SVP, Clinical Pharmacology & Translational Medicine

Julie Bullock

Drug developers know it’s coming. The Food and Drug Administration (FDA) Oncology Center of Excellence has made it clear that new dose optimization expectations for oncology drugs as part of “Project Optimus” are on their way.

The FDA has not yet announced the specifics of Projects Optimus’s guidelines, causing developers to react in ways that range from anxiety to postponing action. But not knowing exactly what’s coming doesn’t mean that drug developers shouldn’t wisely prepare by planning for what is known and what can be reasonably anticipated.

Making ready for a situation with “predictable unknowns” is a lot like preparing for a hurricane. As with putting together a package of supplies for your hurricane preparedness plan, you want to get what you need in hand now. You don't want to wait until the hurricane comes.

Oncology drug developers need to start by asking basic questions: Are we collecting enough data from clinical trials to make decisions? Do we have the right experts lined up? Are we ready from a modelling standpoint? How much will our preparations cost and are we planning our finances accordingly? Will we have enough drug product? Drug developers also need to consider if they are allocating enough time for their preparations, as well as for communicating effectively with the FDA.

Though each company’s situation, molecules, pipeline, and approach will be different, marshalling data will be the critical first step for all. This should be based on a gap analysis of the developer’s available data, from existing clinical data in current study plans to nonclinical pharmacology data. Doing so will allow each company to assess whether what’s currently in hand provides enough input to determine optimal dosages, and if not, identify data they need to obtain to enable decisions.

Developers should review data at all available dose levels from PK/PD, safety, and efficacy standpoints. Ask how the human data is aligning with what was understood in nonclinical studies. Look at the future state too: ask if data being collected is relevant to inform decision making, or if additional data will be needed to evaluate or support an optimized dose. Gathering additional data can be done by either adjusting ongoing protocols or planning additional studies.

Once drug developers are confident that they have made provisions to amass enough data, they can plan next steps. They must ensure there is adequate time and resources lined up to support the analyses FDA will be looking for with dose justification submissions. Most companies don’t have the ability to support complex modeling exercises in-house; they may gravitate towards a more simplistic approach using observed data, which, though valid, can be limiting. Others will invest in external vendors. Whichever approach is more appropriate, developers must make sure they have the experts identified to do required analyses, and that the data is in the right format so it can be easily transferred and analyzed.

Developers also need to plan for when they will seek agency buy-in or feedback on dose and identify what analyses are needed for these interactions. Depending on the meeting type, FDA feedback may take up to 75 days from submission of the meeting request; waiting for this feedback can delay the next phase of development; companies could lose time and money if they fail to plan for these interactions.

Another consideration, which many may overlook, is ensuring the manufacturing process is robust enough to support the additional explorations of dose in early drug development. I had an example recently of a drug developer who only had enough drug product to dose 40 more patients for six months and that additional material would not be available for another 18 months. With this limited supply, they were restricted in their ability to understand dose in a meaningful way.

There will be no one-size-fits-all approach to preparing for Project Optimus. Dose-optimization-specific guidances are not standardized by FDA in other therapeutic areas, so expecting one for oncology may leave developers holding their breath for a long time. In addition, as with other therapeutic areas, developers approach dose optimization in vastly different ways based not only on the character of their programs, but also on of variables specific to them. Optimization strategies are dependent upon each molecule, its mechanism of action, the indication, the risk that a sponsor is willing to take, and the speed at which a developer wants to or is able to move.

Some drug developers have asked, “what if we decide to not optimize the dose now, what's the risk?” Though it may seem that ‘wait-and-see’ is a simpler approach that avoids wasted effort, developers should not pause. The FDA will expect to see efficacy evaluated at more that one dose level before agreeing to a dose and regimen to be used in a registrational trial. Getting ahead and exploring additional doses will avoid delays and put developers in the most advantageous position. Be prepared.

, SVP, Clinical Pharmacology & Translational Medicine

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