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ICH S6 (R1) Preclinical safety of biopharmaceuticals

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ICH S6 (R1) Preclinical safety of biopharmaceuticals

great deal of evolution has taken place in the past few years in the preclinical safety evaluation of biopharmaceuticals. Case-by-case design of appropriate studies has benefitted from productspecific scientific insight with a strong focus on the mechanism of action of the biopharmaceutical. This, combined with years of practical experience, has meant the topics addressed in the recent addendum provide an excellent supplement to an already useful guidance document.

An addendum to ICH S6 reached step four of the harmonisation process in June 2011 and was integrated as part II in the core guideline that has been renamed S6 (R1)1. The addendum provides clarification on S6 and an update of the following topics: species selection, study design, immunogenicity, reproductive and developmental toxicity and assessment of carcinogenic potential. The original tripartite harmonised ICH S6 guideline, covering the preclinical safety testing requirements for biotechnology derived pharmaceuticals, was finalised in July 1997. This document addressed the use of animal models to assess the safety of what were, then at least, amongst the newer classes of pharmaceuticals. The guideline advocated focussing not just on the more traditional approaches to toxicology testing, but also on determining the extent of any pharmacological effect. Most developers of biopharmaceuticals recognise these effects as being amongst the most important considerations in determining safe and effective human doses. This is not to say that biopharmaceuticals are in any way unsafe, they have an excellent safety record - but they are usually very specific targeted therapeutics and as such their intended pharmacological effect may be so efficacious that a therapeutically beneficial effect can be exaggerated and result in a life threatening side effect. These phenomena are referred to by many terms including; exaggerated pharmacology, enhanced pharmacology, superpharmacology or occasionally on-target toxicities. These endpoints are often incorporated into toxicology studies which are intended to more broadly investigate the effects on non-target systems. This means that the toxicologist performing, or interpreting, toxicology studies with a biologic will need to understand the comparative biology of the biologic in both human and toxicology model species.

Small chemical drugs are, for want of a better term, xenobiotics - the body recognises they are not supposed to be there and does its best to clear them as quickly as possible. They themselves have dose limiting pharmacology in the same way as biologics; however they are also prone to off-target toxicities or as a result of break down into toxic metabolites. Biologics are not generally considered foreign in the same way; they are based upon, or are, substances found naturally in the body and as such they can remain in the body for a very long time, delivering a potent effect. So the ethos of regulatory preclinical safety testing of biologics, very much evident in the text of ICH S6 (R1) is to understand the pharmacology of the drug in the test system and set clinical doses that ensure a safe and effective dose is given to have therapeutic benefit. The biomarker most relevant in this context is the pharmacodynamic one and from a safety perspective, understanding the interrelationship between pharmacodynamics, pharmacokinetics and immunogenicity is of crucial importance.

Species Selection
ICH S6 has always placed a great emphasis on the selection of relevant animal models; this is taken to mean species that are pharmacologically responsive to the biopharmaceutical being tested. As discussed in the introduction this has always required a case-bycase approach. The ICH S6 guidance states that two species are preferred, the addendum clarifies this point further. If there are two pharmacologically relevant species for the clinical candidate (one rodent and one non-rodent), then both species should be used for short-term (up to one month duration) general toxicology studies. If the toxicological findings from these studies are similar or the findings are understood from the mechanism of action of the product, then longer-term general toxicity studies in one species are usually considered sufficient. The rodent species should be considered unless there is a scientific rationale for using non-rodents. Studies in two non-rodent species are not appropriate. Clearly there will be instances where although two pharmacologically relevant species have been identified, anti-drug immunogenicity seen in one of the species may preclude its use in longer term studies. Equally there are many instances where only one relevant non-

clinical species can be identified. There has been some concern in recent years that if sponsors had available homologous reagents then there may be requests to use these in a second species. The addendum is clear that there is no requirement to perform such studies, The use of one species for all general toxicity studies is justified when the clinical candidate is pharmacologically active in only one species. Studies in a second species with a homologous product are not considered to add further value for risk assessment and are not recommended. There are some biopharmaceuticals where there is no relevant species, for example where the drug target is an exogenous one. In these instances the addendum recommends that the sponsor considers performing just one short term safety study in a single species. This study would assess only the potential toxicities associated with the formulation itself and not any exaggerated pharmacology. Alternatively, safety assessment may be included in animal models of disease to ensure that target-associated toxicities may be investigated. Again, these risk mitigation strategies must be considered on a case-by-case basis. In the past, tissue cross-reactivity studies where monoclonal antibodies are screened against a panel of human, and in some cases, animal tissues have been performed as part of the species selection process. The addendum clarifies this need, concluding that assessment of tissue cross-reactivity in animal tissues is of limited value for species selection. It does however go on to make two other important points; firstly, that there are potential cases where tissue cross-reactivity studies may be used to guide selection of toxicology species, by comparison of tissue binding profiles in human and those animal tissues where target binding is expected. Secondly, inclusion of a tissue crossreactivity study with a panel of human tissues is a recommended component of the preclinical safety assessment package.

