FDA solidifies its advice on dose optimization for oncology products

Just over a year after it released the draft guidance, the FDA has finalized its guidance on dose optimization for oncology products. In this analysis, AgencyIQ has combed through the newly released final guidance document to tease out what’s new and what’s the same. We will discuss the context and implications of some of the changes in an upcoming second analysis.

By Rachel Coe, MSC | Aug 12, 2024 6:15 PM CDT

Background

  • For decades, sponsors have turned to maximum tolerated dose (MTD) as the primary method for dose selection in oncology. In early-stage development of traditional cytotoxic oncology drugs (i.e., chemotherapies), sponsors have historically pushed the envelope to find the highest tolerable dose when conducting clinical trials for oncology products, since higher doses generally mean increased efficacy for these products. These products have well-characterized pharmacology; sponsors have an understanding of the tradeoff between dose response and toxicity, with each climbing steeply in these products with narrow therapeutic indexes. The MTD represents the point at which the serious toxicities outpace the therapeutic benefits of these products.
  • Even though chemotherapies, both as monotherapy and in combination with other products, have become a mainstay in the treatment of most cancers today, they present many drawbacks. These cytotoxic chemicals have broad distribution throughout the body following administration; by non-selectively targeting rapidly dividing cells, they can cause debilitating and even fatal side effects. Furthermore, these products present risk for serious harm if administered incorrectly.
  • As the field has moved into a new era of oncology products, the MTD approach is less useful. Some treatments with more targeted effects, such as immunotherapies and new molecular targeted agents (MTAs), may present more favorable side effect profiles, while achieving their effects using different—and often more complex—biological pathways. As opposed to the linear dose-response relationships of chemotherapies, the wide therapeutic indexes of many of these newer therapies means that doses can be increased without simultaneously increasing toxicities. However, maximum therapeutic benefit may be reached at relatively low doses for some targeted therapies, before toxicities are experienced. Other issues also arise: Unlike conventional cytotoxic drugs where the relationship between early (e.g., intermediate or surrogate) endpoints and clinical outcome endpoints (e.g., overall survival) are more consistently observed, targeted therapies might improve overall survival without displaying any effect on a commonly measured intermediate endpoint. Further, some newer therapies are associated with immune-mediated adverse events such as cytokine release syndrome that are not always dose-related. Additionally, some immune modulators are meant to be taken chronically, with toxicities that may not appear for months, or even longer.
  • Further, even for conventional cytotoxic therapies, this “highest dose” approach ignores a number of factors, including target interactions and off-target toxicities, longer-term toxicities, and safety considerations outside of dose-limiting toxicities. And regardless of the type of therapy, dose-limiting toxicities may result in dosage interruption, de-escalation, and even discontinuation, in the clinical trial setting as well as with real-world dosing.
  • Returning to long-term considerations, diagnostic and therapeutic advances in oncology have moved many cancer types into the categories of curable or treatable diseases. The areas within oncology that have seen the most success in terms of new and effective treatment options are now entering a new paradigm where the terms “success” and “harm” are being redefined. Previously, burdensome side effects may have been written off as a necessary part of a relatively short course of treatment, with benefits measured in additional weeks or months of survival time.
  • Today, though, patients, clinicians, and regulators expect more. As long-term treatment options become more prevalent, some cancers are being treated like chronic conditions, leading to questions and concerns about long-term effects that can now be measured on a longer time scale as more patients are living longer. The MTD approach evaluates only a few patients at each dose, utilizes a short observation period to observe dose-limiting toxicities (DLTs), and provides limited information on safety beyond DLTs, making it challenging to get a realistic picture of long-term safety and tolerability.

