Drug development has always been a complex process, but the past year has added increased strain on companies’ resources and timelines. Companies had to reprioritize their investments, and as a result, some projects were frozen in place while others faced immense pressure to maximize efficiency. For many, the return to “normal” is unclear and unpromised.

Forward-thinking drug development teams have risen to these challenges and turned them into opportunities to instill new habits. These habits can start at the earliest stages of drug discovery. As companies prepare for preclinical testing, they can use the checklist below to make sure they are ready. 

Drug developers should have a clear sense of each compound’s therapeutic focus, mode of action and even the associated structural activity relationships to assess their team’s readiness when bringing target molecule(s) beyond the discovery phase. Close collaboration between developers and laboratories can help accommodate each project’s unique needs, but this partnership relies on a solid framework. Preparation checklists can’t address the level of complexity each program must consider, but they can create a starting point to determine whether a program is ready to commence preclinical lab work.

Before initiating the preclinical testing phase, developers should start internal conversations to ensure a program is ready to advance on all fronts and the project’s ideal laboratory partnership criteria are unambiguous. Readiness begins by focusing on three areas of preparation: timelines, teams and test articles.

1. Preparing a Proper Timeline
Setting specific goals and communicating the target investigational new drug (IND) application filing date, or an alternative milestone, is mission-critical at the onset of planning. This target date allows testing laboratory partners to work backward from the projected filing and confirm there is time to complete the required studies and analysis. Often, laboratories can provide a GANTT chart (or a similarly detailed project timeline) based on the major milestones before filing an IND. In turn, practicing timeline preparation allows all parties to agree on the path forward before beginning intensive and costly studies.

With such a wide range of therapeutic targets and filing pathways available, developers should also consider collaborating with regulators when establishing target timelines. Whether a team is developing a “me-too” drug, an orphan drug or a first in class therapy, pre-IND meetings with the U.S. FDA can shift many assumptions into answers, thus clarifying the necessary steps to gain approval. Even determining which group within the U.S. FDA (i.e., CBER or CBER) will review the application can affirm the expectations that need to be satisfied to establish safety margins in humans adequately.

Drug developers should always allow for a certain degree of “cushion” before the submission date when forecasting timelines. Many of the steps before submitting an IND are highly complex, particularly with safety and toxicology studies. Further, developers may need to invest in additional supporting analytical studies to evaluate concentrations in highly complex formulations, identify active metabolites and assess tissue distribution. The common assumption is that there will be no issues or surprises in the process, but that is likely unrealistic. Developers should take proactive steps to account for the unexpected, as these situations will provide the most insight into both the risk and benefit of a drug candidate.

While laboratory testing partners can help respond and adjust to delays to some degree, new insights from testing may reveal the need for significant changes to the approach, such as assay redesign. There are several reasons to pad projections, and forecasting potential delays (and responses to minimize their impact) might save a project from various undue stressors. Developers that plan a clear regulatory pathway before engaging partners can properly coordinate study parameters, resource allocation and testing systems in advance.

2. Enlist the Right Stakeholders
The essence of teamwork is critical when building a program. Everybody must work together and communicate effectively for that to happen. Understanding what the communication structure will entail and managing those expectations during the overall process will set developers on the right track.  Additionally, it should be clear to stakeholders what the deliverables on both sides entail and who will take the lead.
Drug developers come in all sizes, levels of experience, abilities and expertise, so pulling together the correct team members can vary on a case-by-case basis. In fact, each developer’s core competencies can lead to different partnership criteria when identifying a testing laboratory. As a baseline, teams in the drug development process need to represent each critical department involved during the planning and execution of an IND application. The pivotal question to ask internally is who could impact the conduct of this program, and are they included in the relevant conversations to assure a common goal.

Each program’s roster of key stakeholders will naturally vary, but a few areas of expertise need consistent representation during the preclinical planning. Regulatory leaders, project team leaders, subcontractors and those involved with putting together the IND dossier are more common examples of these key stakeholders. Still, developers may lack experience with preclinical safety assessments when they plan to use complex assays, uncommon test systems and unique therapeutic areas. Companies should enlist knowledgeable support to focus on the primary safety assessment objectives, avoid compromising quality, reduce overengineering and ensure study results are relevant and applicable to humans.

Rallying the right team members puts the developer at a great starting point. Still, the structure of protocol should outline the individuals responsible for defined elements of the study, such as bioanalysis or pathology. Regulators often take note of the contributing scientists and associated stakeholders on the laboratory testing team. They will expect developers to define these stakeholders in the submission review process clearly. While the study director is the single point of contact for the overall study conduct, other job titles that developers can expect to see include management, supervisory personnel, laboratory staff, veterinary support and principal investigators.

Each study protocol should detail those involved and their responsibilities to evaluate any deviations from the study plan and put them into context. Once this is completed in a timely fashion, the study director assesses the impact on the study quality and integrity. Additionally, documentation needs to clearly state the materials and methods for data collection and reporting platforms used. When there is consistency in the document formats—i.e., Word documents, searchable PDF files, SEND data sets, etc.—it significantly improves the ability to meet reporting timelines and minimize errors or any effects on quality. Holistically, identifying key stakeholders, responsibilities and communications methods establishes a solid foundation for a drug development program. Clear workflows help to actively manage projects, reduce delays and minimize added costs.

3. Assess Test Article Availability
Drug developers must overcome what can seem like insurmountable odds when addressing the practical elements of having sufficient test article of the appropriate quality for preclinical testing. Further, the desired route of administration and dose formulation issues can result in biological and practical limitations to achieving necessary test system exposure. It’s critical that development teams address these issues to assure the proper scale-up in manufacturing, and they conduct supporting analytical techniques and preformulation studies to support studies intended for regulatory review and approval. 

