Justin Hay, PhD

In January 2023, FDA published the draft guidance “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases Guidance for Industry.” While not explicitly stated in the guidance materials, this guidance is being interpreted as the more formal codification of the Agency’s expectations associated with Project Optimus which was launched by the Oncology Center of Excellence (OCE) in February 2022. Key takeaways from the guidance are summarized below:

 Anticipating resistance for certain programs or situations, the Agency has given preemptive ‘no-excuses’ advice in the guidance.

First, the guidance states that it is not addressing selection of first-in-human starting dose and does not address dose optimization for radiopharmaceutical, cellular and gene therapy products, microbiota, or cancer vaccines, which implies that all other therapeutic modalities used in the treatment of cancer will be expected to include dose optimization as part of their development program.

In addition, sponsors developing drugs under FDA expedited programs, including Breakthrough Therapy designation, are also expected to conduct adequate pre-market dose optimization.

Lastly, the guidance is clear that operational hurdles such as the unavailability of suitable formulation strengths will not be adequate justification for a lack of pre-market dose finding.

To mitigate impact on development delays, the Agency points to prior use of seamless development approaches and recommends adequate planning to ensure dosage optimization is built into expeditious clinical development and is conducted in the pre-market setting.

The integrated analysis of all available clinical and non-clinical data to enable dose selection for the next stage of clinical development has been a common FDA/OCE theme since 2022, and it also makes its way into the guidance. This includes analysis of all available translational, clinical pharmacokinetic (PK), pharmacodynamic (PD), safety, and efficacy information to provide a stage-appropriate understanding of dose- and exposure-response (E-R) relationships. The Agency has always encouraged the use of population PK and E-R analyses early in development, and this guidance reiterates the importance of and expectation for these analyses early to justify dose levels selected for evaluation in subsequent development stages. Sponsors should plan for these modeling activities early in development and, at a minimum, plan for exploratory graphical analyses between observed exposure metrics, PD, safety, and activity endpoints.

Specifically, regarding clinical safety information, the guidance reiterates the Agency’s message that when selecting doses sponsors should account for lower grade but persistent symptomatic toxicities which may be difficult to tolerate long-term as patients often receive targeted therapies over extended periods of time. Advice is given to interrogate across dose levels the duration of exposure, the proportion of patients who can receive all planned doses, and dosage modifications or treatment discontinuations due to toxicities. Timing of safety events e.g., early-onset, toxicities which may lessen in severity or not occur with subsequent administration vs cumulative toxicities that emerge after multiple dosing should be considered to design alternative dosing regimens such as step-down or step-up and intermittent dosing. The guidance also encourages including patient reported outcomes (PROs) in early phase dosage finding trials to enhance assessing and understanding of tolerability. For oral drugs, the effect of food on PK and safety should be evaluated early in drug development to support the relative administration of the dosages selected for evaluation in any registration trials with food.

Previously limited to confidential sponsor-FDA communications during the IND stage, we now have a public position that inadequately justified doses may lead to potential clinical holds on trials as ‘FDA may determine that patients are exposed to unreasonable and significant risk, or there is insufficient information to determine risk, or the design of the trial is deficient to meet its stated objectives.’

Includingdose finding in development programs will inherently require more data in early clinical studies than sponsors are used to collecting historically. FDA points to this and mentions that following dose escalation, additional exploration may be needed to gather further safety and activity data to inform which dosages will be further evaluated in a dedicated dose optimization trial. To avoid delays, sponsors should plan for flexibility in dose escalation studies to gather this additional data since it will be uncommon for a dose escalation study in and of itself to gather enough data to determine doses that should be evaluated further for safety and efficacy. The guidance does not expand on specific practicalities on how this additional data should be collected such as recommendations for these early trial designs or how much data is adequate to determine dosages to evaluate further, nor does it mention how tumor heterogeneity commonly observed in early studies should be interpreted. We assume the relative vagueness on these topics is implied because the advice for each of these practicalities would be asset specific.

: Those of us hoping that the guidance would provide more specifics on the dose optimization study designs, number of participants, and endpoints will be left feeling a bit empty. The guidance provides consistent messaging with FDA’s workshops, and publications that were held as early as November 2021. While no one-size-fits-all approach is outlined, the guidance does provide valuable advice regarding adaptive designs, safety monitoring rules, statistical considerations, and incorporating multiple dosages prior to or as part of a registrational trial.

The guidance also states, ‘If safety and efficacy data from multiple dosages will be used to support a marketing application, this approach should be discussed with FDA early in clinical development.’ While the Agency’s message here is unclear, we infer it indicates the Agency’s openness to data from robust dose optimization trials being used to support a potential marketing approval.

An important topic that the guidance does not mention is what specific anti-tumor activity endpoints would be considered adequate to compare dosage in a dose optimization exercise. However, the Agency has previously indicated that it is common to base efficacy assessment in such trials on objective response rate (ORR) (+ duration of response; DoR), as it is an endpoint that can be measured earlier and often with fewer patients than time-to-event outcomes such as progression-free survival and overall survival. The Agency considers achievement of response is a direct measure of drug activity.

 However, in settings where ORR is a poor predictor of the ultimate clinical outcome, other outcomes could be considered.

Subpopulations; Are we muddying the waters? 

The guidance also recommends that population PK and E-R analysis should be used to identify specific subpopulations in which clinically meaningful differences in exposure are expected and to identify potential differences in safety or effectiveness for them. The guidance encourages incorporation of alternative dosages for relevant subpopulations into a registration trial ‘when feasible and appropriate’. In most cases, we consider this recommendation related to but distinct from the key issue under Project Optimus i.e., identifying a dosing regimen/exposure that achieves an appropriate risk-benefit balance in the overall population, to which subpopulations can subsequently be ‘exposure-matched.’ However, the Agency might be looking to potentially identify early on, subpopulations in which exposure-response and therefore risk-benefit balance might be ‘shifted,’ in which case exposure-matching might not be an adequate approach to dose recommendation. Either way, it is unlikely that early clinical trials will be able to (or allowed to) enroll adequately across broad subpopulations to facilitate any meaningful analyses. Instead, the additional variability by those who attempt to do this may cloud the already confusing results seen when using limited data to identify trends in safety and efficacy. Like other therapeutic areas, a more simplistic approach would be to keep the early phase studies as homogenous as possible to detect efficacy and safety signals and identify an optimal dose and slowly broaden inclusion/exclusion criteria as development progresses.

Overall, our impression is that the main messages in the guidance are consistent with and build upon the Agency’s messaging about Project Optimus in the recent past. While the draft guidance might appear lacking in detail, which may be filled out during the comments period, we consider the recent publication by Fourie Zirkelbach et al

, a ‘companion publication’ to the guidance. This publication from FDA authors across the Office of Clinical Pharmacology, Office of Oncologic Diseases, and OCE, provides specific case examples and an understanding of the background/ landscape that potentially formed the basis of the recommendations in the guidance.

, PharmD, senior vice president and head of clinical pharmacology and translational medicine, 

, PhD, associate director, clinical pharmacology, 

, PharmD, director, clinical pharmacology and translational medicine, and 

Fourie Zirkelbach J, Shah M, Vallejo J, et al. Improving Dose-Optimization Processes Used in Oncology Drug Development to Minimize Toxicity and Maximize Benefit to Patients. J Clin Oncol. 2022;40(30):3489-3500. doi:10.1200/JCO.22.00371

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