Celerion Inc.

J. Fred Pritchard

As a clinical pharmacologist working in early clinical research for over 35 years, I understand the need to continually evaluate and embrace new technologies that help deliver better data, faster in order to facilitate go, no-go decisions about new drug products. Such technology must be introduced carefully to meet the demands of a highly regulated research environment. This is of strategic importance for organizations whose focus is on early clinical research through purpose-built clinics and specialized bioanalytical laboratories.

Early clinical studies involve assessment of a drug’s action on the human body (both beneficial and potentially adverse) as well as how fast or slow the body absorbs, distributes and eliminates the drug (pharmacokinetics). Often, modifications to the drug’s dosage is required during dose escalation studies. Compounding of sterile and non-sterile formulations for immediate use in the clinic is one capability that Celerion’s research pharmacy offers. Web-based applications such as Pestle® and Simplifi-797 help ensure that the investigational product is compliant with demanding USP requirements. Advances in technology have been applied to the space in the research pharmacy where a product is handled. For example, hands-free technology for opening/closing doors and hand washing/drying stations, automated pressure differential adjustments/monitoring systems, video preparation verification systems which allow for pharmacist remote verification are all designed to decrease contamination risk. Recently introduced are custom built, modular clean rooms made of non-organic materials to further reduce contamination risk. Such rooms can be easily reconfigured to meet the needs of the study or the pharmacy site.

“Technologies that brings data to investigators almost as soon as it is collected is of high value in early clinical development”

Several new technologies have been introduced in recent years that provide non-invasive assessments of tissue or organ function to follow drug effects as well as disease diagnosis, progression, and regression. Key among these for evaluating cardiac safety is Bluetooth enabled Holter monitoring coupled with computer-assisted 12- lead ECG evaluation. This technology enables accurate measurement of small changes in heart electrophysiology (e.g., QTc interval changes) that can be a safety concern if related to systemic exposure to a new drug candidate. There are now several manufacturers of continuous glucose monitors (CGM) that are used primarily in routine diabetes patient care, but they also have an important role in the clinical assessment of new anti-diabetes drugs and also as a safety marker for potential hypoglycemia induced by other drugs in early clinical research. Smart Pill technology enables the clinic staff to study the effects of GI motility and gastric pH on oral drug absorption. Ongoing research is employing Fibroscan imaging equipment in early clinical studies to evaluate drugs targeting nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), diseases of increasing incidence, and research focus. This instrument utilizes ultrasound waves to estimate the fat content of the liver and its stiffness (a measure of fibrosis). The comparison of Fibroscan results with a collection of inflammatory biomarkers (proteins and cells) in the blood of patients with various stages of these liver diseases will guide the deployment of this new technology in early clinical drug research programs at our clinics.

Advances in digital data capture and electronic laboratory notebook systems have largely removed paper from laboratories that are highly regulated by Good Laboratory Practices (GLP). The amount of time the bench chemist spends on GLP-related documentation dropped from 40% to 15% after deployment of such systems with the associated increases in productivity while assuring total GLP compliance. Robotics has also completely automated many of the time-consuming sample preparation tasks and provided much higher reproducibility than manual methods could. The evolution of flow cytometry has made this an important tool for measuring cell types carrying specific surface proteins related to immune function, antigenicity, and tumor growth. The advancement of multiplex flow cytometry allows for highly sensitive and rapid high through-put analysis of cytokines, antibodies, and HLA genotypes. This, in combination with genomics, proteomics, and transcriptomics has contributed to the development of “cytomics.” Cytomics offer a unique advantage to interrogating a population of cells at individual level compare to “averaged approach” used by genomics and proteomics technologies. Cytomics is better suited to provide useful clinical data reflecting the physiological state of an organism enabling clinical proof of concept studies in a faster and cost-effective manner. Finally, fast computerized complex data analysis is now the mainstay in producing accurate and sensitive measurements of drug, metabolite, and biomarker concentrations from biological specimens collected during early clinical studies.

Technologies that facilitate the capture of information directly from the patient are having a major impact on clinical studies. The development of computer applications for smartphones and tablets allow for more data to be collected from each patient while away from the research clinic and in their normal environment. Vital signs such as heart rate and blood pressure can be now readily assessed using wearable devices similar to fitness watches and the data securely transferred at regular intervals to the clinical research site for remote evaluation. Validated questionnaires that capture the perceptions of the patient, such as Quality of Life tools can be easily repeated at regular intervals in the comfort of the patient’s home. More of such data, properly processed, often leads to greater statistical power to discern signals of drug effect over time that would be difficult to capture otherwise.

Finally, technologies that brings data to investigators almost as soon as it is collected is of high value in early clinical development. Web-based portals enable investigators, medical monitors, and scientific staff to evaluate clinical and laboratory safety data in a blinded form and in real time allowing more responsive oversight and decision-making during dose escalation studies to ensure subject safety. This technology also has an application to the emerging field of remote clinical monitoring.

Implementing new technology in a highly regulated research environment can be challenging; however, the reward of producing better data faster is key to supporting better early clinical development decisions.