The way we test drug safety is changing: we are now relying on Novel Approach Methods (NAMs) more than ever before. And now, the requirements from regulatory bodies, such as the Food and Drug Administration (FDA), on the safety of drug candidates is changing too.
In this blog post, we’ll discuss when the Carcinogenicity (CARC) Weight of Evidence (WoE) approach (in lieu of a 2-year rat CARC study) is best implemented in your own drug discovery pipeline and how our experts, here at ApconiX, can help.
In November 2022, the FDA introduced the ICHS1B(R1): an addendum to S1B: ‘Testing for Carcinogenicity of Pharmaceuticals’. This addendum, and its associated guidance document, provide an alternative method (so-called ‘Weight of Evidence’) to ascertain whether carrying out a two-year carcinogenicity study in the rat is likely to add any real value.
Instead of relying on the results from a single animal study, the WoE approach can be used to robustly evaluate carcinogenicity risk in humans by integrating data from a range of different sources.
Here, we’ll focus on implementing the WoE approach for carcinogenicity assessment.
However, it’s worth noting that ApconiX has strong expertise in building structured weight of evidence packages for CARC, Developmental and Reproductive Toxicology (DART) and paediatric safety studies, aligned with current ICH guidelines and expectations.
Using the WoE approach to reduce reliance on animal studies
The use of WoE assessment in place of animal studies is a key example of a wider trend in drug development: that is, an ongoing commitment to ‘Replacement’, ‘Reduction’ and ‘Refining’ of animal testing (The 3Rs).
This is because the WoE approach integrates data from a range of sources including from existing toxicology studies and published literature to determine if a rodent study would add any real value to a drug safety assessment.
At ApconiX, we believe that NAMs, alongside the WoE approach, can help reduce our reliance on animal studies. For example, we have developed an innovative NAM to tackle seizure liability in drug discovery and are at the forefront of responsible, science-led study design. We are also contributing to the HESI NAMs and the NC3Rs expert working groups such as NAMs and species selection.
The WoE approach is a vital part of modern drug safety assessment
Carrying out an effective WoE assessment is a crucial part of your critical path — helping you determine where best to invest critical time and resources.
The standard 2-year rat CARC study is a case in point here. Carrying out a WoE assessment can help you determine whether the 2-year rat study is likely to tell you anything new about the safety of your drug candidate.
For example, evaluation of target biology (including data from similar drugs), histopathology and/or findings of concern in repeat dose studies may show that human risk of carcinogenicity is likely. So, the results of carrying out a 2-year rat study offer limited value in this case, as the risk has already been established.
Conversely, there is a lack of value in conducting a 2-year rat study when the risk of carcinogenicity is unlikely. This evidence may stem from the target biology already being well understood (for example from rodent CARC data from drugs with a similar mode of action) and from finding nothing of concern when investigating other factors relevant to the WoE assessment.
In both scenarios, the WoE approach can be used to evaluate evidence from rodents and other species to determine the likelihood of drug carcinogenicity in human.
In other cases, the results of conducting a meaningful 2-year rat study may not be possible based on feasibility. For example, a 2-year rat study may not be useful from a technical point of view, e.g. because of route constraints, or if the rat animal model is not pharmacologically or biologically relevant for the drug being tested.
How implementing the WoE approach can help your CARC assessment
If the regulatory body finds that your WoE assessment can be accepted in lieu of a 2-year rat CARC study, then there are many benefits: in terms of resources, timelines for your critical path and regulatory compliance.
For each rat CARC study that did not need to be implemented, 600 fewer animals would be tested and up to $4.25 million would be saved both in performing the study and evaluating results. In addition, a rat CARC study adds up to 3 years to the nonclinical aspect of the drug development process — in terms of both carrying out the study and establishing the dose.
Building a successful WoE case with ApconiX
Here at ApconiX, we take an expert-led, integrated and tailored approach to WoE. Whilst we embrace using the latest AI and data analysis tools as part of our process, ultimately, we are an organisation that puts human expertise front and centre.
Here’s how we do it:
- Our Safety Science Group and experienced toxicologists first carry out a Pre-WoE assessment. This enables us to decide which lines of evidence justify a lack of value of the 2-year rat CARC study. We will also determine a likely timeline needed for us to complete the full WoE assessment.
- If you choose to go ahead, our Safety Science Group will then carry out a Target Carcinogenicity Assessment (TCA). This specialist database and literature review includes the assessment of drug target biology and pharmacology, as well as relevant CARC data from mouse and human genetic models and studies. This forms part of the ‘Target Biology’ section of a CARC WoE and the first of six lines of evidence needed for a full WoE assessment. We can also deliver a TCA as a stand-alone option.
- To complete the other required factors for the CARC WoE, our team of experienced regulatory toxicologists and pathologists work together to assess: any potential secondary, ‘off target’, effects, concerning changes in cells and tissues from histopathology studies, potential effects on hormonal regulation, evidence of damage to cellular DNA and, finally, any implications on immune modulation, including overstimulation and suppression.
- Our experts will then incorporate evidence from all six WoE factors to determine the value of a 2-year rat study for the assessment of carcinogenicity potential in humans. You will receive our WoE assessment as a fully integrated document, with all the relevant information at your fingertips.
A note on timing from our expert team at ApconiX
Conducting an effective WoE analysis requires extensive expertise – and like anything worth doing, that takes time (although considerably less compared to a 2-year rat study).
Once completed, the time taken for regulators to review the WoE case can vary, but at the time of writing, the FDA is taking around six months to review small molecule CARC WoE cases. It’s also worth noting that each key region has their own approval system, and decisions across regulatory agencies can vary. Therefore, to avoid delays to other critical path activities, we would recommend that you schedule adequate time for completion and approval of a WoE assessment across all key regulators.
At ApconiX, our WoE process includes project scoping, researching and expert consultation — all in close collaboration with you, our client.