Clinical Pharmacology Gap Analysis: Lessons Learned

Clinical Pharmacology Gap Analysis: Lessons Learned

Clinical pharmacology gap analysis is a tool for outlining your drug program’s needs, prioritizing these needs, and providing a framework for how to satisfy them. This tool can create value for drug development programs. While gap analysis can be performed at any point in the drug development continuum, early engagement is best for maximizing its benefits. In this blog post, I’ll share with you some real cases of clients who leveraged gap analysis and their resulting outcomes.

Case 1: Biotech client with point of entry prior to FIM

This first client engaged us prior to their first-in-man (FIM) studies, and the engagement lasted throughout development. They had eight clinical trials supporting various key questions: six clinical pharmacology and two patient safety/efficacy studies.

They leveraged data across studies to answer multiple questions. This negated the need for up to five additional dedicated studies for food effects, drug-drug interactions (DDIs), as well as cardiac risk assessment (the through QT study). The FIM strategy de-risked food effects and DDIs early, which allowed food and co-medication restrictions to be lifted for subsequent efficacy trials.

The early quantitative planning also allowed modeling and simulation to be leveraged. For example, the FIM and first in-patient study assessments were used to support the concentration-QT analyses to determine the relationship between drug exposure and potential QT interval prolongation. This strategy allowed the client to avoid a thorough-QT study which can cost up to one million dollars. These clinical trial data were also used in population pharmacokinetic (PopPK) analyses to assess the effect of co-administration of acid-reducing agents as well as renal impairment on PK.

A robust physiologically-based pharmacokinetic (PBPK) modeling and simulation (M&S) strategy was used to diminish the DDI and steady state organ impairment study needs. This meant that the organ impairment study could be performed following a single drug dose, which was much faster than a steady state dosing evaluation.

Thus, early planning decreased the study burden from eleven clinical pharmacology studies to six and allowed leveraging quantitative methods from the FIM studies through Phase 3 studies. In conclusion, the clinical studies and the planned M&S analyses for this client supported the regulatory expectations for this therapeutic area.

Study/Analysis Need Status Notes
Clinical Pharmacology Evaluations
Single-dose PK Completed Study 1
Multiple-dose PK Completed Study 1, 2
ADME Completed Study 3
Food effect Completed/Ongoing Study 1/Study 5
Hepatic impairment Ongoing Study 4, mild/moderate/severe
Bioequivalence (BE) Ongoing Study 5
CYP3A inhibitor Completed Study 1
CYP3A inducer Completed Study 6
CYP3A substrate Completed Study 7
CYP3A8 substrate via PBPK (see below)
pH altering agents via PBPK and PopPK
Modeling and Simulation Evaluations
Concentration QT analysis Completed using data from Study 1, 2
Population PK
– effect of covariates
– effect of renal impairment
– effect of acid reducing agents
Planned using data from Study 1, 2, 8
Exposure-response for efficacy Planned using data from Study 8
Exposure-response for safety Planned using data from Study 2, 8
PKPD Planned using data from Study 2
PBPK
– CYP2C8 substrate*
– CYP3A4 substrate*
– CYP3A4 and CYP2C8 substrate*
– strong CYP3A4 inhibitors*
– moderate CYP3A4 inhibitor*
– hepatic impairment*
– gastric pH
Completed
Completed
Completed
Completed
Completed
Ongoing
Completed
rosiglitazone
midazolam
ripaglinide
ketoconazole, itraconazole
fluconazole

(* includes simulations at steady state)

Case 2: Small biotech company finishing Phase 2 studies

The next case was a small biotech who engaged us as they were finishing Phase 2 and planning Phase 3—a late stage engagement. They had five completed studies: three patient-safety and efficacy studies; and two clinical pharmacology studies mostly on bioavailability and food effect evaluation.

During the gap analysis, we found outstanding items related to QT prolongation assessment, DDIs, dose justification, and assessing the effect of organ impairment on PK. Unfortunately, gathering the relevant data in early studies to answer these questions was a lost opportunity. Since the FIM program was already completed, the only option was conducting simultaneous dedicated studies before the new drug application (NDA) submission.

Study/Analysis Need Status Notes
Clinical Pharmacology Evaluations
Single-dose PK Completed Study 1, 2, 3
Multiple-dose PK Completed Study 1
ADME Needed Study 3
Food effect Completed Study 3
Organ impairment Needed
Bioavailability (BA) Completed Study 2, 3
pH altering agents Completed Study 3
DDI as victim Needed
DDI as perpetrator Needed
DDI as combinations
– Drug 1
– Drug 1 + Drug 2
Ongoing
Ongoing
Study 4
Study 5
Modeling and Simulation Evaluations
Population PK (effect of covariates) Needed
Exposure-response for efficacy Needed
Exposure-response for safety Needed

Case 3: Small biotech seeking accelerated approval

This client engaged us early—during conduct of their expansion cohorts in Phase 1. Because their program was rapidly moving towards accelerated approval, this engagement fell between an early and a middle time point. They had seen efficacy for their drug in patients with a rare cancer in expansion cohorts from the FIM study. Therefore, their regulatory strategy was to submit data from expansion cohorts for accelerated approval.

