During the earliest stages of clinical drug development, pharmaceutical and biotech companies need to make critical go / no-go decisions for their investigational products. Any further investments in the candidate drugs are strongly driven by early signals of drug efficacy, in addition to favorable safety profiles. With a drive to work faster–better-smarter, innovative solutions can expedite the transition from First-in-Human (FIH) studies in healthy volunteers to Proof-of-Concept (POC) studies, often enrolling patient populations, to demonstrate that a drug works in the manner it was designed. One such approach is to incorporate biomarkers into healthy volunteer or patient studies as soon as possible in the development process to demonstrate the intended drug effector prove its mechanism of action. Biomarkers can include molecular, histologic, radiographic or physiologic characteristics. Advances in molecular assays, sophisticated genetic testing and digital (wearable) devices have had significant impact on clinical trial designs and conduct to accelerate drug development.
One field that has significantly gained from a boon in biomarker technology is that of respiratory diseases. Researchers have optimized sputum (a mix of saliva and respiratory track fluids) collection and analysis for biomarker assessment, which can add great value in an early clinical stage. For instance, inflammatory biomarkers and their receptors on white blood cells can be quantified with sophisticated cell-sorting equipment in sputum samples from healthy volunteers to prove a drug’s mechanism of action after artificially triggering an immune response, e.g. by inhalation of bacterial lipopolysaccharide(LPS), to establish proof-of-mechanism1.Likewise, inflammatory biomarkers can be evaluated in sputum samples from study patients. During a multiple ascending dose (MAD) study conducted in people with cystic fibrosis2, sputum biomarkers including neutrophils and elastase were assessed. After 2 weeks of treatment with a new drug candidate, reductions in these sputum biomarkers corresponded with the drug’s mechanism of action in cystic fibrosis, and suggested a positive effect on lung inflammation status. These early signals of efficacy helped the drug sponsor secure further investments3.
Nonalcoholic steatohepatitis (NASH) is another indication that continues to benefit from technological biomarker advancements, as drug developers seek to move away from liver biopsies for study inclusion criteria, trial outcomes and disease monitoring. Here, non-invasive, state-of-the-art imaging equipment such as magnetic resonance imaging (MRI) or FibroScan® can measure changes in hepatic fat and fibrosis as (exploratory) signals of efficacy while offering a painless and more practical solution. In addition, imaging devices like FibroScan® applied as a NASH pre-screening tool can reduce screen failures (by only selecting those participants likely to satisfy the main inclusion criteria)as well as prevent unnecessary invasive and expensive screening exams4.
Early signal biomarkers and pharmacodynamic assessments are not the only clinicalareas benefiting from innovation. Technological advancements can accelerate the timelines of the drug development process.For instance, high-tech tools can be leveraged for expeditious participant recruitment, efficient study conduct and better decision making. For example, prior to initiating any testing on healthy volunteers or patients, informed consent must be obtained. Recent advancement in electronic consent (eConsent) has revolutionized this process to replace paper copies. eConsent offers interactive content to increase participant comprehension, improve compliance by ensuring all sections are thoroughly reviewed before signing the document, as well as provide traceability and versioning control. As a user-friendly experience for study volunteers, eConsent also reduces staff burden, saving time and maintaining a beneficial environmental impact.
The goal of a FIH study is to establish safety and tolerability of a new drug candidate. However, due to the escalating dose design, exposure levels achieved in a FIH study often represent the widest range in doses explored during drug development, thereby providing an excellent opportunity to collect exposure-response cardio dynamic data. The corrected QT (QTc) interval of an electrocardiogram (ECG) is a well-recognized biomarker of proarrhythmic risk, and can be collected using 12-lead continuous digital ECG recording with a Holter device5.Furthermore, Bluetooth® technology allows for direct data capture and enables prompt onsite as well as remote review of safety ECGs to monitor potential adverse events. Such early assessment of proarrhythmic risk can help save time and money, as positive findings at this stage may lead to a drug’s attrition while negative results (i.e. no risk) could support a waiver and prevent the need for a thorough QT (TQT) study.
Clinical sites are alsoleveraging remote technology for study volunteers and sponsorsalike. For instance, the use of apps on tablets and smartphonesfor eDiaries or eQuestionnaires, anddigital wearable devicessuch as fitness monitors or continuous glucose meters provides data on an ongoing basis, even between clinic return visits. This electronic capture of data results in greater data volume, which can add statistical power to the eventual analysis. In addition, the data do not need to be transcribed, so errors are reduced and a significant amount of time is saved.Furthermore, sponsors can benefit from remote auditing, virtual site tours, and remote viewing of dose preparations, which can boost productivity as well as efficiency while reducing cost. Finally, all the data collected over the course of a clinical trial can be made accessible to sponsors at the moment of data capture through innovative cloud-based solutions6. As an example, real-time access to clinical laboratory, adverse events and pharmacokinetic data can support dose escalation studies with real-time monitoring, allowing for faster, data-driven decision making.
Taking advantage of biomarker assessments, sophisticated technologies and efficient study designs, sponsors can achieve clinical POC for their drug candidates sooner and accelerate overall timelines of clinical development, which often helps attract investors and may increase return on investment. Moreover, future innovations could leverage artificial intelligence and machine learning tools for greater efficiencies in data analysis, protocol design and mechanistic understanding of a drug’s mode of action as well as potential adverse events.
References:
- Stalder,A.K., Lott, D., Strasser, D.S., Cruz, H.G., Krause, A., Groenen, P.M.A., Dingemanse, J. (2017),Biomarker-guided clinical development of the first-in-class anti-inflammatory FPR2/ALX agonist ACT-389949. Brit J Clin Pharmacol 83: 476-486. https://doi.org/10.1111/bcp.13149
- Elborn, J., Horsley, A., MacGregor, G., Bilton, D., Grosswald, R., Ahuja, S. and Springman, E. (2017), Phase I Studies of Acebilustat: Biomarker Response and Safety in Patients with Cystic Fibrosis. Clin Translational Sci, 10: 28-34. https://doi.org/10.1111/cts.12428
- https://www.prnewswire.com/news-releases/celtaxsys-secures-45m-in-capital-to-fund-novel-anti-inflammatory-phase-2-programs-in-cystic-fibrosis-and-acne-300095152.html
- The FibroScan® Advantage in Early NASH Clinical Studies. https://live-celerion.pantheonsite.io/wp-content/uploads/2019/06/Celerion_FibroScan-Advantage-in-Early-NASH-Clinical-Studies_WP_011419-1.pdf
- Grenier, J., Paglialunga, S., Morimoto, B.H., Lester, R.M. (2018) Evaluating cardiac risk: exposure response analysis in early clinical drug development. Drug Healthc Patient Saf 10:27-36. https://doi.org/10.2147/DHPS.S133286
