Early Phase Clinical Trial Development

Background

Early phase clinical trial development is a critical step required to advance medical products through drug development pipelines. Early phase trials are also the riskiest and exhibit the highest failure rates compared to pharmaceutical products in later phases, mostly due to safety-related and pharmacokinetic (PK) issues. At ExL’s 5th Clinical Trials Phase I & Phase IIA Summit, there were discussions on how to lower early phase trial risk including tips on adaptive protocol design, designing safer studies, and monitoring oversight.

Adaptive design in protocol writing

Rosemarie Pincus, principal medical writing scientist at Johnson & Johnson, described the general process of adaptive protocol design and offered tips on the process. Pincus indicated that the protocol sets the stage for all study-related activities, which informs and guides the clinical trial registry, case report form design, the statistical analysis plan, the clinical study report, and the drug label. In adaptive trial design, Pincus suggested that eligibility criteria, randomization allocation ratio, dose/arm removal or addition, sample size, and early trial termination can be adjusted. Pincus emphasized that protocol amendments are time-consuming and costly, and to avoid amending the protocol, protocol writers should consider protocol clarity/consistency, controlling enrollment increases, being consistent with previous studies, integrating input and medical practice requirements from investigators, and meeting regulatory authority requirements. Pincus recommended that protocol writers also conduct a quality control review when amending protocols including checking areas for potential inconsistencies, looking over the time and event schedule, and reviewing from front to back, and then from back to front to ensure all changes were incorporated.

Designing safer early phase studies

Howard Uderman, clinical pharmacologist at Novo Nordisk, discussed failed phase I studies due to unforeseen safety issues. In one example, Uderman highlighted the impact the Anti-CD28 Monoclonal Antibody had on cytokine storms six patients experienced, which led to prolonged cardiovascular shock and intensive organ support. This unfortunate outcome occurred because species used in animal/preclinical safety models lacked CD28 expression on CD4+ effector memory cells, a critical pathway associated with the mechanism of action, which did not predict the adverse effects in humans. Uderman emphasized the importance of reviewing EMA’s guidelines on risk mitigation in first-in-human and early clinical trials, which includes information on dose exposure responses, and generating substantial PK/PD evidence to inform dosing escalation and schedules. While it is challenging to predict safety outcomes in early-phase drugs fully, Uderman made important recommendations when planning and implementing first-in-human clinical trials, specifically, creating start and maximum dose ranges, and PK values must include the maximum exposure, the maximum duration of treatment, route and rate/frequency of administrations, and washout times. Additionally, researchers must evaluate biomarkers for PD and toxicity, assess populations carefully for inclusion, define stopping rules, generate monitoring parameters, and include a placebo. Moreover, it is essential to establish an emergency protocol to transfer patients to the ICU and communicate with that ICU beforehand to convey expectations and treatment options, should adverse safety events occur.

Monitoring oversight in early phase trials

Ryan Tiver, associate director of Translational Sciences Operations at Teva, spoke about the uniqueness affiliated with monitoring phase I studies. Tiver indicated that phase I studies are typically data-dense in a short period, where a large volume of safety and PK/PD data is collected, and timing is precise with brief assessment windows. Given the nature of phase I design and conduct, errors that are not caught quickly enough will rapidly spread through many subjects and adversely impact the study’s data and subject safety. Tiver recommended that sponsors and CROs should examine and revise the draft protocol with clinical research units to avoid potential risks. Tiver suggested that most study monitoring and oversight should focus on the dose run-in period (typically Day 1 and Day 1 dosing visits), and monitoring should be done on-site and carefully to closely observe procedures, while not distracting staff or interfering with their ability to conduct study procedures. If issues are discovered, they should be escalated to the clinical research unit manager, rather than interacting directly with site staff. Despite demonstrating sufficient monitoring oversight, Tiver indicated that sponsors should take accountability by demonstrating an ability not only to identify the problems, but also taking necessary action to resolve and address them. Specific items to observe during monitoring visits include reviewing subject eligibility, the schedule of events, verifying PK blood draws, and investigational product (i.e., quantity, storage, preparation, and labeling). Tiver emphasized that dosing is the top priority, followed by PK/PD samples and safety procedures.

Summary

In summary, early-phase trials are challenging studies by design and exhibit the highest risks not only towards advancing drug development, but mainly because of patient safety concerns. Designing robust protocols, conducting appropriate safety assessments in preclinical models, and ensuring proper monitoring oversight during early-phase study conduct help reduce inherent study risks.

Moe Alsumidaie, MBA, MSF is Chief Data Scientist at Annex Clinical, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.