2025-07-07
美國食品藥品監督管理局（FDA）『Optimus 計畫』：劑量優化策略與應對措施
As oncology treatments evolve from traditional cytotoxic chemotherapies to precision‑targeted agents, the FDA finalized guidance emphasizes the importance of early dose optimization. The guidance—titled “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases” on August 2024—reinforces FDA expectations that sponsors must proactively evaluate efficacy versus toxicity when selecting doses, beginning in Phase I trials ([1], [2]).
Historically, oncology dose-finding studies have prioritized identifying the maximum tolerated dose (MTD), a strategy appropriate for cytotoxic therapies where increased dosing often correlated with enhanced efficacy, despite heightened toxicity. However, with the advent of targeted therapies and immunotherapies, this approach has proven suboptimal, as efficacy may plateau below the MTD while adverse effects continue to escalate.
In response, Project Optimus, an initiative aimed at reforming dose optimization in oncology drug development, advocates for a paradigm shift from the traditional MTD-centric model to a more holistic approach. This new approach emphasizes the integration of pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response analyses early in the clinical development process. The goal is to identify dosing regimens that maximize therapeutic benefit while minimizing toxicity, thereby enhancing patient safety and treatment efficacy. ([3],[4]).
Project Optimus encourages sponsors to engage in early and ongoing dialogue with the FDA to discuss dose optimization strategies. This includes the design of optimized dose-finding studies that evaluate a range of doses to establish a comprehensive understanding of the dose-response relationship. By adopting this patient-centric approach, the initiative aims to facilitate the development of oncology therapies that are both effective and well-tolerated.
Impact of FDA’s 2024 dose‑optimization guidance (Project Optimus) to pharmaceutical companies—particularly startups:
Incorporating the FDA’s final guidance under Project Optimus presents significant challenges for sponsors, particularly smaller biotechnology firms. Since the release of the draft guidance in January 2023, Phase I studies aligned with Project Optimus have become more complex, often requiring extended durations, increased financial resources, and additional operational efforts due to the necessity for more extensive patient enrollment and data collection.
A primary challenge introduced by the final guidance is the heightened requirement for comprehensive data during early development phases. Specifically, there is an increased emphasis on collecting clinical PK data, PD data, and biomarker information that demonstrates biological effects. Many sponsors currently lack robust Phase I plans capable of gathering sufficient data to accurately identify the biologically optimal dose and substantiate the recommended Phase II dose. This deficiency may lead to substantial FDA feedback on Investigational New Drug (IND) submissions, potentially causing delays in development timelines.
Strategy and Recommendation: Early FDA Engagement and Strategic Trial design
To address the above challenges, it is advisable for sponsors to engage in early and continuous dialogue with the FDA is crucial. This proactive communication can help de-risk dose-finding strategies and ensure alignment with regulatory expectations. Additionally, to adopt integrated first-in-human trial designs that encompass dose escalation, optimization, and expansion within a single protocol is one of the strategical options. Such designs can streamline the development process and reduce redundancies, ultimately facilitating a more efficient development pathway.
Conclusion
MTD is no longer automatically equated with RP2D. The FDA now emphasizes a structured dose optimization process, as outlined in the guidance and Project Optimus, which advises the evaluation of multiple dosing levels—considering efficacy, safety, pharmacokinetics, pharmacodynamics, and patient-reported outcomes—to identify the optimal therapeutic dose rather than relying solely on MTD
Efficient Pharma Management Corp, an expert-based CRO with extensive experience in early-phase oncology trials, can support sponsors in implementing dose-optimization strategies from the outset of drug development. Our services include:
[Reference]
[1]: https://www.federalregister.gov/documents/2024/08/09/2024-17771/optimizing-the-dosage-of-human-prescription-drugs-and-biological-products-for-the-treatment-of.
[2]: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases.
[3]: Front Oncol. 2023 Mar 3;13:1144056. doi: 10.3389/fonc.2023.1144056
[4]: Transl Clin Pharmacol. 2022 Jun 22;30(2):71–74. doi: 10.12793/tcp.2022.30.e9
[5]: https://friendsofcancerresearch.org/news/clinical-leader-fda-finalizes-guidance-on-dose-optimization-for-oncology-therapies.
