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Benefits of Apocalyptic Clinical Pharmacology During Regulatory Review

When developing a drug, pharmaceutical companies need to answer many questions to successfully undergo regulatory review and bring the drug to market. Apocalyptic clinical pharmacology is a framework that drug developers can use to uncover essential relationships between the drug dose and response or outcome. In other recent blog posts, I have covered what the framework of apocalyptic clinical pharmacology is and how to adjust the four different levers to obtain useful information for the drug development process. Also, there are case studies on how pharmaceutical companies have used apocalyptic clinical pharmacology at various stages to help gather information that ultimately helped them decide how to proceed with the drug they were developing. This blog will focus on how apocalyptic clinical pharmacology can benefit drug developers during regulatory review.

Four important questions for regulatory review

Every drug developer knows that regulatory review can be challenging. And sometimes the process takes much longer than expected. Apocalyptic clinical pharmacology can help drug developers tease apart important information related to the relationships between the drug dose and the eventual outcome. US Food and Drug Administration regulators ask four questions about each New Drug Application (NDA) they receive:

1. Does the clinical pharmacology information list provided in the submission provide pivotal or supporting evidence of effectiveness?

2. Is the dosing regimen appropriate for the general patient?

3. Is an alternative dosing regimen required for subpopulations based on intrinsic factors?

4. Are there clinically relevant food-drug or drug-drug interactions (DDIs) and what is the appropriate management strategy? How is the dose going to be adjusted based on these extrinsic factors?

How apocalyptic clinical pharmacology helps answer these questions

In an earlier blog, I described the four levers that can be adjusted through an apocalyptic clinical pharmacology approach to help drug developers answer the questions that are important for regulatory review. Let’s circle back to the levers.

Lever 1: Dose and its relationship to response, pharmacokinetics (PK), and pharmacodynamics (PD)

For the first question, apocalyptic clinical pharmacology helps uncover the relationships between drug dose and response, which helps drug developers understand how the dose is related to effectiveness (that is what the drug does, and how well it performs in the biological system). Through careful analysis of the relationships of dose to PK, PK to PD, and PD to effectiveness/clinical outcomes, more useful information is uncovered to provide supporting evidence about why a particular dose is chosen and the expected effectiveness (and safety) of the drug at that dose.

Since a key milestone in early clinical development is proof of concept (POC), how can this approach be applied in POC studies which tend to be small and of relatively short duration and in which the clinical outcome is often impossible to assess? A key part of POC studies is the need for clarity on will be measured, the justification for the measurement in terms of clinical relevance, and what magnitude of response is likely to be of clinical relevance. The measurement may be a response measurement related to pharmacology or any PD response measurement where the drug developer can be confident that a measurable change in the response is representative of the drug acting as expected. Since the successful POC acts as a stage gate to often substantial further investment in development, the choice of parameters to assess meaningful drug response and the definition of meaningful are of high importance. Thus, thinking about the relationship of the dose and a response that is justified leads to a thoughtful POC study that can inform next steps for drug development.

Lever 2: Frequency of the dose

Through uncovering the relationships between dose to PK and PK to PD, the drug developer can understand the optimal dosing rate, which includes the dose and how frequently the dose is administered. There are many ways to uncover these relationships using apocalyptic clinical pharmacology and understand how the relationships impact the dosing schedule. In the case studies presented on apocalyptic clinical pharmacology, I discussed the case of needing to optimize the target testosterone concentration in treating prostate cancer. Understanding the interplay between dose, drug exposure, response in terms of desired response as well as safety responses allows patients to derive the maximum benefit that the drug can offer.

Another area of drug development to consider is for large molecules. Most of what I’ve described so far about apocalyptic clinical pharmacology comes from my small molecule background. But in the case of developing large molecules or even gene therapy, apocalyptic clinical pharmacology still applies and can benefit these development approaches equally well. With large molecules, there is still the need to understand what dose to give and how often to administer that dose. This understanding needs to be supported through understanding the relationships that underpin the dose and response relationship.

Lever 3: Extrinsic factors and conditions

Apocalyptic clinical pharmacology can provide insight into how the dose will be adjusted based on extrinsic factors. In the case study on Ibrutinib, DDIs involving the drug’s principal route of clearance were substantial. Physiologically based pharmacokinetic (PBPK) modeling enabled the drug developers to provide meaningful prescribing advice on the basis of a relatively limited clinical DDI program – please refer to the webinar for more on this.

It seems that PBPK can be used in two different ways for drug development. First, PBPK modeling can reduce the number of studies that are required at the regulatory stage. For example, there might be a co-treatment that is likely to be administered with the drug under development. Then, the simulation in the PBPK model can be done to determine if there is an interaction. Second, during drug development at early stages PBPK modeling can be used to understand DDI risk and then help to streamline the clinical development plan. That is, the apocalyptic clinical pharmacology framework can help avoid doing expensive DDI studies early on in clinical development, and through the use of modeling and simulation a drug developer can predict the DDI risks and then work on decreasing the risk through the understanding gained. For example, if a drug was shown to have a moderate risk of an interaction of about 10 fold increase in exposure (e.g. ~10-fold increase in exposure with an inhibiting co-administered drug), the clinical DDI study may be scheduled earlier in clinical development. However, if the PBPK model indicated a probability of little or no interaction, then DDI studies could be backloaded or avoided completely in the development plan.

With question 4, such approaches provide insights into how to sequence clinical development studies depending on the development stage. These approaches are now well understood by regulatory agencies, and it is up to the ingenuity of the drug developer to apply such approaches to streamline development and provide meaningful labeling for prescribers.

Lever 4: What are special considerations for the populations that the drug is given to?

Question 3 is about altering the dose for sub-populations based on intrinsic factors. This has been illustrated already with the Case Study 2 example in a blog I posted previously. The example focused on a drug that had highly variable PK. By investigating the relationship of the drug’s metabolism to the drug’s PK, the drug developer was better able to understand that certain populations metabolized the drug at a different rate than others, and the resulting increased exposure was shown to be relevant to both drug safety and efficacy. Ultimately, an understanding how the dose to exposure relationship is altered in special populations is needed to optimize the safe use of medicines. As mentioned above, describing relationships in models and simulating scenarios allows dose setting and dose adjustment recommendations in such populations.

Interested in learning more about how to apply apocalyptic clinical pharmacology to your drug development process? Listen to my webinar here.

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By: Graham Scott

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