Early phase clinical trials remain a critical inflection point for innovative product investment, licensing, and portfolio prioritization. As a consequence of an effort to generate more actionable data earlier in development, these studies are becoming increasingly complex.
First-in-human (FIH) studies continue to assess safety, tolerability, pharmacokinetics, and, frequently, pharmacodynamic biomarkers for many indications in both healthy volunteers and patients; however, now they often inform dose optimization, early signs of activity, target patient population, and the design of later global studies. Early-phase clinical trials are increasingly the stage at which the direction of a development program is set [1,2, 11].
An Emerging Trend in Early Clinical Development
In our experience, early development is increasingly being designed to combine the assessment of safety with the search for early signals of efficacy in a single study. This differs from the more traditional model, where one study focused primarily on safety, and a later study was used to explore proof of concept.
Integrating the assessment of safety and early efficacy of an asset / investigational medical product (IMP) into a single study has some advantages. Stand-alone standard dose-escalation and expansion studies are frequently designed to identify a tolerable dose, but they may not sufficiently characterize dose-response, exposure-response, or schedule-response relationships needed for later-stage confidence, i.e., demonstration of efficacy. Data from a study that integrates safety and efficacy, on the other hand, permits characterization of these relationships, or at the very least, a prediction of these relationships.
From these relationships, a dose can be selected for later phase clinical studies, thus, dose-finding is a critical element in the early clinical development process. In practical terms, a suboptimal early dosing decision can distort safety interpretation, blur efficacy signals, and make later study design materially harder. Early programs can also be weakened when a tolerable dose is identified, but the dose-response relationship needed for confident later-stage selection is not adequately characterized. For this reason, dose selection and dose optimization should be treated not as narrow technical exercises, but as strategic development decisions aimed at maximizing benefit, minimizing unnecessary toxicity, and improving the likelihood of later-stage success [3].
Biomarkers are redefining when proof of concept begins
More recent advances in the identification, analysis, and quantification of molecular biomarkers have contributed to the ability to integrate safety and early signals of efficacy together into studies. Molecular biomarker strategy is changing what early-phase studies can be expected to deliver. While molecular biomarkers have been used for study population selection for some time now, a 2025 review in Frontiers in Immunology points out that biomarker discovery, validation, and enrichment strategies are moving into early-phase trials, with growing use of high-throughput platforms to refine endpoint strategy [4]. The key implication is that proof of concept, i.e., a signal of efficacy due to the IMP's mechanism of action, can be determined earlier in the clinical development process when serial biomarker monitoring is used to detect response. An example of this is the increasing use of circulating tumour DNA (ctDNA) kinetics, which can help sponsors judge whether a signal is biologically meaningful before later clinical endpoints mature or even earlier than conventional imaging [15].
A recent Cancer Cell commentary on (ctDNA) reaches a similar conclusion, describing ctDNA as a practical biomarker tool for detecting targetable alterations, predicting response, monitoring tumour evolution, and informing pharmacokinetic and pharmacodynamic effects in early studies [5]. A 2025 review in the Journal of Experimental & Clinical Cancer Research extends this point, arguing that in addition to patient selection, ctDNA can support earlier decisions on dose optimization, proof of mechanism, and molecular response in Phase I development [12].
The ability to identify an early signal of efficacy through biomarker measurement can be highly valuable to investors because it helps inform which assets to back and how confidently to invest. For sponsors, especially emerging biotechs with limited capital, the impact can be significant.
Biomarkers and Patient Selection
As mentioned previously, in addition to providing an early signal of efficacy, molecular biomarkers are also known to be of value for enabling a more targeted study population patient selection, and this can be advantageous since broad early enrolment can sometimes weaken a program. A broad population may accelerate recruitment or generate exploratory hypotheses, but it can also produce signals that are directionally positive yet not actionable. Adaptive enrichment designs are increasingly being used to address this problem by allowing broader enrolment initially while refining recruitment toward biomarker-defined subgroups as early data emerge. That approach can reduce the risk of diluting treatment effect in heterogeneous populations and improve the likelihood that early findings are decision-ready. For capital-constrained sponsors, biomarker strategy can create the most value when it shapes not only what is measured, but who is studied [12,13].
Operational Execution of Complex Studies
A clear trade-off of this integrated approach is greater complexity in both study design and operational execution.
That complexity raises the importance of operational excellence.
Operational execution quality and scientific quality are intertwined. Small execution gaps erode data quality and decision value in an early study. In early oncology and other complex studies, regulatory timing, site activation, sample logistics, and biomarker turnaround can directly influence screening feasibility, patient eligibility, and the interpretability of early signals. Operational planning is no longer downstream of science. It is one of the conditions that determines whether the science holds up in practice.
