Many companies have tried and true clinical pharmacology practices. But when the rubber hits the road for your drug program, will these practices support regulatory success? Has your historic approach to drug development been updated to include the latest modeling and simulation innovations? It’s hard to change how you’ve historically done things. But, do you really want to miss out on opportunities to de-risk your program? Or streamline your clinical trials? Or decrease costs?
Clinical pharmacology gap analysis is a tool that can help you evaluate and address any potential gaps in your program before the FDA does. In a previous blog post, I explained how this approach can create value for drug development programs. In this blog post, I’ll discuss why an early engagement maximizes the benefits of a gap analysis.
Let’s break development into three phases: early, mid, and late. The early phase would be during pre-clinical and then go through to either the middle or end of Phase 1. The mid-phase entry point occurs after the conclusion of Phase 1 and/or in parallel to Phase 2. And late phase is anything that occurs after the conclusion of Phase 2 studies.
Early point of entry
Early engagement facilitates developing a rigorous plan and strategy, which includes a variety of dedicated clinical studies as well as quantitative strategies to address the clinical pharmacology program needs. For a client that engages during the first-in-man stage, we discuss topics ranging from human dose projections (HDP) to an early outline of the entire clinical pharmacology program, including quantitative method plans. Incorporation of HDP modeling is valuable to some programs as it can minimize or accelerate dose escalations and aid in identifying doses for expansion cohorts.
During an early-stage gap analysis, the first-in-man study can either be designed or amended to ensure gathered data will be value-added and de-risk the future program. This includes ECG monitoring to support QT analyses and assurance that the appropriate exposure data is being collected to support exposure-safety, -PD, and -activity relations for dose justification. We also want to ensure that data collection and dataset construction will be appropriate for population PK modeling. In addition to other assessments, we can discuss preliminary food effect and/or drug interaction screens.
An outline of the clinical pharmacology program needs is a key component of an early engagement gap analysis. This roadmap allows the client to prioritize execution of these studies after proof of concept (POC) has been established. Quantitative pharmacology approaches are often a component of the strategy. For example, the pros and cons of developing early PopPK models can be discussed so that modeling and simulation can be incorporated quickly if decisions require these types of analyses. In addition, pending the in vitro drug screens and study results, we can also determine which potential drug interactions should be assessed through standalone clinical studies versus physiologically-based pharmacokinetic (PBPK) methods.
Middle point of entry
Some clients approach gap analysis at the mid-point of development—the end of the first-in-man study. In this case, the focus of the gap analysis would be preparing for the health authority interactions. This would include reviewing or constructing exposure-response based dose justification for Phase 2 studies and outlining plans for the clinical pharmacology development and quantitative methods for inclusion into the briefing books. In addition, we review the Phase 2 program to ensure that the designs are capturing data needed to support the quantitative strategy, including further dose justification through exposure-response analyses and additional data for the population PK model.
A strategy to address needs via PopPK will also be made and compared with planned and ongoing trials to assure that the right patient populations will be included in Phase 2 and 3 studies to support the analysis conclusions. One of my favorite “sponsor tricks” I caught as an FDA reviewer were the companies who would promise to assess the impact of organ impairment on their drugs via PopPK models to avoid conducting dedicated clinical studies. They would provide great justifications for sampling and data analysis to support drug label claims for patients with mild to severe organ impairment. Then, I would read their inclusion criteria and see that they restricted patients to those with normal organ function. So while quantitative strategies to address clinical pharmacology needs are well accepted and should be incorporated, you need to allow the appropriate patients into your clinical trials to support the conclusions for the data analysis.
At this stage, the clinical pharmacology needs will be discussed and prioritized for filing. These will be balanced with your overall regulatory strategy for the compounds and the development timelines. While the midpoint of development is a great engagement point for a gap analysis, it can require a decent dedicated study burden depending on the design of the first-in-man study and what assessments it included.
Late point of entry
A client that delays addressing clinical pharmacology strategy until Phase 3 will face some hard decisions. Delaying clinical pharmacology and quantitative strategy limits the data that can be leveraged to answer concerns regarding QT, organ impairment, dose justification and the effect of co-variates. Delaying the clinical pharmacology strategy will increase the number of dedicated studies needed to support labeling and could holdup filing if these studies cannot be submitted post-approval.
Dedicated studies can be expensive, and executing multiple studies concurrently can impose a high operational burden. Regulators will expect analyses to support safe use of the drug at the time of NDA submission in as wide a population as possible. The FDA typically has concerns regarding subgroups or situations that are going alter exposure and thus increase toxicity or decrease efficacy. And they will also look for trends for both response and safety over a large dose and exposure range. If you lack critical data in your NDA submission, you will be stuck with restrictive labeling and, possibly, a high post-marketing burden.
Earlier planning is best for maximizing the benefits of a proactive and integrated clinical pharmacology and quantitative method strategy. The goal of the gap analysis process is to establish a clear path forward to enable decision-making during 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.