Navigating Complexity: A Look at the Shifting Landscape of Clinical Development By Philipp Diesinger and his Team

Over the last twenty years, clinical development has been transformed by advances in technology, patient-centric approaches, regulatory changes, and precision medicine. Digital technologies, big data, and AI have streamlined trial design, patient recruitment, and data analysis, while virtual trials have improved access and efficiency.

Patient-centric approaches have led to adaptive trial designs and better patient-reported outcomes [1] , enhancing relevance and tailoring therapies, especially in oncology and rare diseases [2]. Regulatory pathways like the FDA’s Breakthrough Therapy designation have expedited approvals for high-need conditions, and collaborations have increased to address global health challenges [3] .

Precision medicine, powered by genomics, has enabled targeted therapies, particularly in cancer, resulting in more personalised treatment and better success rates. However, clinical trials have also become significantly more complex [4]. Broader inclusion criteria now ensure diverse representation, encompassing different genders, ethnicities, and age groups, which necessitates broadening recruitment across multiple regions [5]. This globalisation of clinical research requires managing diverse regulatory requirements and logistical challenges, particularly as trials are conducted across more countries than ever before [6]. The rapid expansion in the number of trial sites has necessitated sophisticated coordination to maintain consistency [7]

The shift towards personalised medicine, focusing on targeted therapies tailored to specific genetic markers, demands intricate trial designs and precise patient selection, adding new layers of complexity. Adaptive trial designs, which require ongoing adjustments based on interim results, further contribute to the challenge [8]

Advanced technologies, such as wearables and digital health tools, have also added to the complexity of clinical trials. The collection of data from diverse sources presents challenges in data integration, monitoring, and privacy maintenance. Additionally, the use of real-world evidence from electronic health records and patient-reported outcomes imposes further demands on data management and analytics [9] .

Furthermore, a growing focus on rare disease treatments, the rise of combination therapies, and the use of advanced endpoints have also played roles in adding complexity. Rare disease trials often require creative methodologies to address small patient populations, while combination therapies necessitate extensive evaluation of potential drug interactions. Moreover, the sophisticated endpoints and patientreported outcomes require nuanced measurement and analysis [10].

To quantify changes in clinical development and gain insights into trends, diversity, and the growth of clinical research across various disease areas and regions, we analysed 617k interventional clinical studies initiated since 2000, using data from 17 trial registries. These studies spanned 186 countries, involved approximately 680k clinical sites, and were supported by 200k unique sponsors, enrolling a total of 121 million participants.

FIGURE 1
TRENDS AND INCREASED COMPLEXITY IN GLOBAL CLINICAL DEVELOPMENT SINCE 2000
Figure 1 shows an increase of reach and complexity of interventional clinical studies.

Figure 1A illustrates the significant rise in the number of clinical studies registered globally from 2000 to the present. This growth reflects not only stricter regulatory policies that require registering clinical studies in public study registries but also the increasing demand for new drugs, innovations in treatments, and a wider acceptance of transparent clinical research as a crucial component of medical progress.

Figure 1B highlights the parallel growth in the number of registered participants involved in clinical studies. This increase aligns with the expanding number of studies and reflects efforts by researchers to ensure diverse and representative participant samples. Such diversity enhances the robustness of study results and supports a better understanding of drug efficacy across different populations.

Figure 1C demonstrates a twofold increase in the number of countries participating in clinical studies.

This trend emphasises the globalisation of clinical research, with expansion beyond traditionally dominant regions like North America and Europe. The inclusion of new countries broadens patient diversity, making clinical findings ethnically and globally more relevant. Additionally, extending research into emerging markets has facilitated access to new patient populations, expertise, and potentially lower operational costs, ultimately accelerating pharmaceutical innovation.

Figure 1D focuses on the growing number of clinical sites involved in trials worldwide. This increase reflects the expanded infrastructure needed to accommodate the rising volume of studies and participants. More clinical sites contribute to better patient access and enhance the capacity to test diverse therapeutic interventions.

Figure 2

DRILL-DOWN INTO CLINICAL DEVELOPMENT ACTIVITY OF NEOPLASMS AND DIABETES MELLITUS STUDIES

Globally, clinical development has intensified. However, examining individual medical conditions reveals more nuanced trends in concluded clinical trials. For instance, while studies related to neoplasms (Figure 2A) have seen an increase in both volume and participant numbers, diabetes mellitus studies (Figure 2B) have shown a recent decline in these metrics. This highlights how clinical research priorities can shift over time, reflecting changing needs, constraints and focuses across different medical conditions and therapeutic areas.

The increasing focus on neoplasm research can be attributed to several factors. Cancer remains one of the leading causes of death worldwide, and there are still many types of cancer with limited treatment options, which drives continued investment in oncology research. Advances in precision medicine, particularly genomics and immunotherapy, have made oncology a promising field with breakthroughs in targeted and personalised treatments, attracting significant funding and patient interest. Furthermore, governments and private organisations provide substantial incentives for cancer research, and regulatory bodies often expedite approval processes for cancer drugs. Strong patient advocacy also fuels this momentum, ensuring that cancer remains a priority in clinical research and driving ongoing innovation.

In contrast, diabetes mellitus research has seen a decline in recent years. Diabetes, especially type 2 diabetes, has been extensively researched, leading to the development of numerous effective treatments, which reduces the immediate demand for new diabetes drugs [11]. The focus has increasingly shifted toward prevention and lifestyle interventions rather than new pharmacological treatments. Additionally, diabetes trials are often long and complex due to the chronic nature of the condition and the presence of comorbidities, making recruitment challenging and costly for sponsors [12]. As the market for diabetes medications has matured, pharmaceutical companies may have reallocated resources to emerging areas, such as obesity, metabolic syndromes, and other novel conditions, where there is more opportunity for innovation and growth.

