医薬品企業が治験薬の非動物試験へ移行するための方法

For decades, animal testing has been the standard practice in the pharmaceutical industry for evaluating the safety and efficacy of drugs before they enter the clinic. However, animal tests often do not accurately predict drug effects in humans. Additionally, there are ethical concerns associated with animal testing, particularly regarding the use of costly and difficult-to-source non-human primates (NHPs). Thus, the pharmaceutical industry has been striving for the 3Rs (reduce, refine, and replace) of animal testing for decades.

NAMs are more human-relevant, non-animal studies that fall into four main categories:

• Microphysiological systems (MPS): 2D/3D cultures and organ- or organoid-on-chip platforms that mimic human tissue function.
• Advanced in vitro assays: Tools such as cytokine-release and T-cell activation panels to assess immunotoxicity.
• Advanced ex vivo human systems: Including tissue culture and pluripotent stem cells for high-throughput safety screening.
• In-silico tools: Computer-based models that simulate drug absorption, distribution, metabolism, excretion (ADME), off-target effects, and immunogenicity.

A range of modeling and simulation tools supports the move away from animal testing. AI-driven modeling and simulation provide rapid, cost-effective solutions for both large and small molecules. The pharmaceutical industry is already deploying established in silico models for a range of applications.

One of the biggest challenges drug developers face in this era of tight funding from investors is making “go/no go” decisions on which candidates to progress through the development process. In silico models can help make earlier assessments on the safety liability of drug candidates. For example, Certara’s ToxStudio® software suite brings together a suite of cutting-edge NAMs to address three critical areas in preclinical safety:

• Cardiac safety (QT prolongation risk)
• オフターゲットの安全性
• 薬剤誘発性肝障害（DILI）

Mechanistic modeling uses in vitro data to simulate human pharmacokinetics and pharmacodynamics (PK/PD). This approach helps determine appropriate dose levels and reduces the need for animal studies.

Immunogenicity refers to the body producing an immune response to a foreign substance. If a drug produces significant immunogenicity, it can pose both efficacy and safety issues. Certara’s IG Simulator (QSP platform) predicts immunogenicity using human data, validated by pharma partners, and supports regulatory submissions without animal data.

The 2022 FDA Modernization Act 2.0 opened the door for replacing expensive animal testing with cheaper, more effective human-relevant methods. However, drug developers need confidence that NAMs will be accepted by regulators. Without clear guidance from the agency and consistent review practices, sponsors will default to animal testing, even when NAMs are more scientifically valid. Here are some ways that you can confidently incorporate NAMs into your development strategy.

Transitioning from animal-based testing to NAMs requires a “weight of evidence” approach. Instead of directly replacing each animal test, sponsors should weigh multiple factors, including the disease being treated, clinical need, and drug target information, as well as clinical, modeling, and in vitro data. Together, these data streams form a more complete and human-relevant picture of drug safety and efficacy.

The FDA will continue expanding the use of NAMs by validating them with real-world clinical data and updating its guidance for including them in drug submissions. It also plans to support pilot programs focused on NAMs, lead efforts to align with international regulatory standards, and build shared data repositories to collect and compare study results.

Additionally, the FDA will train its reviewers to assess NAM evidence and track their effectiveness in streamlining drug development. The pressure will be mounting for drug development programs to adopt NAMs as the US National Institutes of Health (NIH) just announced an end to funding for animal-only studies.

Regulators now expect holistic submission packages. Sponsors should combine NAMs to develop their drug’s evidence base. The NAMs they use must be reproducible, standardized, and benchmarked against clinical outcomes. To ensure both regulatory and patient trust, NAMs must confer predictive power that meets or exceeds traditional animal tests.

The FDA’s eventual goal is to eliminate animal testing for all drugs. But the FDA Roadmap prioritizes reducing non-human primate testing for monoclonal antibodies (mAbs), potentially eliminating an average of 144 NHPs per drug at $50K each. The nonclinical testing of mAbs presents unique challenges due to their precise target specificity, which often means there are no suitable non-human species for study, or NHPs may be the sole viable option.

To facilitate regulators accepting NAMs in mAb programs, companies can focus on a few key steps. These recommendations are particularly relevant for “me too” mAbs that target the same proteins as existing approved therapies. If the target and antibody are already well understood, more animal testing may not add much value.

By carefully comparing the new mAb to approved ones, examining its structure, binding mechanism, potency, and behavior in the body, and utilizing in vitro data and other robust evidence, companies can demonstrate that the safety risks are already well understood. This makes it possible to reduce or skip some animal studies, especially for long-term and reproductive toxicity. The goal is to only use animal studies when truly needed. Otherwise, sponsors should leverage existing clinical data as well as lab and in silico model results to fill knowledge gaps.

To successfully adopt a NAM-based approach, sponsors should connect with the FDA early to discuss their plans. They should also consider participating in pilot programs offered by the agency.

It’s important to use well-validated tools, like PBPK and QSP models, and organ-on-chip systems. Sponsors should also clearly document all assumptions and data. Submissions should include human-relevant evidence that ties closely to clinical outcomes.

Early-phase study designs, especially first-in-human trials, should reflect learning from NAMs. Because of minimized animal testing, sponsors should take particular care in monitoring dosing and safety in these studies. Finally, sponsors should align with international guidelines, like those from the ICH, to streamline global regulatory submissions.

We recently gave a webinar on this topic and asked our attendees about their current use of NAMs (Figure 4). The fact that over 40% of respondents reported not having used any NAM means that we must educate drug developers about the potential benefits of these emerging tools. This also suggests that we will see rapid growth in the non-animal alternative testing market in the coming years.

Navigating this shift away from animal testing requires more than just new tools. It demands the right strategy and experience. Certara’s Non-Animal Navigator™ solution positions sponsors to lead confidently in this new era of drug development. To learn more about this topic, watch our webinar.