New Approach Methodologies, or NAMs, are becoming an increasingly important part of drug development. These approaches include human-derived cell systems, organ-on-chip technologies, computational models, stem-cell assays, and other methods intended to improve human relevance while reducing reliance on traditional animal studies.

The growing interest in NAMs has prompted an important question for cardiovascular safety pharmacology:

Where can these methods meaningfully replace existing studies, and where are they better used to complement them?

A recent multi-stakeholder workshop involving regulators, pharmaceutical companies, CROs, and scientific organizations explored this question in the context of a potential revision of ICH S7A. The discussions focused on the minimum weight-of-evidence package needed for regulatory decisions, where NAMs can replace or support existing studies, and where important scientific gaps remain.

Moving from fixed testing batteries to weight of evidence

One of the clearest themes was the need to move away from a rigid, checklist-driven approach toward a more flexible weight-of-evidence framework.

Under this model, cardiovascular safety decisions would integrate multiple sources of information, including:

• Primary and secondary pharmacology
• Target biology
• Drug modality
• Pharmacokinetics and tissue exposure
• In vitro and in silico findings
• In vivo functional data
• Toxicology results
• Available clinical information

The goal is not simply to perform a predefined list of studies. It is to assemble the most scientifically appropriate evidence for the safety question being asked.

This approach is particularly relevant as drug development expands beyond traditional small molecules to include antibodies, peptides, oligonucleotides, targeted protein degraders, and cell and gene therapies.

Context of use is critical

A recurring message throughout the workshop was that no NAM should be evaluated separately from its intended context of use.

The context of use defines:

• The precise safety question
• The stage of development
• The type of therapeutic product
• The biological endpoint being measured
• The decision the result is intended to support
• The limitations of the assay

For example, an isolated vascular preparation may provide useful evidence that a compound directly contracts or relaxes a blood vessel. It does not necessarily predict the net effect on blood pressure in an intact organism.

The same assay may therefore be highly valuable for mechanistic investigation but unsuitable as a stand-alone replacement for an integrated cardiovascular study.

Scientific validity must be fit for purpose

NAM validation is unlikely to involve a universal standard that applies equally to every method and every regulatory decision.

Instead, the required level of validation should reflect the intended use.

Important considerations include:

• Biological and mechanistic relevance
• Clear and reproducible endpoints
• Appropriate positive and negative controls
• Assay sensitivity and specificity
• Technical reliability
• Reference-compound performance
• Applicability across relevant chemical or biological domains
• Transparent limitations
• Reproducibility over time and, where necessary, across laboratories

A method used internally for early compound screening does not require the same evidence as a method intended to establish the absence of a cardiovascular safety liability before first-in-human dosing.

This distinction between scientific use and regulatory use is essential.

Where NAMs are already adding value

NAMs are already useful throughout discovery and development.

Common applications include:

• Early hazard screening
• Candidate ranking and selection
• Target-safety assessment
• Secondary pharmacology
• Mechanistic investigations
• Interpretation of unexpected findings
• Selection of follow-up studies
• Cross-species and human translation
• Clinical monitoring and risk-mitigation planning

Cardiac electrophysiology is among the most developed areas. Ion-channel assays, computational action-potential models, and cardiomyocytes can contribute meaningfully to the evaluation of repolarization and proarrhythmic risk.

NAMs are also being used to investigate cardiac contractility, conduction effects, vascular mechanisms, and modality-specific off-target risks.

Their current strength is often not in replacing a complete study, but in explaining why a finding occurred and helping determine what additional evidence is needed.

Hemodynamics remains a major challenge

The hemodynamics discussions highlighted one of the largest gaps in the current NAM landscape.

Blood pressure is not controlled by a single tissue or molecular pathway. It reflects the interaction of:

• Vascular resistance
• Cardiac output
• Heart rate
• Contractility
• Autonomic reflexes
• Central nervous system activity
• Renal regulation
• Hormonal responses
• Tissue distribution
• Compensatory physiology

Human vascular preparations may identify direct vascular effects, but their scope is limited. They do not reproduce the integrated contributions of the heart, nervous system, kidney, or endocrine system.

