Following the 2021 launch of Project Optimus by the Oncology Center of Excellence and an extensive workshop on the topic of dose optimization in oncology trials, the FDA has codified its recommended approach for sponsors. The new draft guidance document has few surprises, making crystal clear that a rational dose optimization plan is now a prerequisite in trials for oncology products.
Background on dose-finding in oncology
- In the early phases of clinical development of oncology products, sponsors conduct dose-finding studies to determine the maximum tolerated dose (MTD) of an investigational product. MTD seeks to find the tolerability and safety of treatment at the highest dose that can both be tolerated and treat the cancer.
- There are several limitations to the MTD approach. This approach, which was initially developed for systemic chemotherapies, is generally no longer applicable to new treatments that are more targeted in their effects, such as immunotherapies and new molecular targeted agents (MTAs). In addition, the MTD approach ignores target interactions and off-target toxicities, evaluates too few patients at each dose, offers only a short observation period to observe dose-limiting toxicities (DLTs), and offers limited consideration of safety information beyond DLTs. These challenges may result in approved treatments that may be poorly tolerated by patients, eventually affecting their quality of life and potentially leading to drug discontinuation.
- There have been several workshops on oncology dose finding hosted by the FDA in the last few years. In 2015, the FDA, along with the American Association for Cancer Research (AACR), held a workshop on dose optimization for small molecules. A year later, a similar workshop was conducted that included biologics and nonclinical models for efficacy, as well as modeling and simulation for dose-finding and dose optimization trials design. A third workshop was held in 2017 and focused on combination products, use of biomarkers and novel endpoints, and modeling and simulation approaches. Friends of Cancer Research (FOCR) has also been working to improve tolerability and dose optimization programs in collaboration with various stakeholders. [Read our analysis of the meeting held by FOCR here.]
- The FDA’s Oncology Center of Excellence (OCE) recently established a new program, Project Optimus, focused on dose optimization. The Project was first unveiled in an interview in 2021 when Richard Pazdur, the Director of the FDA’s OCE, explained that the field of oncology has long suffered from a cultural bias that “more is better” when it comes to dosing oncology products, under the idea that the highest dose that a patient can withstand is preferable to a lower dose. “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. [Read our brief here.]
- Last year, the FDA dedicated a two-day workshop to Project Optimus, partnering with the American Society of Clinical Oncology (ASCO) to focus on dose optimization strategies in oncology drug development. At the workshop, FDA and external presenters highlighted the importance of conducting randomized dose-finding trials early in the development program and of capturing patient-reported outcomes (PROs) when measuring toxicity; presenters also provided strategies for the use of non-clinical pharmacology and model-informed drug development (MIDD) to bolster dose optimization work during drug development. [ Read AgencyIQ’s analysis of the workshop here.]
Now, the FDA has released a new draft guidance document on dose optimization for drugs and biologics to treat cancer
- The new guidance is aimed at sponsors of both prescription drugs and biologics to help them identify optimal doses of their products during the development process, before regulatory submission for approval. The document specifically excludes dose optimization for radiopharmaceutical or cell and gene therapy products; cancer vaccines and micriobiota-related products are also excluded. The guidance also is not meant for “selection of the starting dosage for first-in-human trials,” the FDA clarified.
- In the new guidance document, the FDA outlines 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. “Additionally, the MTD may never be reached in certain situations.” 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.
- The FDA advocates for an approach that can take advantage of the “seamless” design of many newer oncology trials, “characterized by rapid transitions between initial dose-finding trials and registrations trial(s) to expedite development.” With good planning on the sponsor’s part, dose-finding strategies “can be merged into a seamless development program.” In any case, dosage optimization should happen before approval.
General recommendations for dose optimization
- When selecting doses for a clinical trial, sponsors should look to “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 relevant data,” both because of the potential risk to patients and because the trial design might not be able to meet required objectives for approval.
- These considerations also apply to drugs being developed under expedited pathways, such as breakthrough designation. 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 optimal dosage(s) prior to submitting a marketing application.”
The specifics of how to identify optimal dosage(s), according to the draft guidance:
- First, trials involving dose-finding should have a robust clinical pharmacokinetic (PK) component that includes PK characteristics such as linearity, absorption, and elimination of the candidate drug, after multiple doses. The sampling and analysis plan should also support population PK and the required analyses of dose-response and exposure-response relationships.
- When these data are available, they should be evaluated “along with the anti-tumor activity, safety, and tolerability data” to select which doses should be evaluated further. Additional PK and safety data should be gathered, as appropriate, for oral drugs.
