Implementing ICH S6(R1): Preclinical Safety Evaluation in Biotechnology
- Dr. Catherine Kennedy
- May 16
- 5 min read
Updated: Jun 4
The ICH S6(R1) guidelines provide a framework for preclinical safety evaluations of biotech-derived pharmaceuticals. They are used as a key regulatory document for major health authorities to ensure that pharmaceuticals undergo sufficient safety evaluations before their use in clinical trials in humans. The primary objectives of the guidelines revolve around identifying safe doses and dose escalation schemes, identifying potential target organs for toxicity and assessing reversibility, and identifying safety parameters for clinical monitoring. In addition to ensuring patient safety, the guidelines are also beneficial to the drug development process by streamlining safety evaluations, significantly reducing timelines.
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Understanding Preclinical Safety Evaluation
Preclinical safety is a crucial aspect of pharmaceutical development. It incorporates full assessments of the drug or product’s potential to cause harm, including testing for toxicity, pharmacokinetics, and pharmacodynamics, before the product is moved forward to testing in humans. Safety and efficacy can be confused in preclinical safety evaluations. Safety evaluations are carried out to uncover the potential harm that a drug may pose to humans, whereas efficacy evaluations assess whether the drug is producing the desired biological or therapeutic effects. Both are necessary in preclinical research, but the ICH S6(R1) guidelines are solely focused on safety.
Technical Review of Safety Data
Preclinical safety evaluations involve a technical review of safety data. This should include a comprehensive data assessment where all available safety data is compiled and checked for quality and reliability, in addition to assessments of:
Relevance and context so that only data relevant to humans and for the drug’s intended use is included.
Weight of evidence, including evaluating the strength, quality, and amount of evidence to determine whether it passes the threshold for inclusion.
Clinical significance to ensure that the relevant information is prioritised for inclusion, particularly the recognition, diagnosis, and prevention of adverse reactions.
Applying ICH S6(R1) to Different Biotech Products
The ICH S6(R1) guidelines provide a framework for preclinical safety evaluations that can be applied to all biotech products, with alterations made to account for the unique properties and mechanisms of action of each product.
Monoclonal Antibodies
Preclinical safety evaluations of monoclonal antibodies involve an assessment of biological activity, including a detailed description of the immunological properties of the antibody, such as its antigen specificity and unintentional reactivity with human tissues separate from the intended target. Animal species selection is a crucial aspect of antibody testing, where the chosen species must express the desired epitope and have similar cross-reactivity to human tissues.
Recombinant Proteins
Species selection must be carefully evaluated when testing recombinant proteins. A species should be chosen where the recombinant protein interacts with the intended biological target and produces a similar response to humans. The study design should be tailored to the clinical context of the protein, considering the route of administration and dosing regimen. For example, if the recombinant protein is to be dosed daily as opposed to intermittently, repeated dose toxicity studies should be completed.
Gene Therapies and Novel Biologics
Study design must be considered when assessing the safety of gene therapies. The distribution profile and transduction rates of the vector and the time taken to reach steady state need to be evaluated to aid in a decision on study length. For example, a study where the transgene expression steady state is reached within 4 weeks will require a study duration of approximately 3 months. Species selection should be based on whether the vector and transgene are biologically active within the species and if they mimic human responses. If no suitable species can be found, transgenic animals may be used.
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Translating Nonclinical Findings to Clinical Risk Assessment
Following the framework set out in ICH S6(R1) will help to bridge preclinical results to human clinical trials. The guidelines will help to ensure the safe and scientifically justified progression from animal studies to human trials using key principles of translation:
Safe dose identification – using pharmacokinetic and pharmacodynamic data and considering the level of exposure leading to toxicity in animals and how this will compare to human exposure.
Mechanistic understanding – establishing whether toxicities seen in animals are due to exaggerated on-target pharmacological effects or off-target effects.
Risk mitigation – using non-clinical findings to guide areas requiring specific monitoring in clinical trials.
Weight-of-evidence – integrating all available data to assess the clinical relevance of nonclinical findings.
Navigating Regulatory Submissions and Timelines
The full list of key components for regulatory submissions under ICH S6(R1) can be found within the official guidelines. In summary, they should include: justification of species selection and study design; an immunogenicity assessment; reproductive and developmental toxicity findings; and carcinogenicity results. These should all incorporate ethical considerations, scintific justification, and clear documentation.
ICH S6(R1) does not define strict timelines. It instead forms guidelines that regulatory submissions, such as Pre-IND, IND/CTA submissions, and clinical trial applications should align with. The preclinical stage of the drug development process can take years to complete. However, by following the ICH S6(R1) guidelines and prioritising scientific relevance over routine testing, these timelines can be significantly reduced.
Practical Strategies for Successful Implementation
Successful implementation involves carefully following the ICH S6(R1) guidelines and advice. Common pitfalls include:
Inappropriate species selection – species must be pharmacologically relevant and should be justified based on target binding and pharmacodynamics.
Overuse of non-human primates (NHPs) – studies should only be conducted in NHPs when they are the only relevant species. Alternative species and in vitro models can be just as useful while also being cheaper and not facing regulatory pushback.
Misinterpretation of immunogenicity – anti-drug antibodies should be evaluated early in preclinical tests and throughout development, as they could confound toxicity and drug exposure data.
Conducting unnecessary studies – studies should be carried out using case-by-case planning and risk-based approaches to minimise the number of studies needed while ensuring all safety points are covered.
The ICH S6(R1) guidelines encourage the incorporation of emerging technologies into preclinical safety evaluations, including advanced in vitro systems to reduce the number of animals used, transgenic animal models to ensure pharmacological relevancy and the generation of meaningful safety data, and novel analytical tools. The integration of these new strategies should involve clear scientific justification and transparent documentation.
Conclusion
The ICH S6(R1) guidelines provide a detailed, flexible framework for evaluating preclinical safety in biotech-derived pharmaceuticals. By focusing on scientific relevance and risk-based approaches, the guidelines support full preclinical patient safety evaluations while streamlining timelines. Successful implementation depends on careful species selection, scientifically justified study design, immunogenicity assessments, relevant toxicity investigations, and meaningful data interpretation, ensuring a smooth transition from laboratory research to human clinical trials.