FIGURE 3

GROWING DIVERSIFICATION IN THE SCOPE OF CLINICAL DEVELOPMENT OF NEOPLASMS AND DIABETES MELLITUS STUDIES

Figure 3A shows an analysis of 3132 completed phase 3 neoplasm studies. Figure 3B shows an analysis of 1275 completed phase 3 diabetes mellitus studies. Studies were carried out by industry sponsors since the year 2000.

Figure 3A depicts how the number of unique medical condition terminologies used to tag phase 3 neoplasm clinical studies has increased over time as reported in global clinical study registries. This steady increase in unique terms suggests a growing diversification in the scope of clinical research. At the same time, the average number of medical conditions per study has stabilised at 2-3 conditions per trial, indicating a consistent focus on multi-faceted approaches while keeping study designs manageable. The expanding medical condition vocabulary reflects the increasingly complex nature of neoplasm studies and points to an evolving landscape where trials are designed to address a growing range of specific cancer types and subtypes.

Figure 3B shows a similar trend for diabetes mellitus. The number of unique medical condition terms has grown steadily despite the decline in the number of studies, indicating a diversification of study focus in diabetes research. Although the number of conditions tagged per study remains stable, this trend reflects the evolving complexity of diabetes trials, with researchers targeting more nuanced subgroups of the disease.

The findings in both figures highlight a broader strategy within clinical development to refine and specialise the focus of studies, aiming for more precise interventions and a better understanding of specific conditions.

In summary, the evolution of clinical development over the past two decades has been marked by increasing complexity, patient-centric innovations, and a move towards precision medicine. The diversification in study design and medical condition focus demonstrates an industry adapting to address the needs of various diseases and patient populations. Moving forward, further advances in digital health, adaptive trial methods, and an emphasis on diversity and inclusion in clinical research are likely to shape the field. These ongoing changes may influence the pace and direction of clinical development, ultimately affecting how treatments are brought to patients worldwide.

In today’s increasingly complex clinical research landscape, AI and data sources like real-world evidence, patient registries, and study databases are essential tools for addressing and managing emerging challenges. To prevent a potential slowdown in medical breakthroughs, clinical studies must be optimised, with processes streamlined to enhance efficiency and effectiveness.

REFERENCES

[1] Mullins CD, Vandigo J, Zheng Z, Wicks P. Patient-centeredness in the design of clinical trials. Value Health. 2014 Jun;17(4):471-5. doi: 10.1016/j. jval.2014.02.012. Epub 2014 May 5. PMID: 24969009; PMCID: PMC4497570

[2] Grant, M.J., Goldberg, S.B. Precise, pragmatic and inclusive: the modern era of oncology clinical trials. Nat Med 29, 1908–1909 (2023). doi.org/10.1038/s41591-023-02466-6

[3] Shea, M., Ostermann, L., Hohman, R. et al. Impact of breakthrough therapy designation on cancer drug development. Nat Rev Drug Discov 15, 152 (2016). doi.org/10.1038/nrd.2016.19

[4] Martin, L., Hutchens, M. & Hawkins, C. Clinical trial cycle times continue to increase despite industry efforts. Nat Rev Drug Discov 16, 157 (2017). doi.org/10.1038/nrd.2017.21

[5] National Academies of Sciences, Engineering, and Medicine; Policy and Global Affairs; Committee on Women in Science, Engineering, and Medicine; Committee on Improving the Representation of Women and Underrepresented Minorities in Clinical Trials and Research; BibbinsDomingo K, Helman A, editors. Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups. Washington (DC): National Academies Press (US); 2022 May 17. Appendix B, Key Trends in Demographic Diversity in Clinical Trials Available from: www.ncbi.nlm.nih.gov/books/NBK584392/

[6] Kristina Jenei, Fabio Y Moraes, Bishal Gyawali – Globalisation of clinical trials in oncology: a double-edged sword?: BMJ Oncology 2023;2:e000163

[7] Carlos H. Barrios et al., The Global Conduct of Cancer Clinical Trials: Challenges and Opportunities. Am Soc Clin Oncol Educ Book 35, e132-e139(2015). DOI:10.14694/EdBook_AM.2015.35.e132

[8] Duan, XP., Qin, BD., Jiao, XD. et al. New clinical trial design in precision medicine: discovery, development and direction. Sig Transduct Target Ther 9, 57 (2024). doi.org/10.1038/s41392-024-01760-0

[9] Khosla S, Tepie MF, Nagy MJ, Kafatos G, Seewald M, Marchese S, Liwing J. The Alignment of Real-World Evidence and Digital Health: Realising the Opportunity. Ther Innov Regul Sci. 2021 Jul;55(4):889-898. doi: 10.1007/ s43441-021-00288-7. Epub 2021 Apr 29. PMID: 33914297; PMCID: PMC8082742

[10] May, M. Rare-disease researchers pioneer a unique approach to clinical trials. Nat Med 29, 1884–1886 (2023) doi.org/10.1038/s41591-023-02333-4

[11] Eriksson JW, Eliasson B, Bennet L, Sundström J. Registry-based randomised clinical trials: a remedy for evidence-based diabetes care? Diabetologia. 2022 Oct;65(10):1575-1586. doi: 10.1007/s00125-022-05762-x. Epub 2022 Jul 29. PMID: 35902386; PMCID: PMC9334551