There is no one-size-fits-all approach to study design, but teams can begin to gauge test article needs by understanding the drug- and population-specific factors that will impact testing. These efforts help pull together a picture of the quantity, form, potency and timing of test article needs. This process can also unearth some unexpected obstacles along the way. Doing the appropriate homework adds to the chance of a successful drug development program.

There are scenarios during first in human (FIH) studies where the target patient population may not be constituted by normal healthy volunteers, as the therapeutic target is only seen in the disease state. As a result, modifications to the test system, molecule or study endpoints may be needed and a “standard” IND-enabling program isn’t sufficient. For example, developing drugs for patients with ultra-rare diseases requires a novel approach. Companies typically design these programs in close communication with regulators that understand the disorder and are familiar with options to refine (and hopefully accelerate) drug development. Working with therapies for these diseases impact several factors about the overall program composition. However, with adequate planning they can be managed while still assuring safety and maximizing the chance for efficacy.

The goal of safety assessments should be to assure that the range of dose levels proves an adequate therapeutic window. There may be an abbreviated number of studies depending on the disease at hand. For example, oncology drugs go through a very different pathway because of the patient population. The physiology of target end-users impacts the structure, makeup and expectations of a testing program. Drug developers who use this lens as a starting point can then move on to forecasting the quantity and formulation of their compound.

A test article’s availability is subject to a number of influential inputs and conditions. First, consider the structure of the molecule and the associated manufacturing process. Some compounds are easier to manufacture than others. Specifically, candidates that rely on complex chemical reactions might require more forethought to develop adequately. New chemical entities (NCEs) may also have limited stability or a matrix that is difficult to manufacture consistently, which could present obstacles during preclinical testing. Biologics typically have complex structures and require unique processes to manufacture, maintain concentrations and guarantee potency. It is far more difficult to conduct reliable, long-term studies if a molecule becomes unstable under conditions of storage and use in less than 24 hours. Developers need to ask themselves if handling will impede practical study conduct or if small production quantities could be a limiting factor.

Testing programs cannot begin when test article availability is a rate-limiting factor. Those who cut corners at this step in the process can present real and apparent risks in later development stages. Early exploratory studies frequently use relatively small amounts of a test article that are provided at the outset. When testing laboratories begin study activities requiring significantly more test substance, there needs to be a clear understanding of what will be required for all phases of study conduct and the needs for the overall IND-enabling program.

Developers armed with a clear understanding of how studies will be conducted and in what types of test systems can account for creating a sufficient quantity of test articles. In addition, there will be unavoidable needs for analysis of drug substance, characterization of dose formulations and wastage associated with batch size and dosing method. Waste can be a forgotten factor because it can happen at different points of study conduct. Factors such as the preparation process, analyzing each batch against acceptance criteria and growth over time can all increase the quantity of test article necessary. Experienced laboratory testing partners should work closely with drug developers to assist in this step, as well as define who will provide the necessary elements for dose formulation and analysis.

It’s important to envision the impact of reaching the halfway point of a pivotal in vivo study and being held up by insufficient test article to complete the study. The situation could compromise the target endpoints and the investment made. Appropriate planning and investment in resources can help avoid these occurrences.

The route of administration is a pivotal element in the decision process when considering the dose formulation appropriate for dose administration in test systems. Additionally, adjustments to the concentration impact the achievable dose levels, and developers may face difficulty striking the right balance. In times of uncertainty, developers are encouraged to lean on trusted industry partners to work through any challenges. Drug developers could face challenges on many different fronts when gathering their test articles, but none of which they need to overcome without support from their partners.

4. Translate the Checklist into a Tool
Successful collaboration between drug developers and laboratory testing partners hinges on mutual responsibility. The implications of poor partnership vary, but missing a filing deadline could have insurmountable financial impacts on a project’s success or even viability. Teams that identify consistent gaps or obstacles in a development program can leverage them to inform current or potential testing partnership qualifiers.

Every team’s needs will vary, but there are a few qualities that every program should consider when selecting a laboratory testing partner. First, a laboratory’s track record from an overall regulatory compliance standpoint helps gauge its ability to offer support. The number of differences and nuances between regulator’s expectations is a familiar conundrum to those in the drug development industry, and experts accumulate a wealth of knowledge through experience.

Some key indicators of a laboratory’s quality are the questions they ask a development team. Both sides of the partnership should be actively managing expectations to ensure program success. Of course, experience in the therapeutic area, disease model or test system is important to consider, but partnership works both ways. A high-quality laboratory testing partner should ask about all of the factors discussed above, from sufficient test article quantities to the supporting roster of team members. With such an intertwined effort, an engaging laboratory can help close even unrealized gaps.

5. Do the Homework
No one expects developers to have all the answers before beginning preclinical lab work. But regardless of the therapeutic area or regulatory pathway, the most successful teams do their homework. Drug development is an inherently collaborative process that allows teams to leverage existing resources and expertise while challenging norms and assuring that safety is primary goal. Developers should refrain from working in a silo and instead take advantage of the resources available to them.

The checklist approach above cannot provide all the answers before beginning preclinical laboratory work, but it can help start the right conversations and prepare teams for successful partnerships. Laboratory testing partners around the world are eager to support companies progressing their compounds and plug into the knowledge or experience gaps a team may face. 

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Dr. Mark Walker, Senior Technical Director of Toxicology at WuXi AppTec Laboratory Testing Division, has over 25 years of preclinical toxicology and drug development experience. Walker is a veterinarian and toxicologist by training, specializing in the preclinical safety assessment of novel drug and biotherapeutics. His areas of interest include primate medicine, comparative pathobiology and the care and use of appropriate animal models for regulatory drug development.