Three strategies to meet Project Optimus requirements

By Amy McKee, M.D., Chief Medical Officer & Global Head, Oncology Center of Excellence
Sinan Sarac, M.D., Ph.D., M.Sc. , Vice President, Technical - Regulatory Strategy
Pengfei Song, Ph.D., Vice President, Regulatory Strategy

7 min

Three strategies to meet Project Optimus requirements

The FDA’s Project Optimus, launched in 2021, transformed the study designs and dosing assumptions that had dominated decades of oncology drug development (Table 1). The agency hopes that the added time and cost of collecting comprehensive dose- and exposure-response data will benefit patients by ensuring that cancer drugs are effective and safer and improve their quality of life. It also should benefit sponsors by defining the benefit-risk profile of new cancer products more precisely. Recent studies have found that treating patients with lower doses of precision oncology medicines for a shorter duration may lessen toxicities, allowing patients to remain on treatment longer, ultimately leading to better efficacy.1

A ‘perfect storm’ of challenges for small biotechs

Extensive dose optimization requires sponsors to enroll more patients, gather more data, conduct more thorough analyses, and spend more time and resources on early-stage oncology trials. This can be challenging for small biotechs with limited funding and in-house expertise. In 2022 and 2023, emerging companies faced a “perfect storm” of increased dose-optimization requirements, inflation, and high interest rates.

However, small biotechs play a critical role in precision oncology, originating 46% of first-in-class cancer drugs approved by the FDA from 2010 to 2020.2 At Parexel, we work with sponsors to develop regulatory strategies that achieve comprehensive and compliant dose-optimization within their business constraints. We’ve identified three strategies that work.

1. Design an integrated first-in-human study

We advise sponsors to use an integrated first-in-human trial design that mitigates risks by systematically removing the uncertainties at each stage.

We advise sponsors to use an integrated first-in-human trial design that mitigates risks by systematically removing the uncertainties at each stage.

Recently, we met with a small biotech company that wanted to conduct a simple dose-escalation trial so they could show investors quick progress and seek the next round of funding. The company felt that designing an adaptive Phase 1-2 trial to cover dose escalation, optimization, and expansion in a single protocol was too complex and time-consuming. But this was short-sighted, because submitting a Phase 1a dose-escalation trial for IRB and ethics committee approvals to activate sites—and then repeating the process for a Phase 1b dose-optimization trial—is inefficient; the sponsor could pursue a seamless design that proceeds through the process just once. Slowing down for a few months to design a robust, flexible, data-rich, and adaptive Phase 1/2 trial will result in a faster overall development time. A sponsor can always pause between portions of a seamless trial to seek investors or a co-development partner. 

Slowing down for a few months to design a robust, flexible, data-rich, and adaptive Phase 1/2 trial will result in a faster overall development time. A sponsor can always pause between portions of a seamless trial to seek investors or a co-development partner.

An integrated FIH study includes three stages:

Dose escalation: Pre-Project Optimus, the goal of dose escalation was to find the maximum tolerated dose (MTD). Now, the goal is to find a range of effective doses for further optimization. In the initial dose escalation phase, sponsors enroll patients in a prespecified set of doses. Based on preclinical toxicology or other data, this will include the starting dose, an escalation scheme, a target dose, and a maximal dose. Many companies use the classic toxicity-based 3x3 format at this stage to collect safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) data. However, we suggest they explore more flexible trial designs that leverage the available nonclinical data and modeling techniques to determine a range of effective doses.

After establishing safety, we recommend that sponsors backfill up to ten patients at various stages of disease progression into each potential effective dose cohort to detect an early signal of anticancer activity. A backfilling strategy can determine the lower bound of the effective dose range with a prespecified overall response rate (ORR): MTD or PK/PD modeling and simulation can determine the upper bound.