A recent Novotech FIH oncology study illustrates this well. The challenge was not speed alone, but coordinating complex start-up requirements across biosafety oversight, site readiness, and parallel regulatory activity while working with a limited pool of suitably experienced sites. The broader lesson is that in complex early-phase studies, start-up quality can directly shape whether early data is robust enough to guide the next decision [14].
Operational execution is a significant determinant of whether early data is either decision-ready or remains merely descriptive. Early-stage programs rarely fall short because there is no data; they fall short because the data generated is not strong enough to support the next decision with confidence. ICH E6(R3), finalized in 2025, reinforces that quality should be built into trial design and conduct from the outset, with critical-to-quality factors identified early and processes kept feasible and fit for purpose [6].
In addition to FIH studies with healthy volunteers, early‑phase oncology trials have also become markedly more complex, shifting from simple dose‑escalation studies to highly adaptive, biomarker‑driven development programs. Modern designs frequently incorporate Bayesian and model‑based approaches such as BOIN (Bayesian Optimal Interval), CRM (Continual Reassessment Method), and seamless Phase I/II expansions, which often require larger patient numbers to support multiple cohorts, dose levels, and exploratory efficacy signals rather than a single maximum tolerated dose. At the same time, trials increasingly mandate molecular pre‑selection, serial tumour biopsies, advanced imaging, and longitudinal biomarker assessments, reflecting the rise of targeted therapies, ADCs, cell therapies, and immuno‑oncology combinations. These requirements have increased operational intensity, screening failure rates, and data complexity, placing greater demands on sites, infrastructure, and coordination across laboratory, imaging, and clinical teams - well beyond the traditional scope of early‑phase oncology trials - even further emphasizing the need for operational excellence in these studies.
The Context of a Complex Early Phase Clinical Study
A clear understanding of where a complex early-phase clinical study lies in the context of a sponsor’s overall clinical development strategy enhances the probability of success for a program. A document that captures this strategy is the clinical development plan (CDP). The CDP details the subsequent mid and late phase clinical trials, which will follow the early phase clinical trial, focusing on the target study population and pertinent study endpoints/outcome measures pertinent to the target indication, in particular those that will be considered clinically meaningful and determine whether or not regulatory agencies will approve the IMP. Often, the CDP incorporates the regulatory strategy, particularly if the sponsor is seeking approval in a variety of geographic regions that are regulated by different agencies, for example, the FDA, EMA, or PMDA. In our experience at Novotech, early alignment between clinical development planning and regulatory strategy is increasingly important, particularly for sponsors pursuing multiregional development.
Why Australia is a strategic setting for early development decisions
Australia remains strategically relevant in early-phase development not simply because studies can start quickly, but because the regulatory and operational environment can help sponsors reach critical decisions earlier and with greater confidence. For capital-constrained biotechs, the question is increasingly not whether Australia can support early development, but what may be lost by excluding it from the strategy. Faster start-up, lower net early-phase cost, and earlier proof-of-concept readouts can extend runway and increase strategic flexibility, supported by rapid initiation through the TGA Clinical Trial Notification (CTN) scheme and the R&D Tax Incentive, which can improve net trial economics for early development programs. This is particularly important in programs where early data influences financing, partnering, or global regulatory planning. In those settings, even a 3–6-month acceleration in decision timelines can materially affect the direction of a program [7, 8, 9].
Australia’s relevance in early-phase development is no longer only about speed or cost. It is about reducing the time between the first data and the next high-stakes decision. In a market where early readouts influence financing, partnering, and global planning, that is a strategic advantage, not just an operational one.
Sponsors often choose Australia when they need high-quality early data that can inform the next regulatory step, shape global development strategy, and withstand scrutiny from regulators and investors alike. This is especially relevant for advanced biologics, including cell and gene therapies, where execution quality and data credibility carry even greater weight. Australia also benefits from a high density of dedicated Phase I and FIH units, particularly in oncology and advanced therapies, as well as a strong concentration of investigators and sites relative to population, supporting complex adaptive designs and expansion cohorts. We have seen programs move rapidly from concept to FIH dosing through Australia’s CTN pathway, with early clinical data later supporting broader development discussions and being presented confidently on a global investor stage.
Australia’s regulatory framework permits clinical trials involving unapproved therapeutic goods under two pathways administered by the Therapeutic Goods Administration (TGA): the Clinical Trial Notification (CTN) scheme and the Clinical Trial Approval (CTA) scheme. The CTN pathway is generally used when the Human Research Ethics Committee and approving institution take primary responsibility for scientific and ethical review, while the CTA pathway is used when TGA review of the product data is required before the trial can commence [7, 8]. In parallel, Australia’s clinical trials determination guide states that covered clinical trial activities are deemed to meet the requirements for core R&D activities under the R&D Tax Incentive [9]. Together with current national reforms such as the National One Stop Shop for health and medical research, these features help explain why Australia continues to be viewed as a strategically important setting for early development decisions [10].
