale (PK or PD), design, dose rationale, and interpretation of appropriate DDI studies

• Recommend appropriate doses for future studies.

Initial assessment of QTc risk

• Meta-analysis of concentration-QTc data from Phase 1/2a

• Estimate QTc-risk potential to inform development strategy

Inform Pediatric Investigation Plan (PIP)/strategy

• Pediatric development strategy. Exposure-response modeling to justify pediatric dose(s), study design(s) and PK sampling

• Dose regimen(s) that provide optimal response for a range of ages and development groups  

Support EOP2a regulatory submission

• Exposure-Response and Clinical Pharmacology sections of FDA End of Phase 2a briefing document and other global regulatory briefing documents

• Regulatory review of rationale for dose regimen(s) based on exposure-response relationships,  Clinical Pharmacology strategy, Phase 2b study design

Inform and support formulation strategy

• Apply modeling techniques (e.g. IVIVC) to predict in vivo performance of selected formulations.

• Guide development of formulations to maximize the probability of success to deliver desired concentration-time profile in humans.

Objectives

Tools/Deliverables

Impact on Drug Development

Characterize the clinical PK in larger patient populations

• Population PK analyses of Phase 2b and Phase 3 studies with identification of covariates

• Determine sources (intrinsic and extrinsic) of variability in exposure in patient populations.

Innovative dose-ranging trial design proposal

• Clinical trial simulation of predicted dose response and power to estimate EC50/ED50 and other key parameters

• Predict outcome for various trial designs, patient populations, endpoints to inform optimal designs

Execute dose- and model-based meta-analysis of exposure- response for key efficacy/safety endpoints

• Simulation strategy to support selection of optimal Phase 2b/3 dose(s)
• Apply population modeling methods to characterize exposure-response for labelling

• Enhanced understanding of benefit and risk.
• Dose regimen(s) and trial designs that deliver safety and efficacy for a differentiated product for patients that maximizes benefit and reduces risk.
• Avoid replicate trials

Support/design Phase 1 studies:

• Definitive Food Effect
• Drug-drug interaction studies.
• Bioequivalence study (if necessary).

• Identification of appropriate studies.
• Rationale, design, analysis and interpretation of  PK

• Identify appropriate dose and dose regimen for the appropriate patient population.

Conduct definitive assessment of QTc risk

• Concentration-QTc analysis of thorough QTc study

• Clinical QTc-risk defined

Support EOP2 regulatory submission

• Clinical Pharmacology sections of the FDA and EMA briefing documents

• Regulatory review of rationale for dose regimen(s), Clinical Pharmacology strategy, Phase 3 study design

Evaluation of special populations (e.g., renal/hepatic impairment)

• Clinical PK evaluation of exposure in special populations
• Model-based extrapolation of alternative dosing regimens

• Recommend appropriate doses in special populations (e.g., renal/ hepatic impairment)

Assessment of demographic
and responder/non-responder differences in exposure- response

• Population PK/PD analyses with identification of significant covariates that impact PK and/or response

• Identify groups that demonstrate different efficacy or safety based on exposure-response relationships

Objectives

Tools/Deliverables

Impact on Drug Development

Deliver Clinical Pharmacology sections of global regulatory submissions (adults and pediatrics).

Enable registration in global markets
Enable use of non-EU/US data in EU/US

• CTD Modules 2.7.1 and 2.7.2
• Contribute to CTD Module 2.7.3 (dose justification) and Module 2.5
• Labeling sections (i.e. PLR, PIL, GDS): Dosage and Administration, Drug Interactions, Use in Specific Populations, Clinical Pharmacology;  Clinical Studies/Contraindications/ Warnings/Precautions (as applicable)
• Provide responses to regulatory questions pertaining to Clinical Pharmacology and dose

• Clinical Pharmacology science (understanding of drug) and labelling optimal for appropriate use of medication in patients and for registration
• Reduces / eliminates need for local studies, shortens approval times.

Objective(s)

Deliverable(s)

Impact

• Post-approval regulatory support

• Provide responses to regulatory questions pertaining to Clinical Pharmacology, labeling [PLR, GDS], registration in additional countries, post-approval studies

• Clinical Pharmacology science (understanding of drug) and labelling optimal for appropriate use of medication in patients

• Alternative indications and routes of administration

• Dose regimen(s) rationale based on exposure-response and model extrapolation
• Sections of regulatory submissions (as above)

• Efficient Clinical Pharmacology strategy for appropriate use of medication in patients

• Guide new formulation strategy

• Apply modeling techniques (e.g IVIVC) to guide new formulation clinical development strategy

• Formulation delivers desired concentration-time profile in humans