During my years reviewing applications for the US FDA, I encountered a lot of poor planning concerning a drug’s clinical pharmacology program. This poor planning left the company either lacking data to make informed decisions or scrambling at the end of development to address unanswered issues. Early planning is key to regulatory success, not only for the clinical pharmacology program, but also to support decision making throughout development. In this blog post, I’ll explain how clinical pharmacology gap analysis can create value for drug development programs.
What is clinical pharmacology gap analysis?
Clinical pharmacology programs can be complex. Deciding how and when the varied needs will be met is important. In brief, a gap analysis will outline your program needs, prioritize these needs, and provide a framework for how to satisfy them. Gap analyses will also provide direction to ensure that planned and future studies are not only budgeted for but are designed to be value-added and fit for purpose. Lastly, gap analyses will facilitate interactions with regulators.
This process can still be valuable even though you may not be taking your compounds to a new drug application (NDA) and approval. Many early-stage biopharma companies have an exit strategy of selling their assets before phase two. Based my due diligence experience, a well thought out clinical pharmacology plan—including data-driven dose justification and risk/benefit analyses—enhances your asset’s desirability to commercial partners. These plans and analyses provide a thorough understanding of the product’s characteristics and mitigate the risks of their investment.
Overall, the goal of the gap analysis is to create value for you. It’s focused on getting your drug approved or bought by a commercial partner, and optimizes the safe use of your product. In addition, gap analysis will provide you with certainty, increase your program efficiency, and therefore improve the overall cost effectiveness over the development timeline.
Many companies, especially large ones, may have tried and true clinical pharmacology practices. But, how often have these practices been pressure tested? Or updated based on recent learnings from approvals or uptake of new solutions? Moving away from known successes to try different approaches can be hard. However, as the speed of drug development and regulatory policy is quickly changing, repeating historical approaches can mean missing opportunities to lessen burdens or decrease costs. Having an external team of experts with years of varied industry experience and pressure tested practices can open the door for your company to consider new approaches to old practices.
What is assessed during a clinical pharmacology gap analysis?
Clinical pharmacology program needs can be diverse and complex and are unique to each compound. In addition, the needs vary throughout development. Unfortunately, there’s no “cookie-cutter way” to address all the compound-specific needs. However, best practices can be employed.
The gap analysis data review considers clinical pharmacology needs. Some needs apply to all drugs, such as single and multiple dose pharmacokinetics (PKs) or characterization of elimination and metabolism. Other needs—such as food effects, drug interactions, dose justification, QT prolongation, and quantitative strategies—are tailored to your compound.
Once all the needs have been identified, the next question is how and when to assess each. Accomplishing this requires considering your asset’s timeline. Is it a breakthrough therapy? Will you seek accelerated or regular approval? What is the FDA’s overall tone regarding your compound? What do other global regulators expect? Understanding these considerations will ensure that the gap analysis provides appropriate recommendations for your situation.
Why early planning is best
Early strategic planning can streamline your development by ensuring that studies capture the data needed to support decision making and future strategy. Although my personal experience is heavily founded in FDA regulations, many Certara Strategic Consultants have vast global experience. Early global planning can diminish the pharmacokinetic/pharmacodynamic (PK/PD) bridging needs and facilitate global phase three programs.
In addition, early strategic planning also allows combining coinciding needs into protocols to answer multiple questions. I refer to these protocols as “cornucopia studies,” as they often combine two or more sequential or parallel arms into one protocol. This bundling can diminish protocol and operational burden. An added benefit is that control arms can be realized more than once, which can diminish the number of study subjects needed and thereby reduce overall cost.
Being prepared with proper data collection, programming, and analysis enables “go/no go” decision making during development. Many clients request models to be built to simulate alternative doses or dose regimens while they’re in the middle of phase one dose escalation studies. While this is a legitimate request, it often is made in urgency without early planning or guidance by clinical pharmacologists or pharmacometricians who understand that this exercise takes time and requires organized data. Developing modeling plans early so that data sets are ready and resources are planned is an invaluable advantage to ensuring your data will be “model ready” when the need arises.
Early planning and execution of clinical pharmacology studies can inform modification of inclusion-exclusion criteria. These modifications can expand the patient population for subsequent trials and lessen restrictions for food and even co-medications during development.
Regulatory expectations: Investigational new drug (IND) stage
Some sponsors think that they don’t have to worry about these considerations until they submit the NDA or biologics license application (BLA). But, that’s not the current reality. During the pre-IND and IND phase, the FDA is mostly focused on safety. So they will ensure that the inclusion-exclusion criteria align with product characteristics, especially as they relate to drug elimination and metabolism.
By the end of phase one (EOP1) or end of phase two (EOP2) meeting, the FDA will expect an integrated exposure-response based dose justification. Even for oncology drugs, the maximum tolerated dose approach is not an acceptable dose justification approach anymore. At this stage, the FDA will also be looking for your clinical pharmacology development plans and quantitative methods plans. And they will ask whether you plan to include sparse sampling in future studies and, if so, how will you utilize this data for analysis?
If clinical pharmacology plans are missing from the EOP1 or EOP2 briefing packages, you risk receiving a FDA list of standard comments. You will then have to respond to these comments, likely in a Type C meeting. This requirement can be burdensome as it requires additional resources and medical writing. By the time you hit Pre-NDA, the goal is to focus the discussion on what would be included and how the analyses will be summarized in the NDA module. The pre-NDA meeting is not to discuss development strategy.
NDA stage: FDA OCP Question Based Review (QBR)
The FDA Office of Clinical Pharmacology (OCP) employs a question based review (QBR) template for all NDA and BLA submissions. The QBR template was updated a year ago and has been utilized in many 2017 approvals. The new QBR is focused around dosing with regard to food effects, DDIs, and alternative doses for sub-populations.
In addition, many developers overlook the first QBR question (“To what extent does the available clinical pharmacology information provide pivotal or supportive evidence of effectiveness?”). In short, your clinical pharmacology program can be used as evidence of effectiveness to diminish the requirements for two adequate and well-controlled studies. This is typically accomplished through robust understanding of the dose and exposure-response relationship for efficacy or surrogate markers of efficacy and requires advance planning to be successful.
To learn more about how clinical pharmacology gap analysis can create value, please watch this webinar I presented on this topic.