Dose optimization: Sponsors must select at least two doses for the dose-optimization phase. We recommend randomizing patients to the dosage arms per FDA guidelines instead of using alternate unblinded assignments. Randomization reduces the likelihood of systematic bias between arms, which could make results uninterpretable. Sponsors are sometimes shocked to learn that the FDA expects a sample size of between 20 and 40 patients per arm for the randomized dose-finding stage. They also must set futility and response criteria to decide which dose to advance as the recommended Phase 2 dose (RP2D). 

The patient population for the randomized dose-finding study should be relatively homogeneous. Non-clinical findings, epidemiology, and clinical outcomes—including PK, PD, safety, and anticancer activity—from the escalation stage can be pooled to determine dose levels for further testing. 

Dose expansion: The final stage of a Phase1/2 trial offers sponsors with robust data a chance to expand a cohort (or cohorts) for breakthrough therapy designation (BTD) or even accelerated approval (AA).

2. Reach agreement with the FDA at each step

In January 2023, the Oncology Center of Excellence released a draft guidance on dose optimization for oncology drugs.3 Milestone meetings, such as the pre-investigational new drug (pre-IND) and the Initial Targeted Engagement for Regulatory Advice on CBER/CDER producTs (INTERACT) meeting, are valuable opportunities that sponsors should seize. However, additional FDA meetings are needed to de-risk a dose-finding strategy at each stage of a seamless trial. The agency has clarified that discussions about dose-finding strategies need not be tied to milestone meetings. Sometimes, a separate meeting is warranted as clinical data becomes available.

We advise clients to design a randomized dose-finding study after analyzing all the data from preclinical studies and clinical data from the dose escalation portion of an integrated trial and meet with the FDA before they initiate the study. Companies need to present a complete data package to justify the dose optimization plan, including the following:

  • A summary of how the sponsor identified the range of effective doses for further testing with an upper and lower bound, the design of the proposed randomized dose-finding portion of the trial—including the patient population and sample sizes—and how the doses will be modified for adverse reactions and specific populations.
  • All nonclinical and clinical data (safety and tolerability, antitumor activity or efficacy, PK and PD data) that provide a preliminary understanding of dose- or exposure-response relationships.
  • A model or simulation of the relationships that can be adapted as new data become available

The goal of the meeting should be to reach an agreement with FDA review teams on the dosage(s) for optimization and subsequent clinical trials. After randomized dose optimization is complete, we advise clients to meet again with the FDA to agree on the RP2D determination based on integrated dose-exposure-response analyses with the emerging data.

3. Challenge guidelines with a compelling rationale

We recently advised an emerging company developing a promising precision cancer medicine that Project Optimus guidelines would require them to enroll at least 20 patients per arm for dose optimization. They did not have the money to fund such a trial, and the competition for patients was fierce in the target condition. However, their treatment showed no safety signals at any dose levels they tested during escalation. In a case like this, we advise presenting regulators with the option of backfilling 5 or 10 patients to two of the dose levels in the escalation part rather than enrolling 40 additional patients in optimization arms. The sponsors should better characterize the safety profile of the most promising doses and request that regulators allow them to select one and proceed directly to the dose expansion stage.

A regulatory guideline is not the law, and development decisions are the sponsor’s responsibility. If sponsors can justify deviating from the guideline with scientific evidence, they should make their case. For example, one consequence of Project Optimus is that enrolling large numbers of patients in dose optimization arms is increasingly slow and difficult because the demand for patients has increased. Recruitment is especially problematic when sponsors of multiple products targeting the same genetic mutation or pathway compete to enroll the same pool of patients. The FDA understands this issue and may sometimes help to accommodate it.

Understanding nuances in the attitudes and priorities of regulators is critical to crafting an effective strategy and making compelling arguments.

The days of cursory dose-finding in oncology are long gone

Sponsors who don’t generate enough data to justify their Phase 2 dosing strategy could face significant delays, including clinical holds and requests for additional Phase 2 trials during development, and refuse to file (RTF) decisions and complete response (CR) letters during FDA review of the marketing application. Finding the optimal dose(s) early and properly improves safety and potentially decreases development time and cost. Using adaptive designs and a model-informed drug development (MIDD) approach for early-stage trials and prioritizing early interactions with regulators leads to smoother regulatory approval, fewer post-marketing requirements, and faster reimbursement.


