FDA Project Optimus was announced toward the end of 2021 but made a splash in the headlines late last year as it started affecting cancer drug developers. 

IQVIA’s Senior Medical Strategy Lead at the Oncology Center of Excellence, Dr. Edward Espinal, elaborated on the FDA guideline which proposes a shift from the conventional maximum tolerated dose (MTD) paradigm stemming from the development of chemotherapeutic drugs to an optimal dosing development.  

With years of experience under his belt from a combination of well-known pharmaceutical companies such as Pfizer and Boehringer Ingelheim, Espinal is currently using his experience as a trained medical oncologist to develop the most up-to-date strategies to optimize doses for any protocol from sponsors at IQVIA.

"In Europe, the EMA is not yet requesting this but given that the European Society of Medical Oncology (ESMO) collaborates with the MDICT Taskforce, a highly respected multi stakeholder expert consensus group, which have issued dose optimization guidelines akin to Project Optimus, there is a high chance for the EMA and other regulatory agencies such as the Ministry of Food and Drug Safety in Korea to also adopt a similar approach," said Espinal.

What does it mean?

He went on to elaborate that in the past, the development of oncology drugs was centred in cytotoxic chemotherapy which meant that cancer patients had to accept a high-risk scenario for high benefit, resulting in using the maximum tolerated dose as the aim of early phase studies. This outdated system is not well suited for targeted therapies like immuno-oncology drugs and antibody-drug conjugates (ADCs)

MTD describes a dose level that patients did not develop many dose-limiting toxicities which is usually determined by incrementally increasing the dose until you find a dose where many patients are presenting a dose-limiting toxicity. 

The dose below this is commonly used in phases 2 and 3  and subsequently becomes the approved dose, explained Espinal.

"Sometimes we escalate the dose, but the maximum efficacy you're going to get is probably at a lower dose than the MTD," explained Espinal. "If you keep dosing at the MTD, the efficacy eventually plateaus but the toxicity will continue to increase."

The whole idea of Project Optimus is to be patient-centric so that once drugs get approved, they've already been optimized to be the safest within the best efficacy possible to reduce the number of patients exposed to non-optimal doses. 

This signifies good news for patients because by the time a drug is marketed a lot of effort has been used to determine the most efficacious dose with the best safety profile but requires larger efforts in phase 1/2 trials by including more patients, which could cause delays in the early phases of drug development, he noted.

Dose optimization offers added market value

While he admitted that it might be a little bit more stressful and time-consuming for sponsors to devise dose optimization early on, he dispelled common beliefs that the rule will stifle innovation.

“I think it's more akin to how innovation should work as we are finally moving away from a decades-old system designed for chemotherapy drugs,” he noted. "This is going to help innovation as drugs will be more tailored to their actual mechanism of action to determine the dose with the maximum clinical benefit for patients.”

He reasoned that marketing a drug that is too toxic tends to lead to patients interrupting their treatment which can lead to reduced overall survival rates for patients.

Consequently, this represents personalized medicines as the dose can be optimized for indications and even different populations, said the expert.

Espinal also explained that the U.S. comprises the largest oncology market so eventually, a vast majority of Korean biotechs will likely want to launch their drug in the U.S. which means they will be challenged by the FDA.

As U.S. biotechs already engage in early conversations with the FDA pre-IND, coming with a trial design that is already dose optimized, Korean biotechs now have an imperative to catch up to ensure they are not left behind, he went on to say. Even if Korean pharmaceutical companies would like to license out in phase 3 trials, Espinal said that Korean companies should still pay attention to the FDA regulation as it could affect the asset’s market value. Companies will be more willing to license in products if it has already been dose optimized so they can start phase 3 without any problems. 
 

Using modeling and simulation for dose optimization

While Espinal admitted that current guidelines by the FDA on dose optimization are still very broad, he explained that it can virtually be done at any phase but will vary depending on the data available such as pharmacokinetic (PK), safety, and efficacy data, to do modeling and simulation.

“For example, if you have a drug that is targeting a specific mutation such as the HER2 exon 20 insertions, the most frequent indications that present is already known, so when first-in-human trials are started, you can start your dose escalation using data from all comer tumors that have the exon 20 mutation,” said the expert. 

Subsequently, backfill cohorts can be performed to enrich these cohorts to include more patient with one particular tumor indication which accrues more data from phase 1 to be modelled for overall response and other safety endpoints.

On the contrary, if the indication is unknown such as immuno-oncology checkpoint inhibitors, simulations should be conducted on all types of tumors that have a good response to PD-L1 inhibitors. 

“For example, you can gather the necessary safety and pharmacokinetic data in phase one studies and then conduct a phase 1b where you have a dose expansion for different indications, and use that data to devise a model to generate two or three possible doses which can be the optimized dose,” said Espinal.

He said there is a possibility to do dose optimization in phase 3, but it might be "more complicated as you have to factor in a comparator arm with the standard of care, and more adaptive designs to be used."

Consequently, he advised pharmaceutical companies to factor in dose optimization studies in the clinical development plan at phase 1b or phase two or in a seamless phase 1b/2 study to determine which data needs to be captured. Additionally, he encouraged early engagement with the FDA as they support consultations to discuss the trial design and determine whether it falls within the scope of Project Optimus.

“While it may sound like more steps, the FDA wants to see a holistic view and not just phase one safety study,” said Espinal. “It’s all about streamlining the process and dose optimization at an early stage to avoid approval delays.”