What came before this final guidance

  • Dose optimization for oncology products has been an issue flagged for improvement even prior to the creation of FDA’s Oncology Center of Excellence (OCE) in 2017. However, in recent years, FDA leadership has gradually taken an increasingly stronger stance that the era of simply defaulting to MTD is coming to an end. In parallel, stakeholders have advocated for recognizing the importance of treatment tolerability when determining doses and regimens. The side effects of some newer anticancer treatments can also result in dose interruptions or de-escalations, or even outright discontinuation of an efficacious therapy. These issues are especially apparent in treatments that are intended for chronic use. As a result, products receiving approval due to their demonstrated safety and efficacy in the clinical trial setting may lack real-world effectiveness, with patients failing to see material benefit as they deal with persistent and severe side effects.
  • In 2021, FDA’s efforts on dose optimization came to the forefront with the announcement of Product Optimus. At the time, OCE Director RICHARD PAZDUR remarked that the field of oncology had long suffered from a cultural bias that “more is better” when it comes to dosing oncology products. “We’re not asking anything more than [we are for] any other therapeutic areas,” Pazdur explained, adding that OCE is “going to start making it more of a requirement” that companies conduct dose-finding to facilitate optimization and that it is in companies’ “best interest” to follow this approach.
  • In January 2023, FDA’s work on dose optimization made the leap from research to policy, starting with the release of OCE’s long-awaited guidance on dose optimization for oncology products. In the guidance, FDA outlined why the MTD strategy is particularly inappropriate for targeted therapies, which “demonstrate different dose-response relationships compared to cytotoxic chemotherapy, such that doses below the MTD may have similar efficacy to the MTD but with fewer toxicities,” according to the guidance, which also noted that “Additionally, the MTD may never be reached in certain situations.” The FDA also noted the shifting considerations for evaluating toxicity in modern products meant for long-term or chronic use. Furthermore, the guidance noted that when subsequent indications are being considered for already-approved products, sponsors should recognize that dosages may differ because of differences in the tumor biology, patient population, and concurrent treatments, among other reasons. Accordingly, nonclinical and clinical data will need to be gathered to support a subsequent indication, the guidance document clarifies, adding that “strong rationale for choice of dosage should be provided” before a registration trial for a new dosage is launched. However, the response to FDA’s draft was mixed, ranging between solid support and fervent opposition to the operational approaches proposed by FDA’s guidance. [Read the analysis of the comments submitted here]
  • Since then, this topic has continued to be a priority for the FDA. Just a few months after the draft guidance on dose optimization was published, a handful of OCE staff, including its leaders, published a landmark article in March 2023. Foreshadowing several announcements that followed, the publication casted doubt on several of the most popular surrogate endpoints used for oncology approvals and proposed a few potential explanations for why they sometimes appear to diverge from long-term, outcome-related clinical endpoints. The possibilities cited included magnitude of effect, trial design, inadequate attention to dose optimization, and differential effects on various subpopulations within the overall intent-to-treat population. In particular, the paper stated that the relationship between dosage, toxicity, and efficacy or dose optimization is not always adequately explored by sponsors before initiating randomized trials for drug registration. And as investigational drugs are increasingly delivered orally and for longer periods of time, better dose optimization is critical to maximize adherence. Furthermore, the authors stated that inadequate attention to dose optimization, for both monotherapy and combination regimens, may contribute to randomized trials with potential overall survival (OS) detriments.

What’s new?

  • On Friday, the FDA issued its final guidance on optimizing the dosage of human prescription drugs and biological products in treating oncologic diseases. Per the Federal Register notice, the agency made a handful of changes to the draft based on stakeholder feedback, including an enhanced focus on “FDA’s availability to provide product-specific advice since there is not a one size fits all approach and clarity on the collection and analysis of key pharmacologic data.”
  • Scope: In line with the draft, the final version of the guidance provides general recommendations to sponsors on how and when to perform dose-finding studies to “adequately evaluate a range of dosage(s)” and select appropriate dosages to be further investigated with consideration for “all available clinical data, and a preliminary understanding of dose- and exposure-response (such as for safety, tolerability, and activity).” Likewise, it still omits radiopharmaceuticals, cancer vaccines, cell and gene therapy products, and microbiota-related products from its scope. The final version newly clarifies that oncolytic viruses also fall outside the scope of the document and includes a new disclaimer that the guidance is not intended to address unique considerations of pediatric drug development.
  • In general, the take-home messages from the background and introductory portions of the guidance are the same as they were in the draft. The background section outlines the shortcomings of the long-standing MTD strategy and explains why this approach is particularly inappropriate for targeted therapies, which “demonstrate different dose-response relationships with wider therapeutic indices compared to cytotoxic chemotherapy, such that doses below the MTD may have similar activity to the MTD with fewer toxicities or the MTD may never be reached,” according to the guidance. The FDA makes the additional point that many modern therapies are meant to be taken for long periods of time, even chronically in some cases, shifting considerations for evaluating toxicity. Several minor changes scattered throughout these sections rein in some of the previous draft’s wide-ranging assertions about the process used by sponsors to select a product’s dosage. For example, the draft stated that after identifying the MTD, “Sponsors typically administered the MTD, or a dosage close to the MTD, in subsequent clinical trials without further efforts to optimize the dosage.” The final guidance removes the latter half of this sentence. It also newly adds that, “In some cases, adverse reactions may negatively impact overall survival,” a point that we have heard several times from OCE leadership in recent years.
  • Dosage optimization recommendations: As before, the guidance states that the dosages selected for administration to patients in a clinical trial should be supported by “relevant nonclinical and clinical data,” as well as what’s known about both dose-response and exposure-response for the candidate drug or biologic in terms of both safety and efficacy. The FDA will take a dim view of approaches that select doses “without adequate justification or consideration of all relevant data,” both because of the potential risk to patients and because the trial design might not be able to meet its stated objectives. The guidance emphasizes that identification of an optimized dosage(s) can occur prior to or concurrently with the establishment of the drug’s safety and efficacy; however, this process should occur prior to the submission of a marketing application. Another addition to FDA’s general advice is a recommendation for sponsors to engage early with the FDA “early in clinical development” (as opposed to “at relevant milestone meetings”).
  • Pharmacokinetic (PK) sample and analysis planning: Generally, the recommendations in the final guidance are nearly identical to those contained in the draft, with a few exceptions. Trials involving dose-finding should feature a robust clinical pharmacokinetic (PK) component that includes PK characteristics such as linearity, absorption, and elimination of the product, “following the first dose and at steady-state (or after administration of multiple or repeated doses if steady-state will not be reached) for each dosage evaluated in the trial.” The distinction between first dose and steady state is new to the final version of the guidance. Still, it reiterates that a pre-specified sampling and analysis plan should support population PK and the required analyses of dose-response and exposure-response relationships.
  • Timing of population PK and exposure-response analyses: Another change is the final version now clearly recommends that recommends that these analyses should be initiated early and updated as additional data become available to “identify specific populations (e.g., defined based on weight, age, sex, race and ethnicity, organ impairment, genetic factors) in which the PK demonstrate clinically meaningful differences in exposure.” It further clarifies that the metrics used in these analyses “for evaluating safety (such as laboratory data and adverse events) and activity (such as tumor-assessment based endpoints or other biomarkers) should be appropriate for the stage of development, drug, and disease setting”; also, they should incorporate relevant covariates.
  • To be [administered with] food or not to be? The draft specified that 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 dosage(s) selected for evaluation in a registration trial(s) with food.” The final version refers to “pivotal trial(s)” rather than registration trials, and also tacks on the phrase “when applicable” to the end of the sentence.
  • Model-informed approaches and leveraging previously collected data: The incorporation of this new theme starts with the addition of a recommendation that sponsors should consider whether the FDA’s Model-Informed Drug Development (MIDD) paired meeting program could be utilized. Furthermore, the guidance later (page 5) endorses the use of semi-mechanistic or mechanistic modeling to support the selection of dosage(s) to be evaluated in clinical trials. Regarding the design of trials to compare multiple dosages, it newly adds that “Data from products in similar classes or with the same mechanism of action can also be used, when appropriate, to support the dosages for further evaluation, if relevant” and that “Model-informed or model-based approaches can be helpful to identify and select the dosage(s) to be compared.”
  • Other trial design considerations: The importance of randomization was emphasized in the draft and has been carried through to the final version. Additionally, the final version endorses two new measures to improve the rigor of oncology trials and the analyses of their results. First, it states that “blinding patients and investigators to dosage arm assignment may be considered as there could be bias that higher dosages are associated with greater activity.” Secondly, it notes that “If crossover is permitted, the analysis plan should pre-specify how safety and activity will be assessed to account for crossover.”

