Regulatory guidelines outline all crucial studies and documentation that should be in place before a drug product can be tested in humans for the first time. However, such guidelines do not tell you when different studies are ideally run or how to best prioritize between studies. Here, I share ways to save time and limit costs on your way to clinical trials.
Establish a coherent program early during drug development
Before first-in-human trials, regulatory guidelines instruct you on chemical and pharmaceutical quality requirements, nonclinical pharmacology, when good manufacturing and laboratory practices are necessary, and what to address in the clinical trial. However, it is not only about knowing what needs to be done but also when.
Time and money are limited resources in early-phase drug development. Still, resources can be saved by establishing a coherent drug development program where resources are wisely allocated to the most critical studies. The aim is to optimize timelines to get closer to clinical studies.
Three ways to save time and costs on the way to clinical trials
1. Identify bottlenecks
Given the current development phase of your project, it is important to identify the most relevant studies to perform. This typically requires an experienced multidisciplinary team. Moreover, when planning and executing a drug development program, it is essential to consider common bottlenecks.
Required nonclinical studies
Before a clinical trial with a new drug can be performed, potential safety issues must be identified in nonclinical studies. A solid understanding of the studies that are required is vital, as there is no “one size fits all” in a nonclinical safety program. Depending on the type of compound, previous knowledge of the drug and/or similar compounds, the intended clinical indication, and predicted pharmacologically active exposure levels, the design of the nonclinical safety program can be very different. Mapping this out early will reduce time, cost, and frustration within the development program and enable a smooth interaction with authorities.
Lead times for drug substance manufacturers
Another common bottleneck is the lead times for drug substance manufacturers. Substantial amounts of drug substance at a purity level acceptable for the different nonclinical studies and for the first-in-human study will be necessary. The solution is to establish a comprehensive drug manufacturing plan covering all activities from the start of your program. A lack of compound will delay studies, which may create a snowball effect, jeopardizing the whole program. It is also likely that different formulations will need to be developed and documented for various nonclinical studies compared to those used in the clinic due to physiological/practical limitations when dosing animals or running in vitro studies. In addition, don’t forget the validated analysis methods for these formulations, plus validated bioanalysis methods for plasma concentrations in the animal species used.
The take-home message is that proactive planning and contracting services in good time before critical activities can avoid frustrating delays.
2. Decide which studies should be run in parallel or in succession
While two studies can be run in parallel to save time, running them in succession is sometimes more appropriate to avoid unacceptable risks — the results of one study often give critical information on how to design the next one.
Optimal dose selection for toxicity studies and later clinical evaluation of a new drug is typically an iterative process. It includes data on, for instance, in vitro metabolism and plasma protein binding in animal and human material, concentration/dose-effect relationships in vitro and in vivo, and exposure data in the species used in the nonclinical studies. Accordingly, time can be saved by planning and executing all these studies in parallel.
Risks associated with running parallel studies
Running parallel studies can be risky. If some of the assumptions in your initial plan are wrong, one or several studies may need to be repeated based on the new data. From an ethical (and scientific) perspective, it is also required that a smaller dose range-finding study be conducted prior to a larger pivotal study using many animals in order to select appropriate dose levels for the larger study; the relevant national ethical committee must approve the design of all animal studies before they commence, and changes may be necessary.
Optimal decision-making cannot be derived from reading guidelines. Selection of the best approach, given your budget, can be achieved by including multiple relevant competencies in your team.
3. Know when to deviate from regulatory guidelines
An experienced team will be able to identify when deviations from regulatory guidelines may be relevant, which can help you save time and limit costs. For instance, can a specific study be omitted for your drug product, or can it be performed in a more resource-efficient way?
As an example, for most types of drugs, safety pharmacology studies should be performed before the first clinical trial. These studies are designed to address cardiovascular, CNS, and respiratory safety. In some situations, it may be desirable from the project point of view to include such endpoints in toxicity studies. Whether this is possible — meaning that it will generate relevant data that authorities will accept — depends on a range of factors, such as type of drug, previous knowledge, and relevance of the animal model.
Choosing contract research organizations
Also, the ability of the chosen contract research organization to perform a relevant assessment of these endpoints must be ensured. The decision to include endpoints in studies not primarily designed to assess these endpoints is more complex than it may seem. Make sure that your team has a sound knowledge base for these kinds of decisions.
Avoiding guidelines that do not make scientific sense
Following steps in a guideline that do not make scientific sense won’t provide any relevant data and is thus not a valid alternative. Regulatory agencies can accept a case-by-case approach if presented with sound scientific arguments. However, to avoid unpleasant surprises, make sure that the authorities agree with you on your assessment and proposed study design. Discussing the plans with regulatory agencies at the right time in the development program is a critical point in these situations to ensure smooth and efficient development. As a bonus, establishing a carefully planned and executed development program will increase the chance of convincing investors.
Interested in learning more? Watch our webinar “The Road to First-in-Human Trials: Insights from a Real-World Example”:
About David Dahlgren
David Dahlgren is Consultant, Drug Development, at Cytel and Associate Professor (Docent) of Translational Drug Discovery and Development at Uppsala University. He is an expert in drug development and pharmacokinetics, including in vitro, in vivo, and in silico biopharmaceutics research and regulatory consultant work.
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