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What is the FDA’s Project Optimus & How Will it Affect Oncology Drug Development?

Project Optimus is an initiative proposed by the U.S. Food and Drug Administration’s Oncology Center of Excellence (OCE) which will develop new expectations for cancer drug makers to evaluate the efficacy of a wider range of doses in development and to shift from using maximum tolerated dose (MTD) approaches to establish the dose for pivotal clinical studies.

In this blog, I’ll explain what the MTD approach involves, and why the FDA’s Project Optimus is now moving away from it.

What was the impetus for Project Optimus?

Historically, an MTD is identified in the first-in-patient study via a dose escalation design where cohorts of 3 patients are given increasing drug doses until 2 of the 3 patients experience a dose-limiting toxicity (DLT), which is usually defined as a severe or life-threatening toxic effect. The decision to select the highest tolerable dose evaluated for pivotal clinical studies is a carryover from the cytotoxic drug development era. It is also a reflection of the desire to make oncology drugs rapidly available to patients and the belief that higher drug doses will have better therapeutic activity.

For targeted oncology drugs, giving excess drug over your target may not enhance antitumor activity and may add to DLTs or long-term tolerability issues after multiple cycles.

Targeted drugs are often taken daily for years unlike cytotoxic drugs which are given weekly for about 6 months. Thus, for targeted drugs, the relative tolerability, especially long-term tolerability and tolerance of persistent low-grade toxicities, has become an issue. Patients deserve more thoughtful approaches to dosing, and I think this is where the FDA really sees the need for change.

As a former FDA reviewer, I’ve reviewed drug submissions where it was clear that patients were unable to tolerate therapy but still responded favorably after receiving multiple dose reductions. However, if lower starting doses are not evaluated in development, it is exceedingly difficult to retrofit these findings into an optimal starting dose at the time of approval.

Put bluntly, MTD is easy, but identifying an optimal dose takes time and effort.

What was the genesis of this FDA initiative?

Dose finding for targeted agents has been a recurring topic at the FDA since 2013 when some concerning toxicities were being reported for a recently approved drug. In addition, high rates of dose reductions and general intolerability during new drug application reviews for several targeted agents were a noticeable trend, which led to several post-approval dose finding requirements.

Since 2013, the FDA, American Society of Clinical Oncology (ASCO), American Association for Cancer Research (AACR), and Friends of Cancer research have sponsored numerous workshops, in addition to publications, discussing the need for dose optimization strategies. Project Optimus is an accumulation of these years of learning and discussion. Unfortunately, none of these workshops or publications led to any meaningful changes in the way companies evaluate dosing in early development. Hence, the OCE saw a need to provide a framework, and quite possibly a requirement, for sponsors to follow.

The Project Optimus framework will assist sponsors in establishing an optimal biological dose as they navigate early development and dose finding. In some instances, it may require randomized studies looking at multiple doses to determine what dose to use in pivotal efficacy and safety studies. While many see establishing efficacy across a dose/exposure range as burdensome, in the long term, having this data, benefits patients and sponsors who may need to rely on the collected data later in development as opportunities to expand dosing arise.

How will this affect the current oncology drug pipeline?

No one knows how Project Optimus will impact the current pipeline. But drugs with poor dose optimization or weak dose rationales may have difficulty securing funding or sustaining their current development speed. The FDA is increasingly pushing back on sponsors in investigational new drug (IND) meetings and requesting more information regarding dose and dose regimen justifications which is delaying the start of pivotal efficacy trials.  This impact on timelines may be unsustainable to some high-risk assets (i.e., those being developed in popular indications with marginal risk/benefit).  This could cause a culling in the field, as weak programs are halted. A much needed focusing of efforts may occur as well; since the risk of initiating multiple indication or combination specific expansion cohorts will be untenable until the optimal dose has been identified. Given the saturation of agents in clinical investigation now, this could be a saving grace to allow more patients to enroll into the stronger programs. To learn more about what steps you should take regarding your upcoming oncology clinical trials, please watch this archived webinar:


What Oncology Drug Developers Should Expect from the FDA’s Project Optimus


About the author

Julie Bullock, PharmD
By: Julie Bullock, PharmD

Julie has over 10 years of drug development experience within the FDA and contributed to over 14 new molecular entity approvals. She has unique insights into pediatric development, PK/PD analysis and approaches for biologics, oncology dosing strategy, and development of breakthrough therapies and accelerated approvals.