Table 1. How Project Optimus reprioritized cancer drug development

Old Framework

Project Optimus Framework

The pre-IND meeting is perfunctory. 

Initiate your Phase 1 trial as quickly as possible. In-person IND meetings are not necessary.

The pre-IND meeting is imperative. 

Use the IND meeting to pressure test your overall drug development plan, including the dose-finding strategy

Meet with the FDA at the End of Phase 2 (EOP2). 

Determine the recommended Phase 2 dose (RP2D), then run the Phase 2 trial(s). Use the EOP2 meeting to reach agreement with the FDA on the pivotal trial design.

Meet with the FDA during Phase 1-2 development.  

Interact with the FDA early and often via End of Phase 1 (EOP1), Type C, and Type D meetings. Present regulators the totality of available evidence to justify your dose-finding strategy and RP2D determination with emerging clinical outcomes. Ensure that FDA agrees that your dose justifications and efforts are adequate.

Safety is the primary objective. 

Find the highest tolerable dose for maximal response.

Safety and efficacy are both considered. 

Find a well-tolerated dose that achieves optimal balance between safety and efficacy. Optimal dose means the dose cannot go higher or lower. 

Find the maximum tolerated dose (MTD). 

Once you determine the MTD, proceed directly to Phase 1b/2 or possibly a pivotal trial with a single dose.

Identify a range of active doses. 

Test multiple dose levels in subsequent dose expansion cohorts or randomized dose-finding studies for dose optimization before determining RP2D. The MTD approach is not acceptable anymore.

Use a static, rules-based 3+3 dose escalation design. 

Enroll as few patients as possible in 3-person increments to reach the recommended Phase 2 dose (RP2D).

Use flexible and efficient trial designs. 

Capture efficacy and safety across a range of doses, expanding cohorts to find the optimal dose. 

Speed through early development. 

Proceed from dose escalation to a single expansion cohort as soon as possible.

Explore dose-/exposure-response thoroughly. 

Conduct integrated dose-exposure-response analyses. Pool all available nonclinical, pharmacokinetics, and clinical outcomes data, including safety (conventional safety biomarkers and clinical events), pharmacodynamics (target-engagement and pathway-related biomarkers) and efficacy (radiographic and blood-based biomarkers).

Focus on severe and life-threatening toxicities. 

Grade 3 or higher adverse events (AEs) are the most important dose-limiting toxicities. Collect patient-reported outcome (PRO) data about tolerability later in development, if at all.

Safety includes quality of life. 

Collect PROs early in development with tools such as CTCAE-PRO. Consider all AEs, including low-grade ones such as mild diarrhea or pain. Assess general safety and tolerability using objective and subjective tools at each dose level. Consider the totality of the data in the context of pharmacodynamics and efficacy to refine the dose.

Advance all cancer drugs as quickly as possible. 

Late-stage trial failures are an expected part of the “cost of doing business.”

Advance only the most promising molecules. 

Use a seamless Phase 1b/2a study to improve Go/No-Go decisions by systematically removing uncertainties. “Fail fast” rather than rush into a Phase 2b/3 trial with incomplete evidence.

Expedited regulatory programs lower the evidence bar for dose optimization. 

For example, Breakthrough Therapy Designation and Accelerated Approval drugs require fewer trials.

Evidence-based dose selection and optimization is essential for all anticancer drugs. 

Sponsors must conduct adequate dose-finding studies regardless of which regulatory pathway a drug utilizes.

Post-marketing commitments are commonplace. 

Let physicians sort out the dosing details once a drug is approved.

Characterize the relationships among dose, exposure, safety, and efficacy during pre-market evaluations. 

Sort out the dosing details before approval.  

Sources: Parexel expert analysis and Friends of Cancer Research Q&A [April 7, 2022] Optimizing Dosing in Oncology Drug Development.

Key to acronyms: CTCAE=Common Terminology Criteria for Adverse Events; DMC=Data Monitoring Committee.

Contributing Expert