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Safety Assessment
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Ria Falvo, BSc, DABT

Musings of a Toxicologist – A Symbiosis with a Research Associate

In the preclinical arena, what does it mean to say a drug is safe?

The Study Director assigned to a preclinical study is defined as the single point of control and holds the responsibility of the overall scientific and technical conduct of the study. This is one of the first principles learned, but certainly not the most imperative, and not the solo eyes of the study. Because while the proper and thorough execution of a preclinical study is guided by the Study Director, it’s the Research Associate (RA) that is present every step of the way, guiding the logistics, and helping ensure the study’s integrity.

Our RA is the central communication point, the resource, and the coordinator to carry out the studies successfully, based on the Study Plan (Protocol) and Standard Operating Procedures. The RA is continuously adaptable and supportive. The connection between the Study Director and Research Associate is indispensable and built on mutual trust, synergy, and, just as importantly, good humor to flit away the innate tensions that might occur in the lab.

The Study Director’s connection with the RA is linked once the study is assigned; the sooner the conversations on the study’s requirements can start, the sooner the brainstorming and leverage on each other’s experience is welcomed.

Fine-tuning the study plan

With my first draft of the Study Plan (Protocol) prepared, I ask the RA assigned to work with me on this study, Isabelle, to review it with me and verbally sketch out the activities in relation to one another. A 28-day study, with a twice-daily dose administration, eight hours apart, via oral gavage in the animals; a pleasing regular structure. Yet even with my almost two decades’ weight of experience, Isabelle’s intuitive eyes will always latch onto an item (or two) that I missed.

Shaping up to its final version, Isabelle and I talk about the Study Plan’s logistics for the two prestudy occasions for clinical pathology evaluations, being mindful of any interaction from fasting and collection set up, and enough timing between the occasions. We plan the prestudy evaluations for ophthalmology and electrocardiology on separate days (or the electrocardiology before ophthalmology on the same day) because the tropicamide (used to dilate the pupils in preparation of the eye examinations) may influence the cardiology assessments. We move on to the collection of the blood samples for bioanalysis (and subsequent toxicokinetic evaluations) that are scheduled against the first daily dose’s nominal time, but with the annotation directing the 8-hour post-dose sample collection prior to the second daily dose.

An important avenue we then discuss is the storage of the dosing formulations between the two daily dose administrations. With the Sponsor’s approval and the documentation of the prepared formulations’ stability at room temperature for up to 24 hours, the formulations will remain in the dosing room, securely and properly, while stirring.

Within an hour or so, while considering the endpoints and time points mandated by the Sponsor outlined in the statement of work, the Study Plan is rendered a clear document driving the activities. I add some final edits and provide this intended final draft to the Sponsor for their overall approval so I can finalize it. A final task at this time is the obtained crucial approval of the study by our animal welfare committee. At long last, the study’s path of scheduled events is in process.

Preparing for launch (dosing) day

While my days before the start of the dosing period are filled with an organized multiplicity of duties and responsibilities on other studies, this current study reserves space in the back of my brain. I know how effortful Isabelle’s series of actions are towards the study, and every Study Director wants each step to systematically align to a cohesive start.

The RA intuitively schedules the toxicology technical team requirements, negotiates the time for the dose formulation preparation, and coordinates everything from securing the availability of the samples’ collection tubes to making sure the runner picks up and delivers the tubes for analysis. During this brew, the RA prepares the required worksheets and I review them without delay to respect the RA’s precious time and win against the temper of time. I verify the animals’ prestudy data to ensure all animals are healthy and sign my gesture of approval. But it is the RA that is the strategic connection between the Study Director and all other teams.

During the hours leading to the initiation of dosing on Day 1, the RA’s conduct of the orchestra is eminent. Isabelle must simultaneously ensure the technical staff arrive five minutes earlier, the collection tubes are in the room (all queued in order with labels squared forward), and the work stations for dose administration, sample collection and processing, and electrocardiogram recording properly set up and labelled.

About an hour before the day’s critical activities are set to start, I visit the Formulations Laboratory to ease my lingering paranoid notions of something amiss (one of my perpetual traits, unconquerable over my almost 20 years’ experience, but also beneficial). The dosing formulations were removed from refrigerated storage and are stirring on the stir plates as expected, yet upon closer inspection, the suspension prepared at the highest concentration is not visually uniform and swirls about, buoyant clumps. Without delay, while the formulation is homogenized (a previously approved remedy by the Sponsor), I call Isabelle in the animal room to inform her of this transient hiccup (open and continuous avenues of communication are key). With my English-French-combined language (having worked with Isabelle over a decade, I confidently affirm our mutual and thorough comprehension), I say, “…there are moutons in the formulation, but all is settling fine”. Isabelle’s peal of laughter sparks in me a mixture of reciprocal laughter and absolute confusion, until she replies with, “there are sheep in there?!”. Apparently, I mistakenly said “moutons” (sheep in French) instead of “motons” (clumps in local French); a lesson in linguistics learned as a side gain, but more importantly, an instant that allowed us to appreciate our synergistic efforts and history. I thought about the numerous smiles shared with this exceptional and devoted RA.

'My focused eyes and ears'

The first day of the study clocks in the timely completed activities, and progresses fluently for those 28 days, as planned. Each day, the RA continues to ensure all data recorded are attributable and accurate, the animals continuously monitored and cared for, and the activities in accordance with the Study Plan. And surpassing her dedication to the projected duties, and without hesitation, Isabelle steps in whenever required to help the technicians maintain alignment with time to preclude any excursion, and just as important, to alleviate stress for the technicians. As the Study Director, I regularly visit the room to oversee critical activities and verify the animals’ condition is well. Isabelle is my focused eyes and ears in the room for the quotidian routine, communicating events and updates for me to then relate to the Sponsor.

So, what does it mean to say a drug is safe? It takes multiple players to create unity, passion, devotion, and trust, as well as support, specifically our RA in this piece. Trust that develops not only with words shared, but actions made in each study’s harvest. The trust of also knowing that we will verify each other’s work thoroughly since, after all, we are all human and we all know what that means! The confidence I have with our RA is mirrored and is paramount to a successful well-executed study, yielding valuable data to support the safety of test items - and ultimately, patients.

Be in the moment. Be intentional. Be inspired. A good way to journey through each day.

Charles River scientist Ria Falvo, BSc, DABT, is creator of Musings of a Toxicologist, an occasional series about life in the lab.