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When to Start Subchronic & Chronic Toxicology Studies

Subchronic and chronic toxicology tests are essential studies that assess long term health effects of test substances, supporting longer clinical study durations and your New Drug Application (NDA) with the FDA. To make informed decisions and hit your timelines, when should these important studies be conducted?

Once the exploratory studies are complete, you’ve optimized your drug and gone through the proper GLP, IND-enabling studies, and submitted an Investigational New Drug (IND) application, you’re ready to start a first-in-human trial.

You know a lot about your drug, and you’ve made it far in the drug development process – few reach this stage.

What now?

Depending on the mechanism of action of your drug, clinical dose and regimen, it might be time for subchronic or chronic toxicology studies.

What Are Subchronic & Chronic Toxicology Studies?

The length of subchronic and chronic toxicology studies typically range from 3 months to 12 months. During that period, a number of potentially treatment-related adverse effects are evaluated. The data obtained from those studies are subsequently used to assess potential risk to human when it’s administered to man. In general, subchronic and chronic studies are conducted post-IND and before an NDA.

Compared to IND-enabling studies, the scale of subchronic and chronic studies are larger. More animals are required and a longer treatment duration is needed, so the studies become more expensive. Technically, however, subchronic and chronic studies are also sometimes considered more straightforward than the earlier exploratory studies. This is because you have a strong foundation of data and a solid understanding of what information you need from these longer duration studies.

However, just because they might be considered “easier,” doesn’t mean they don’t require immense planning to successfully pull off. These play a critical role in assessing long term effects, and interpreting a relatively larger volume of study data is much more complex compared to short-term studies.

For example, a 6-month chronic study would require at least 8 months to complete in-life portion – giving time for animal acclimation prior to treatment and a recovery period required post-treatment (e.g. 4 weeks) – and then another 3 months required for reporting. That’s almost an entire year required for a 6-month study.

After that, you need to submit the data to the FDA, and the agency needs time to review data before approving your clinical treatment. The timeline stretches on.

It’s clear that planning these studies appropriately is critical. You’ve made it this far. How can you stay on track?

It starts with understanding what these studies could include, how long they take, and why they need to happen.

When to Start Subchronic Toxicology Studies

Subchronic toxicology studies are typically 3-month studies that aim to provide safety data that supports the proposed dosing regimens and duration of use in humans. This includes:

Dose-dependent toxic effects
Target organ toxicity
Reversibility of adverse effects

If a clinical program is going to stretch beyond 28 days, subchronic studies are required to support it. You should prepare for this as soon as you know your clinical plan – which happens well before you even begin preclinical toxicology testing.

When to Start Chronic Toxicology Studies

Chronic toxicology studies are typically 6-month studies (rodent) or 9-month studies (non-rodent) or longer that support much longer clinical plans. These studies detect long term toxicity, including:

Cumulative toxic effects
Delayed toxic effects
Immunogenicity
Reproductive toxicity

If your clinical plan demands chronic toxicology studies, you are looking at even more complex aspects of toxicity.

Here are some examples:

Carcinogenicity: These studies expose animals to the test compound for a major portion of their lifespan and assess for the development of non-neoplastic and neoplastic lesions in organs and organ systems.
Immunogenicity: These studies include immune cell profiling, which identifies and characterizes the different types of immune cells to determine if a drug induces any adverse immune responses, and cytokine analysis, which evaluates a drug’s impact on immune system regulation and inflammatory responses.
Development and Reproductive Toxicity: These studies evaluate how a drug may affect both a developing fetus and the reproductive system across 3 stages of development.

Because these chronic studies are more time consuming and resource intensive, they should be planned for as early as possible. This will ensure you have the data you need to complete clinical trials and submit your NDA.

Conclusion

For longer clinical plans, subchronic and chronic toxicity tests are essential for ensuring long term drug safety and supporting your upcoming NDA. You should plan for these as soon as possible, even before you have completed your preclinical testing.

In your planning process, remember to account for the longer duration and more complex reporting required by subchronic and chronic toxicology studies in order to hit your deadlines.

It’s common for researchers to prefer to run subchronic or chronic studies with the same testing facility where the IND enabling studies were conducted, since the lab already has the analytical and/or bioanalytical methods established. However, it’s important to make sure that testing facility is fully equipped with adequate experience, expertise, and resources required to properly handle subchronic and chronic studies. As you continue your drug development journey, make sure you bring up long term testing needs early and, more importantly, properly assess the testing facility’s bioanalytical capabilities for more complex studies. In order to have subchronic and/or chronic studies conducted successfully, it’s critical to select a right testing facility who can be your long term partner.

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