The breakout group did not identify a current in vitro or stem-cell-derived approach that was clearly superior to a conventional in vivo blood-pressure study. There was also no agreement that existing NAMs could replace an in vivo hemodynamic assessment with today’s technology.

The most realistic near-term role for hemodynamic NAMs is therefore to address specific uncertainties, such as:

• Whether a blood-pressure effect is directly vascular
• Whether a known receptor or pathway is involved
• Whether additional studies are needed
• Whether the available evidence is sufficient to proceed clinically
• What monitoring or mitigation may be appropriate

In this setting, NAMs fill a gap in the evidence package rather than replace integrated physiology.

Similar lessons apply to other complex systems

The same general limitation appears in other areas of safety pharmacology. For example, neural microelectrode arrays, ion-channel panels, and related NAMs can help identify seizure-related signals and mechanisms, but confidence remains insufficient to broadly replace EEG-based in vivo assessment.

The broader lesson is that NAM adoption is progressing fastest where mechanisms and endpoints are well defined. Integrated physiological outcomes—including blood pressure, systemic hemodynamics, and complex neurologic responses—remain more difficult to reproduce outside the intact organism.

NAMs must improve decisions, not simply add tests

Another important industry message was that a NAM should ideally replace, reduce, refine, or meaningfully improve something in the existing development process.

A new assay has limited practical value if it:

• Adds cost without changing a decision
• Produces data that cannot be interpreted
• Duplicates information already available
• Requires more time or resources than the study it is intended to replace
• Has no defined action associated with a positive or negative result

Successful adoption will depend on demonstrating that a NAM can improve candidate selection, reduce uncertainty, prevent unnecessary studies, identify liabilities earlier, or support better clinical risk management.

Data sharing is essential

Regulatory confidence cannot develop without adequate performance data.

Many of the most informative datasets involve compounds that failed during development, produced unexpected findings, or generated positive safety signals. These data are often proprietary and therefore difficult to access.

Greater collaboration and data sharing could help establish:

• Standard reference compounds
• Positive and negative control sets
• Assay sensitivity and specificity
• Known failure modes
• Applicability domains
• Comparisons with in vivo and clinical outcomes
• Confidence thresholds for regulatory use

Shared retrospective datasets may be particularly valuable for complex endpoints such as blood-pressure effects, conduction abnormalities, and contractility findings.

Replacement will occur endpoint by endpoint

The workshop did not support the idea that NAMs will replace the entire safety-pharmacology core battery in a single step.

Progress is more likely to occur incrementally.

NAMs may have the greatest near-term impact in areas where:

• The mechanism is well understood
• The assay endpoint has a clear relationship to human risk
• Reference compounds are available
• Technical performance is well characterized
• Animal models have limited biological relevance
• The method addresses a narrow, clearly defined decision

More complex integrated endpoints—such as systemic blood pressure, autonomic responses, cardiac output, and compensatory hemodynamics—will require continued scientific development and validation.

The path forward

A modernized cardiovascular safety-pharmacology framework is likely to emphasize:

• Weight-of-evidence decision-making
• Clearly defined context of use
• Fit-for-purpose validation
• Integration of functional endpoints into toxicology studies
• Recognition of secondary pharmacology as decision-shaping evidence
• Modality-aware but technology-agnostic principles
• Human-relevant in vitro and in silico approaches
• Transparent uncertainty and safety-margin assessment
• Appropriate use of clinical monitoring and mitigation

The goal should not be to select between NAMs and in vivo studies as competing approaches.

The more productive question is:

What combination of evidence provides the most reliable assessment of human cardiovascular risk for this specific compound, modality, and safety concern?

Conclusion

NAMs are already changing cardiovascular safety pharmacology, particularly in early screening, mechanistic investigation, and the interpretation of complex findings.

However, the workshop discussions also made clear that enthusiasm must be balanced with scientific realism. Current methods do not yet reproduce all of the integrated physiological responses captured in an intact organism, particularly for blood pressure and hemodynamics.

For the foreseeable future, the most effective approach will be one in which NAMs, in vivo studies, exposure data, pharmacology, toxicology, and clinical information are integrated within a transparent weight-of-evidence framework.

NAMs are not a single replacement technology. They are an expanding set of tools that, when used within a clearly defined context, can make cardiovascular safety assessment more mechanistic, more human-relevant, and more informative.