Dose Matters: Navigating FDA Guidance for Oncology Drug Development

 Part 1 of 2 – Embracing a New Era of Dose Optimisation

For the last few years the FDA has been engaging with drug developers to reform how dose optimisation is approached for new cancer drugs. In August 2024 they finalised the eagerly-awaited guidance for industry “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases” [1]. As part of our collaboration, Weatherden and Physiomics have worked together to help you understand and put this framework into action. Although this guidance is currently focused on oncology products, the potential benefits of these recommendations are true across therapeutic areas. 

Why this Guidance matters 

As cancer drugs have evolved from systemic cytotoxic agents to targeted therapies modulating specific biological pathways, the acceptability of selecting the Maximum Tolerated Dose (MTD) as the proposed therapeutic dose for subsequent development and/or the to-be-marketed dose has come under increasing scrutiny. Given the wider therapeutic index and different dose-response relationships often associated with the newer generation of targeted drugs and immunotherapies, it can be possible to achieve the same or higher level of efficacy at lower doses – potentially with lower levels of toxicity (Figure 1).  

This goal of reducing unnecessary exposure, and the subsequent risk of toxicity, is a key driver in this push for change. While this may seem an obvious objective from a quality-of life perspective, this additional scrutiny in dose selection provides an opportunity to optimise the benefit/risk profile of a new drug.  

“Particularly as cancer treatment adopts an increasingly multimodal paradigm, it is crucial that clinical development seeks to rationalise effective doses to avoid drug-drug interactions or accumulative toxicity that may limit treatment tolerability and duration.”

Figure 1 - Typical relationships between drug exposure and the likelihood of a tumour response and dose-limiting toxicity [2]. MTD: Maximum Tolerated Dose. 

Key recommendations from the FDA’s guidance

This guidance aims to ensure drug developers and trial sponsors integrate dose optimisation into early drug development, and/or when applying for changes in indication or usage. The FDA may reject or pause trials if evidence is inadequate. With complex biologics and advanced therapeutics, traditional preclinical models may not effectively predict human therapeutic benefits, hindering novel asset development if careful consideration is not given to how these new criteria will be addressed. 

The guidance highlights the following areas to assist drug developers in planning how to approach dose optimisation: 

1. Collection of relevant clinical PK, PD and pharmacogenomic data, to adequately characterise PK after first dose and at steady state. Early initiation of population PK analyses that can run in parallel and continually update and evaluate dose/exposure-response relationships fully for both PD and safety markers – whilst minimising risk to patients.   

2. Thoughtful design of clinical trials to specifically allow comparison of multiple dosages prior to a registration trial, with sufficient size to provide early evidence of potential anti-tumour activity and safety at each dose level. The guidance encourages the pursuit of randomised, parallel dose-response trials and/or adaptive trials, if relevant, and consider different dosing strategies such as intrapatient escalation or a priming dose depending on drug/combination properties.  

3. Extensive analysis and comparison of safety and tolerability across multiple dosages, including less severe/low grade symptomatic toxicities and patient reported outcomes, with pre-specified stopping rules for excessive toxicity alongside defined interventions to address specific adverse reactions.   

4. Creating drug formulations that allow for thorough dosage exploration, with consideration of route of administration and dose frequency to facilitate range of doses. 

5. Awareness that alternative dosage requirements may be necessary for different disease indications or settings and all available and relevant data should be used to determine if so, or additional dose finding studies performed if required 

A global regulatory shift 

The FDA is keen to ensure past experience of poorly characterised dosing regimens for cancer patients does not continue to be repeated. The finalised guidance is just a part of the framework they have in place, under the umbrella of ‘Project Optimus’.  This entails more than just a guidance document: there are regular workshops, public meetings, stakeholder engagement sessions and a whole toolkit of resources which drug developers can draw on to inform their plans, including recommended information to gather to support dosage decision, e.g. PK characteristics, safety information and MIDD approaches.  

There remain some areas where guidance is still lacking, for example with regards to more detail on statistical approaches and how to tackle combination therapies, but ultimately it is patients who will benefit from this clear stance by FDA. One analysis found that over half of the novel oncology drugs approved by the FDA between 2012 and 2022 were issued post-marketing requirements to collect more data about dosing, clearly something to be addressed for future approvals [4]. 

Growing international alignment 

So far, the FDA is unique in publishing such a guideline, but that doesn't mean other regulators are not taking a similar approach. The European Medicines Agency (EMA) continues to encourage companies to ask questions on dosing during scientific advice meetings as well as having more probing questions during the review of a license application [5]. 