- The draft guidance recommends enrolling “an appropriately broad population” to evaluate how the dose will perform in “relevant subpopulations.” Here, the FDA inserts a series of five footnotes referring sponsors to its guidance in related areas, including enhancing diversity of clinical trial populations, making trials available in non-curative settings and for people with organ dysfunction or previous cancers, and more. When doses might differ for subpopulations, these alternative doses can be calculated by “simulated exposure metrics” and included in registration trials.
- Pharmacodynamic (PD) and pharmacogenomic data may also be appropriate for inclusion in the clinical trial; in any case, the FDA should review the proposed sampling and analysis plans before the sponsor proceeds.
- In terms of how dosages should be compared, the FDA recommends a randomized, parallel dose-response trial, when feasible. Though randomization is preferred, the trial does not have to be powered to demonstrate superiority or even non-inferiority of one dose over another. An adaptive design with stopping rules following interim safety and efficacy assessments could be an acceptable strategy, according to the draft guidance.
- Multiple doses can be studied in a registration trial by adding an additional dosage arm or arms. However, a trial that is meant to show that one of the dosages is superior to a control arm should “provide strong control of Type I [statistical] error,” accounting for a design that tests multiple doses against a single control.
- If a sponsor is looking to use safety and efficacy data from multiple doses to support its application for marketing authorization, this design should be discussed with the FDA “early in clinical development.”
- Considerations for evaluating safety and tolerability of doses include capturing a host of variables, according to the draft guidance document. These include duration of exposure, how many patients were able to take all planned doses, and how many patients had dose interruptions, reduction, or discontinuations because of adverse reactions to the candidate therapy. All of these data, as well as the total percentage of patients in each arm with serious or fatal adverse reactions, “should be compared across the multiple dosages,” according to the FDA.
- When a trial will include dosages “associated with a high percentage of dosage modifications or serious adverse reactions,” sponsors should pre-specify safety monitoring rules, including what the sponsor will do if serious adverse reactions or dose modifications cross a given threshold. In such cases, sponsors may pause the trial, reduce the starting dose for future trial enrollees, or even end the trial.
- In a nod to discussions had at the 2022 two-day meeting on dose optimization, the draft guidance notes that some adverse reactions that are reported as “less severe,” such as grade 1 or 2 diarrhea, “may still significantly affect a patient’s ability to remain on the drug for extended periods.” For drug reactions like these, sponsors should track both the frequency and the impact of the reactions on dose interruptions or discontinuations.
- Conversely, for some oncology drugs, the most serious toxicities happen with the first dose, or few doses. Toxicity “may lessen in severity of not occur with subsequent administration” for these drugs; the FDA recommends considering titration or other stepwise dosing “to improve tolerability.”
- Another topic discussed extensively at the dose optimization meeting made its way into today’s draft guidance: PROs. The FDA recommends including PROs “to enhance the assessment of tolerability in early phase dosage finding trials,” since these measures “can provide a systematic and quantitative assessment of expected symptomatic adverse events and their impact on function.”
- The draft guidance document provides considerations for dose formulations, including the admonition that “Perceived difficulty in manufacturing multiple dose strengths is an insufficient rationale for not comparing multiple dosages in clinical trials.” Considerations for both oral and parenteral use are included in the draft.
- Generally, when subsequent indications are being considered, 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. Sponsors should be prepared for the possibility of additional dose-finding studies being required.
- Overall, there are few surprises in this document. The FDA, in this draft guidance, is codifying exactly what it’s been saying for some time, in various venues: That it’s asking sponsors to take seriously their responsibility to find the right dose for the right patient population in the oncology setting. Data presented by the FDA and external participants in various settings recently have clarified that too often, the MTD approach has resulted in dosing regimens that result in many patients experiencing dose interruptions or discontinuations. Newer immunotherapies and targeted agents, some of which may be taken for a patient’s lifetime, call for an updated dose optimization approach in oncology, which the FDA has sketched out in this latest guidance document.
- The draft guidance document will open January 18 for comments via Docket Number FDA-2022-D-2827. Draft guidance documents are typically open for comment for 60 days, though no end date is currently specified.
Featuring previous research by former AgencyIQ Senior Research Manager Kedest Tadesse.
To contact the author of this analysis, please email Kari Oakes ( [email protected]).
To contact the editor of this analysis, please email Alec Gaffney ( [email protected]).