As drug development has become more complex, with a higher risk of failure, greater uncertainty, and increased expense, the need for a quantitative and regulatory science-based strategy becomes clear. The first step in that performing that strategic assessment is a gap analysis and roadmap. Over the last couple of months, I’ve written a series of blog posts on this topic. The first blog explained how clinical pharmacology gap analysis can create value for sponsors as well as their potential partners and investors. In the second blog, I discussed how to maximize the benefits of this approach. The third blog went into the trenches with examples of clients who leveraged gap analysis, and the lessons you can learn from their experiences. In this fourth and final blog in this series, I’ll answer some of the most intriguing questions I’ve received regarding clinical pharmacology gap analysis.
Q: What is the risk of conducting clinical pharmacology studies that don’t align with FDA guidances?
A: Many people think that clinical pharmacology development should be easy because numerous guidances are available. Guidances provide a basic framework for how clinical pharmacology studies should be conducted. But they are not mandates for how studies must be conducted. And guidances typically don’t incorporate state-of-the-art practices. More companies should consider creative and innovative approaches to clinical development. Eventually, these innovations will become incorporated into guidances.
Notwithstanding, clients often ask how to address food effects during development. The relevant FDA guidance has clear and strict expectations for what a dedicated food effect assessment is. But, many clients don’t want to conduct that type of study early in development, so they delay it. Consequently, the food effects study is not completed in time to inform the dosing strategy with regard to food for pivotal efficacy trials.
I typically recommend clients incorporate a food effect evaluation into phase one trials. While this evaluation encompasses aspects of the food effect guidance, it may not hold up to the statistical rigor of the guidance design.
Going outside of the FDA-recommended study designs facilitates collecting early information that can inform your later development. Depending upon how robust your PK is, that early first in-man (FIM) study may satisfy your food effect assessment if you’re capable of collecting PK and understanding the dosing and administration of your drug compound in the clinical scenario of food in your phase two and three studies.
Q: How do you consider cost when creating a clinical pharmacology development plan including prioritizing studies needed for submission?
A: Clinical pharmacology studies can be expensive due to the cost of collecting and shipping samples as well as analysis costs. So try to incorporate cost-efficient approaches. For example, you can save money by diminishing unnecessary samples. Or, instead of conducting multiple dose evaluations, perform single dose evaluations, which also diminishes the time that patients need to stay in studies for assessment. In these situations, we may leverage physiologically-based pharmacokinetic (PBPK) models to simulate the multiple dose scenario while minimizing the study burden.
Likewise, costs can be lowered by taking a smarter approach to prioritizing clinical pharmacology studies. Avoiding performing a dedicated study saves hundreds of thousands of dollars that can be spent doing other studies that better characterize drug safety and efficacy and inform labeling. Or, this funding can be used to develop other drugs that could benefit patients. We consider both cost and operational feasibility of studies when performing a gap analysis.
Q: Do regulators accept model-based approaches for oncology drug development?
A: Oncology drug development has limitations. Sometimes, we can’t utilize healthy volunteers—not only because of possible genotoxicity or carcinogenicity risks—but because the drug may not be tolerated in a healthy volunteer patient population.
When you’re restricted to performing studies in patients with cancer, and your dedicated study burden is high, make sure to leverage quantitative method strategies to address important questions.
Instead of conducting an excessive number of dedicated drug-drug interaction (DDI) studies, the FDA has consistently approved drugs based on PBPK results that have been appropriately validated with dedicated trials. In addition, the agency has accepted the use of PBPK to predict the multiple-dose exposure differences for hepatic impairment studies that were conducted under a single dose condition.
There has been an uptick of model-based informed approaches in the oncology space. I would like to see an increase in model-based approaches being applied outside of the oncology space.
Q: Your approach to gap analysis focuses on FDA requirements. What about other regions’ specific requirements?
A: My FDA experience shines through my gap analyses. Since leaving the agency, I’ve also had substantial experience with Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). Certara’s European group of clinical pharmacologists also supports EMA requirements. So, region-specific requirements can be incorporated into the gap analysis pending your current global strategy. While some clients are eager to develop compounds all over the world, others are focused on getting the initial US approval and then applying their completed development to other regions.
Having an early understanding of your global program—from a clinical pharmacology and clinical standpoint—can make your program more attractive to investors. Even if the client is focused on US FDA approval, we encourage them to think about their global strategy, and we then assign Certara resources appropriately.
Q: What are sponsors’ and regulators’ attitudes towards PBPK compared to other types of modeling and simulation or dedicated studies in preparing clinical pharmacology packages?
A: PBPK is accepted by the FDA. When I was at the agency, I utilized PBPK frequently for oncology because we had very limited information at the time of NDA filing. So, I always tried to leverage PBPK to inform labeling for my practitioners and patients who would be using the drug upon approval. The EMA has a similar view of using PBPK to inform labeling.
Some sponsors are hesitant about this approach. PBPK models are complicated. Many do not understand the math involved and thus, they don’t trust these models. They would rather just perform dedicated studies to answer questions. For example, you have six DDIs scenarios that you need to investigate. Instead of conducting six clinical studies, you can conduct two clinical studies and then use them to validate your PBPK model. The PBPK model can then be used to simulate the remaining four DDI studies in silico. By using PBPK, you saved the time and expense of protocol writing, the clinical operations, the PK reports, etc. You’ve also avoided dosing the drug in a non-effective manner to healthy volunteers or patients who would not benefit from the drugs.
We could also question the ethics of conducting these clinical studies when we have tools such as PBPK that can be just as effective in answering those questions with minimal patient or volunteer risk.
Q: What clinical and pre-clinical data are needed to inform a gap analysis?
A: If you’ve completed the IND process or if you’re getting ready to submit it, you’ve likely got the data needed for your clinical pharmacology gap analysis. Much of these data relates to understanding the solubility and pH dependence of your product, the in vitro DDI study results, and nonclinical information on excretion of the compound in animals. For drugs to treat cancer, sponsors often ask if they can use healthy volunteers in clinical pharmacology studies to make the studies more feasible and speed enrollment. So, early planning to ensure that you’ve performed the appropriate nonclinical studies to support evaluation in heathy volunteers is important. If you plan or need to conduct an ADME study, it will be important to ensure you have quantitative whole-body autoradiography (QWBA) lined up so we can calculate the radioactive dose.
While you might not have any PK information yet, you can still determine what clinical pharmacology studies will be needed based on your pre-clinical data package. The clinical pharmacology program might need to be revisited after you conduct your phase 1 studies. But, an early review is important to ensure that your Phase 1 studies are collecting information that will facilitate future decision-making.
Sponsors tend to cut corners when planning their Phase 1 studies because they don’t know whether there’s proof of concept. Consequently, many drug programs are terminated in Phase 1, not because the drug didn’t work, but because the clinical studies didn’t collect data at the right time to facilitate decision making. An experienced clinical pharmacologist can review your first in-man clinical study protocol(s) and help ensure this data is collected and can also help with data interpretation when the time comes.
To learn more about how a clinical pharmacology gap analysis can create value, please watch this webinar I presented on this topic.