At the time of the gap analysis, the clinical pharmacology program was ongoing, but there was no pharmacometrics strategy. Therefore my focus was reviewing the risks of the current program, including the DDI strategy, in addition to prioritizing the needs for an accelerated approval filing. My recommendations relied heavily on PBPK to minimize the DDI study burdens and to inform drug labeling as well as PopPK to inform the effect of subpopulations on PK.

This gap analysis allowed the client to organize their thinking and justifications for the end-of-Phase 1 meeting with FDA and agreement was obtained on their dose justification strategy and the clinical pharmacology program for accelerated approval. The process also helped the client streamline the pharmacometric analyses and start preparing for these analyses in time for the NDA filing.

Study/Analysis Need Status Notes
Clinical Pharmacology Evaluations
Single-dose PK Completed Study 1
Multiple-dose PK Completed Study 1
ADME Ongoing Study 2
Food effect Completed Study 1
Hepatic impairment Ongoing Study 4
Bioavailability (BA) Ongoing Study  2
pH altering agents Ongoing Study 3
DDI as victim
– moderate CYP3A4 inhibitor
– strong CYP3A4 inducer
Ongoing
Needed
 Study 3
DDI as perpetrator
– CYP3A4 substrate
– CYP2C8 substrate
Completed
Ongoing
Study 1
Study 3
Modeling and Simulation Evaluations
Concentration QT analysis Completed using data from Study 1
Population PK
– effect of covariates
– effect of renal impairment
– effect of hepatic impairment
Needed
Needed
Needed
Exposure-response for efficacy Needed
Exposure-response for safety Needed
PKPD Ongoing
PBPK
– moderate CYP3A4 inhibitor
– weak CYP3A4 inhibitor
– moderate CYP3A4 inducer
– CYP2C8 substrate
– CYP2C19 substrate
– CYP2D6 substrate
– CYP2C9 substrate
Consider
Consider
Consider
Consider
Consider
Consider
Consider

Case 4: Dose justification and development gaps

My last case involved a client who waited for the FDA to tell them what to do. At the time of our engagement, the client had completed Phase 2 and wanted to progress to Phase 3. However, the FDA requested exposure-response (ER)-based analysis to support the Phase 3 dose. Thus, the client was tossed back into Phase 2.

For this gap analysis, we reviewed protocols, dose justification, and a strategy for a dose-ranging portion incorporated into Phase 3 and associated PK- and PD-sampling. We also leveraged PopPK and ER analysis to support the FDA’s ER-based analysis for the Phase 3 dose.

Other critical gaps were also identified during this review and included DDI strategy as well as organ impairment. Some of the DDI missing information included critical in vitro studies that still needed to be executed prior to even informing the in vivo need. We also suggested that the client alter their exclusion criteria to address organ impairment in efficacy trials. This would enable the client to gain information using PopPK models to support the renal and hepatic impairment sections of the drug label and avoid dedicated studies.

We also drafted PopPK and ER analysis plans since we knew that these types of analysis were going to be needed for their Phase 3 dose recommendations at their Type C meeting. By drafting these analysis plans ahead of time, they could start their M&S evaluations right after the dose escalation portion of the Phase 3 study was complete.

Study/Analysis Need Status Notes
Clinical Pharmacology Evaluations
Single-dose PK Completed
Multiple-dose PK Completed
ADME Consider elimination route TBD
Organ impairment Needed potential PopPK/dedicated studies
DDI as victim TBD
DDI as perpetrator TBD
DDI for combinations TBD
Modeling and Simulation Evaluations
Concentration QT analysis Ongoing
Population PK
– effect of ethnicity
– body weight-based dosing
– effect of covariates
– effect of renal impairment
– effect of hepatic impairment
– effect of co-medications
Ongoing
Needed
Needed
Needed
Needed
Needed
Exposure-response for efficacy Needed
Exposure-response for safety Needed
PKPD Planned

Takeaways

Clinical pharmacology has many moving parts with lots of studies and boxes to check. There’s no right way to do things. There are a few wrong ways to do things, but often those learnings are not publicly available. That’s why engaging consultants with a vast depth of industry and regulatory experience to outline or pressure test your strategy can be so valuable.

Earlier planning is best for maximizing the benefits of a proactive and integrated clinical pharmacology and quantitative method strategy. The goal of gap analysis is to establish a clear path forward to enable decision-making during investigational new drug (IND) development and position you for a successful NDA review.

To learn more about how to maximize the benefits of a clinical pharmacology gap analysis, please watch this webinar I presented on this topic.

Julie Bullock

About the Author

Julie Bullock

Senior Director, Consulting Services, Certara

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Dr. Bullock has over 10 years of drug development experience within the FDA. Dr. Bullock’s past appointments include Clinical Pharmacology Team Leader and Senior Clinical Pharmacology Reviewer (FDA). Her regulatory experience was focused in the therapeutic areas of hematology/oncology and coagulation. She has unique insight in pediatric development, PK/PD approaches for biosimilar products, oncology dose finding strategy and streamlining development for breakthrough therapies and accelerated approval. Dr. Bullock has contributed to over 14 new molecular entity approvals during her 10 year FDA career.