[6]: https://www.fda.gov/media/164555/download.
Historically, oncology dose-finding studies have prioritized identifying the maximum tolerated dose (MTD), a strategy appropriate for cytotoxic therapies where increased dosing often correlated with enhanced efficacy, despite heightened toxicity. However, with the advent of targeted therapies and immunotherapies, this approach has proven suboptimal, as efficacy may plateau below the MTD while adverse effects continue to escalate.
In response, Project Optimus, an initiative aimed at reforming dose optimization in oncology drug development, advocates for a paradigm shift from the traditional MTD-centric model to a more holistic approach. This new approach emphasizes the integration of pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response analyses early in the clinical development process. The goal is to identify dosing regimens that maximize therapeutic benefit while minimizing toxicity, thereby enhancing patient safety and treatment efficacy. ([3],[4]).
Project Optimus encourages sponsors to engage in early and ongoing dialogue with the FDA to discuss dose optimization strategies. This includes the design of optimized dose-finding studies that evaluate a range of doses to establish a comprehensive understanding of the dose-response relationship. By adopting this patient-centric approach, the initiative aims to facilitate the development of oncology therapies that are both effective and well-tolerated.
Impact of FDA’s 2024 dose‑optimization guidance (Project Optimus) to pharmaceutical companies—particularly startups:
Incorporating the FDA’s final guidance under Project Optimus presents significant challenges for sponsors, particularly smaller biotechnology firms. Since the release of the draft guidance in January 2023, Phase I studies aligned with Project Optimus have become more complex, often requiring extended durations, increased financial resources, and additional operational efforts due to the necessity for more extensive patient enrollment and data collection.
A primary challenge introduced by the final guidance is the heightened requirement for comprehensive data during early development phases. Specifically, there is an increased emphasis on collecting clinical PK data, PD data, and biomarker information that demonstrates biological effects. Many sponsors currently lack robust Phase I plans capable of gathering sufficient data to accurately identify the biologically optimal dose and substantiate the recommended Phase II dose. This deficiency may lead to substantial FDA feedback on Investigational New Drug (IND) submissions, potentially causing delays in development timelines.
Strategy and Recommendation: Early FDA Engagement and Strategic Trial design
To address the above challenges, it is advisable for sponsors to engage in early and continuous dialogue with the FDA is crucial. This proactive communication can help de-risk dose-finding strategies and ensure alignment with regulatory expectations. Additionally, to adopt integrated first-in-human trial designs that encompass dose escalation, optimization, and expansion within a single protocol is one of the strategical options. Such designs can streamline the development process and reduce redundancies, ultimately facilitating a more efficient development pathway.
- Early FDA Engagement
- Data Integration
- Strategic Trial Design Options
Conclusion
MTD is no longer automatically equated with RP2D. The FDA now emphasizes a structured dose optimization process, as outlined in the guidance and Project Optimus, which advises the evaluation of multiple dosing levels—considering efficacy, safety, pharmacokinetics, pharmacodynamics, and patient-reported outcomes—to identify the optimal therapeutic dose rather than relying solely on MTD
Efficient Pharma Management Corp, an expert-based CRO with extensive experience in early-phase oncology trials, can support sponsors in implementing dose-optimization strategies from the outset of drug development. Our services include:
- Facilitating clear and ongoing interaction with the FDA to ensure alignment with regulatory expectations.
- Provide strategic consultation in trial designing and clinical operation align with Project Optimus.
- Coordinating pharmacokinetic/pharmacodynamic data and interim decision rules.
[Reference]
[1]: https://www.federalregister.gov/documents/2024/08/09/2024-17771/optimizing-the-dosage-of-human-prescription-drugs-and-biological-products-for-the-treatment-of.
[2]: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases.
[3]: Front Oncol. 2023 Mar 3;13:1144056. doi: 10.3389/fonc.2023.1144056
[4]: Transl Clin Pharmacol. 2022 Jun 22;30(2):71–74. doi: 10.12793/tcp.2022.30.e9
[5]: https://friendsofcancerresearch.org/news/clinical-leader-fda-finalizes-guidance-on-dose-optimization-for-oncology-therapies.
[6]: https://www.fda.gov/media/164555/download.