Other global regulatory authorities will also be familiar with Project Optimus, and indeed many will be involved in decisions on dosing in collaboration with FDA through Project Orbis, a multi-agency framework for review of oncology licensing applications. To date this includes Australia, Canada, Singapore, Switzerland, Brazil, Israel and UK. This collaboration underscores a global recognition of the importance of optimising dosing strategies to enhance both the efficacy and safety of oncology therapies. 

What this means for Investors 

The new guidance marks a pivotal shift in how dosing strategies for oncology drugs are developed and evaluated. From a biotech investor’s perspective, this guidance offers several promising implications: 

1. Enhanced Clarity in Drug Development: 
   The FDA is advocating for more rigorous, data-driven approaches in dose optimization, including comprehensive exposure–response analyses and adaptive trial designs. This clarity reduces regulatory uncertainty, potentially streamlining clinical development pathways and lowering the risk of costly late-stage failures. 

2. Improved Safety and Efficacy Profiles: 
   By emphasizing the importance of optimizing dosages to balance efficacy and safety, the guidance could lead to therapies with more favourable risk–benefit profiles. This not only enhances patient outcomes but also increases the likelihood of achieving smoother regulatory approvals, thereby enhancing the commercial prospects of new therapies. 

3. Acceleration of Personalized Medicine: 
   The push for incorporating biomarkers and individualized dosing strategies aligns well with the broader trend toward precision oncology. Companies that leverage these approaches may benefit from faster development timelines and more compelling clinical data, making them attractive targets for investment. 

4. Potential for Cost and Time Savings: 
   With clearer guidelines on what constitutes an optimal dosing strategy, biotech firms can design more efficient trials. This can lead to reduced development costs and shorter time-to-market—a critical factor in a competitive landscape where speed is often linked to market advantage.

   “In summary, the FDA’s updated dosing guidance for oncologic therapies is poised to drive innovation and efficiency in the drug development process. Its emphasis on precision, safety, and adaptability not only supports industry advancements but also creates a more favourable investment landscape in the biotech sector.” 

5. Increased Investor Confidence: 
   For investors, this guidance mitigates some of the inherent risks in oncology drug development by promoting a more predictable regulatory environment. Firms that adapt quickly to these new recommendations may see improved valuation metrics and enhanced growth prospects, making them attractive candidates for future investment. 

The growing role of model-informed drug development (MIDD) 

One of the central themes to this guidance is the emphasis on Model Informed Drug Development (MIDD) to support selection of doses and inform the design of clinical trials. ICH defines MIDD as “the strategic use of computational modelling and simulation (M&S) methods that integrate nonclinical and clinical data, prior information, and knowledge (e.g., drug and disease characteristics) to generate evidence." [6] 

Once seen as a luxury for big pharma, MIDD has received recognition from the FDA for its role in regulatory, clinical, and patient success – with its adoption forming a key part of the regulator’s expectations for cancer drug dose finding in the future. In our next blog we will dive into how MIDD approaches offer a method for articulating the different data sets for justifying optimising dose. 

Ready to make smarter, evidence-based dosing decisions? 

Reach out to Physiomics or Weatherden to discuss evidence-based decision making and quantitative approaches that will ensure you adhere to the FDA guidance described above and maximise your chance of success. 

This article was co-authored by team members at Physiomics and Weatherden: Hayley Close, Mark Davies, Michael Grant, and Simon Hutchings. 

References 

1. US Food and Drug Administration. Guidance for Industry: Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases. August 2024. 

2. Agema BC, Koch BCP, Mathijssen RHJ, Koolen SLW. From Prospective Evaluation to Practice: Model-Informed Dose Optimization in Oncology. Drugs. 2025 Feb 12. doi: 10.1007/s40265-025-02152-6. Epub ahead of print. Erratum in: Drugs. 2025 Mar 20. doi: 10.1007/s40265-025-02174-0. PMID 

3. BALVERSA (erdafitinib) FDA Drug Approval Package. 2019. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212018Orig1s000TOC.cfm 

4. Collins G, McKelvey B, Andrews HS, Allen JD, Stewart MD. An Analysis of Dosing-Related Postmarketing Requirements for Novel Oncology Drugs Approved by the U.S. Food and Drug Administration, 2012-2022. Clin Cancer Res. 2024 Mar 1;30(5):937-941. doi: 10.1158/1078-0432.CCR-23-2268. 

5. European Medicines Agency  EMA presentation on proposals to optimise treatment within current procedures. Cancer Medicines Forum meeting 29 June 2023. https://www.ema.europa.eu/en/documents/presentation/presentation-ema-proposals-optimise-treatment-within-current-procedures-cmf-june-2023_en.pdf  

6. The International Council for Harmonisation (ICH). M15 Model informed Drug development (MIDD) Guideline. Draft 06 November 2024 https://database.ich.org/sites/default/files/ICH_M15_EWG_Step2_DraftGuideline_2024_1031.pdf