What this means for Sponsors
For sponsors, the implication is clear: early-phase development should be approached as the stage where the core assumptions of a program are tested and strengthened. That includes using dose, biomarker, and patient-selection strategy early enough to sharpen the signal, and ensuring operational execution is robust enough to generate evidence that can guide the next stage of development with confidence.
At Novotech, we see the strongest programs using Phase I and early Phase II to test these assumptions early, so later global studies are built on greater confidence rather than avoidable uncertainty. For biotech and small to mid-size pharma companies outsourcing early trials, the key question is not simply who can start fastest, but who can generate evidence robust enough to guide the next stage of development. When early-phase studies produce that level of evidence, they create the foundation for confident, efficient global development.
References
[1] U.S. Food and Drug Administration. Clinical Considerations for First-in-Human Trials. 2024. Available at: https://www.fda.gov/media/184323/download
[2] Frontiers in Pharmacology. Early, precise, and safe clinical evaluation of the pharmacodynamic response. 2024. Available at: https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1367581/full
[3] Schuck RN, Li R-J, Williams M, Parker VJ, Pacanowski M. Dose-finding and optimization in drug development for rare diseases. Nature Reviews Drug Discovery. 2026. doi:10.1038/d41573-026-00035-3. Available at: https://www.nature.com/articles/d41573-026-00035-3
[4] Optimizing early-phase immunotherapy trials: the role of biomarker enrichment strategies. Frontiers in Immunology. 2025. Available at: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1664443/full
[5] Circulating tumor DNA as a biomarker in early phase clinical trials. Cancer Cell. 2026. Available at: https://www.cell.com/cancer-cell/fulltext/S1535-6108(25)00504-5
[6] International Council for Harmonisation. ICH E6(R3) Guideline for Good Clinical Practice. Final version adopted 6 January 2025. Available at: https://database.ich.org/sites/default/files/ICH_E6%28R3%29_Step4_FinalGuideline_2025_0106.pdf
[7] Therapeutic Goods Administration. Clinical trials involving unapproved therapeutic goods may be conducted in Australia under 2 schemes: Clinical Trial Notification or Clinical Trial Approval. Updated 6 May 2025. Available at: https://www.tga.gov.au/products/unapproved-therapeutic-goods/access-pathways/clinical-trials
[8] Therapeutic Goods Administration. Clinical Trial Notification (CTN) scheme. Updated 9 April 2025. Available at: https://www.tga.gov.au/products/unapproved-therapeutic-goods/access-pathways/clinical-trials/clinical-trial-notification-ctn-scheme
[9] business.gov.au. Clinical trials determination guide. Updated 2025. Available at: https://business.gov.au/grants-and-programs/research-and-development-tax-incentive/assess-if-your-randd-activities-are-eligible/clinical-trials-determination-guide
[10] Australian Clinical Trials / Australian Government. National One Stop Shop for health and medical research. Updated 26 November 2025. Available at: https://www.australianclinicaltrials.gov.au/national-reforms/national-one-stop-shop-health-and-medical-research
[11] Okusanya OO, Patilea-Vrana GI, Sireci A, et al. FDA–AACR Strategies for Optimizing Dosages for Oncology Drug Products: Early-Phase Trials Using Innovative Trial Designs and Biomarkers. Clin Cancer Res. 2025;31(23):4882-4890. Available at: https://doi.org/10.1158/1078-0432.CCR-25-1918
[12] Guigal-Stephan N, Lockhart B, Moser T, Heitzer E. A perspective review on the systematic implementation of ctDNA in phase I clinical trial drug development. J Exp Clin Cancer Res. 2025;44:79. Available at: https://doi.org/10.1186/s13046-025-03328-4
[13] Tu Y, Renfro LA. Latest Developments in Adaptive Enrichment Clinical Trial Designs in Oncology. Ther Innov Regul Sci. 2024;58:1201-1213. Available at: https://link.springer.com/article/10.1007/s43441-024-00698-3
[14]. Novotech. Accelerating First-in-Human Start-Up for a Complex GMO Oncology Clinical Trial. Case study. Published March 20, 2026. Available at: https://novotech-cro.com/case-studies/accelerating-first-human-start-complex-gmo-oncology-clinical-trial
[15] Nishizaki D, Law A, Li B, et al. Ultrasensitive ctDNA monitoring reveals early predictors of immunotherapy response in advanced cancer. npj Precision Oncology. 2026. Available at: https://www.nature.com/articles/s41698-026-01287-3