What’s next?

  • One of the most subtle yet significant differences between the draft and the final guidance is the language used to define dosage optimization. While the draft stated that the term “optimal dosage” referred to the “dosage that can maximize the benefit/risk profile or provide the desired therapeutic effect while minimizing toxicity,” the final guidance explains the concept differently. Instead of suggesting that a singular, optimal dosage exists for each product—the new guidance discusses dose optimization as the process used by sponsors to arrive at an optimized dosage, with the identical wording to define this term as was used in the draft version. It goes on to acknowledge that the best approach for identifying optimized dosage(s) “depends upon a variety of factors including but not limited to the drug class, proposed indicated patient population, and prior knowledge about the drug that is pertinent to dosing.”
  • This slight adjustment corresponds directly to the concerns of patient advocacy organizations, who suggested that the term “optimal dose” is deceptive. By the reasoning of these groups, since the word “optimal” denotes a singular, best version of something, the phrase “optimal dose” leads patients into falsely believing that sponsors have undertaken a process to identify the singular, best dosage of a product. The result, as articulated by the LUNGevity Foundation, is that it overpromises the results for patients who may “believe that with dose optimization in place, drug toxicities and dose reductions will be things of the past. However, in reality, no dose will be ‘best’ for everyone regardless of how carefully and with how much information it was selected.” In turn, it requested that OCE adopt “more practical language, such as ‘dose selection,’ and be candid about what the new expectations for arriving at the recommended dose will—and will not—mean for patients.”
  • What happens if sponsors do not adequately support the dosage(s) selected for use in clinical trials? Clarifying the consequences of a trial design that FDA deems deficient, the guidance newly adds that this may cause the FDA to place a protocol on clinical hold. Once again, it states that products being developed under expedited pathways will not be given special treatment. The agency makes this clear in no uncertain terms: “Sponsors should note that development of a drug under an FDA expedited program (e.g., breakthrough therapy designation) is not a sufficient justification to avoid identifying an optimized dosage(s) prior to submitting a marketing application.”
  • Stay tuned for Part 2 of Agency IQ’s analysis of the final guidance.

To contact the author of this item, please email Rachel Coe ( rcoe@agencyiq.com).
To contact the editor of this item, please email Kari Oakes ( koakes@agencyiq.com).

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