The Need for Innovation in Sampling
The high cost of pharmaceutical development today, driven by constantly evolving pathologies and healthcare needs, pushes drug developers to pursue operational improvement while striving concurrently to raise quality and adhere to regulatory standards. These are complex challenges when the stakes include an estimated $1+B needed to bring each new drug to market. With a high proportion of this cost attributed to clinical trials, available efficiencies may be overlooked in the pre-clinical stage, where outcomes can have a substantial effect on the design and efficacy of human trials. Ample opportunities to decrease capital outlay, increase study quality, and satisfy the 3R principle (Reduce, Refine, Replace), exist at the pre-clinical stage.
Integral to successful drug development, most pharmacokinetic (PK) and toxicokinetic (TK) studies are still carried out with the traditional manual sampling method, which involves periodically restraining an animal to dose and then draw blood at planned time points. With the stress involved, extensive human interaction, and manual processing, the manual method has not evolved to today’s stated challenges. The result is a pre-clinical trial that is more expensive, yields less reliable samples, and uses more animals than automated in vivo sampling. The automated sampling method offers the development community resource reduction and process refinement.
Advantages of Automated Sampling - Better Data from Fewer Animals
A significant advantage to automating the sampling process with instrumentation is the measurable reduction in stress experienced by the animals. Stresses caused by handling, restraining, and needle puncture affect activity and hormone levels, which alter how drugs are metabolized. Figure 1 demonstrates differences in stress hormones resulting from manual and automated sampling:
Figure 1. Stress Hormones in the Rat1
Decreasing stress from intervention improves the animal’s quality of life and yields more meaningful data. Additional benefits will be shorter studies and reduced need for compounds in short supply, freeing time and capital to be applied in other stages of development.
Advances realized through automation compared to manual sampling (whether plasma or dried spot) that reduce animal stress and human intervention include:
- Capability to tether catheter in various ways to both small and large animals so they can continue to move freely and need not be restrained for collection, simulating for the animal a normal, unobstructed environment
- All time points can be collected from one animal, eliminating composite sampling in the interest of improved data and, most importantly, greatly decreasing the number of animals needed for the study
- Companion software available for setting user-customized time points; accurate and automatic samples are collected while animal is awake, improving quality of data, and eliminating technician night shifts
- Instrument collection controls will ensure only volumes necessary for analysis are drawn, meaning less vital fluid is collected from animals and/or wasted at each time point in the study
- Contamination and dilution can be reduced or completely eliminated through contained tubing set
- Any fluid not required for sample volume can be returned to the animal, eliminating blood waste and replenishing the subject
- Collection volumes (from 5-μl to 1.75 mL) are customizable, and users can create replicates for each time point
- Sampling instruments are available in a compact structural design that reduces footprint in space-conscious labs
- Software records all time point data, eliminating the need for manual entry
As this list demonstrates, automated sampling creates very substantive advantages. The consistent, reliable delivery of more meaningful data in PK and TK studies improves the quality of the discovery phase. As pharmaceutical developers look for the most efficient way to understand the dynamics of their compounds through dosage, metabolism and excretion, automation creates the quality controls and reduced intervention that simply aren’t possible with manual methods. As described, these process refinements have material implications not just in time and capital expense, but more importantly in laboratory treatment and use of study animals.
Single-animal sampling imparts very meaningful improvement to data integrity, and materially achieves the industry’s efforts to reduce animal use. With automated sampling facilitating the collection of all time points from a single subject, animal use in an individual study can potentially be cut by half or more. Considering the sheer volume of discovery animal studies conducted today, the across-the-board reduction is innumerable. Furthermore, combining sampling with a cost-saving collection technique like dried blood spot (DBS), in supplement to, or instead of plasma collection, would impart additional efficiencies and savings.
Future Impact of Improved Pre-Clinical Studies
More effective pre-clinical trials will result in fewer no-go compounds making it to clinical trials, and for those that do, developers will have pre-clinical data to better plan human trials. Automated sampling has the potential to become a commonly-used method in human sampling, driving further process symmetry that will, again, result in more efficient and better quality drugs that continue to reshape healthcare and improve the lives of their customers.
1Source: BASi (Bioanalytical Systems, Inc.) 2011