reveal potential hazards that would not otherwise be manifested in shorter studies. Whether or not these findings have altered the course of clinical development is questionable? Finally, the purpose of recovery assessment is clarified to be, recovery from pharmacological and toxicological effects with potential adverse clinical impact, and not to assess any delayed toxicity. The addition of recovery groups solely to provide samples with low drug levels to assess for potential immunogenicity is also not required.

Immunogenicity

Immunogenicity is not considered a toxicity read out predictive of preclinical outcome, so the addendum clarifies the purpose of immunogenicity assessment on non clinical safety studies. The general guidance being that any assays performed and subsequent data generated should be used to assist in the interpretation of the study results and design of subsequent studies. Measurement of anti-drug antibodies should be undertaken when there is clear evidence of altered pharmacodynamic activity, where there are unexpected changes in drug exposure (PK), or to investigate any evidence of immune-mediated reactions. In essence the issue of immunogenicity is really only of major concern where there are effects upon PK-PD that require additional interpretation. With regard to immune mediated reactions observed in non-clinical species, these are generally not predictive of clinical risk unless the increased immunogenicity relates in some way to the pharmacological action of the drug itself. It is generally not appropriate to extensively characterise the nature of any anti-drug antibodies generated on toxicity studies. If the PK or PD profiles are altered then it can generally be inferred that clearing or neutralizing antibodies have been generated without using bioassays. However, in the absence of PD markers on studies it might, in some instances, be appropriate to further characterise the nature of the immunogenicity.

Study Design

Several useful clarifications are made in the study design section of the addendum. Of note is the application of PK-PD principles in order to select the most appropriate high doses for safety assessment. Two suggestions are described, either dosing the concentration that gives the maximum intended pharmacological effect in the test species, or a dose that gives a 10-fold exposure over the maximum exposure intended clinically. It would be usual to select the highest of these as the high dose group. On the issue of safety study duration for repeat dose toxicity studies, the addendum states that six-month chronic studies in rodents or non-rodents are sufficient. Experience suggests that there is still a discussion among some who believe that longer studies may

Developmental and Reproductive Toxicology Testing (DART)

Generally when the clinical candidate is pharmacologically active in rodents and rabbits, both species should be used for embryofetal development studies, unless embryo-fetal lethality or teratogenicity has been identified in one species. With regard to fertility, for products where mice and rats are pharmacologically relevant species, an assessment of fertility can be made in one of these rodent species as per ICH S5. Where the non-human primate is the only relevant species a breeding study is unfeasible so the addendum recommends the potential for effects on male and female fertility can be assessed

by evaluation of the reproductive tract (organ weights and histopathological evaluation) in repeat dose toxicity studies of at least three months duration using sexually mature NHPs. The addendum provides detailed instruction on how to conduct combined embryofetal and pre/postnatal development studies for those products where nonhuman primates are the only pharmacologically relevant species. These designs will not be discussed in the article as the addendum discusses them in some depth. Finally DART studies are generally suggested to be performed during phase III and data submitted as part of licence application.

Inclusion of fertility-like endpoints in chronic NHP toxicity studies eliminates the need for separate studies. The enhanced PPND study design in NHP includes assessment of all developmental toxicity endpoints in a single study. The potential use of a homologous products for DART studies, with appropriate justification, may also reduce the use of NHPs.

Conclusion

Carcinogenicity

For novel small molecule drugs it is usual to perform two-year rodent carcinogenicity bioassays. Due to considerations such as immunogenicity and lack of relevant pharmacology, it is often not appropriate to perform these studies with biopharmaceuticals, even if homologous rodent reagents are available. However, the addendum still makes clear that there is a need for a product-specific assessment of the carcinogenic potential of biopharmaceuticals. The addendum advocates a weight of evidence based approach considering the duration of clinical exposure, any relevant causes for concern based upon; published data, class effects, drug target biology and mechanism of action, in vitro data, data from chronic toxicity studies and clinical data. In some cases this data review will be sufficient to address the risks without performing nonclinical studies. Where the weight of evidence supports a carcinogenic potential, potential hazard may be addressed by product labelling and risk management practices. However, in some cases additional studies may be appropriate.

The ICH S6 (R1) addendum is clearly a welcome addition to the guidance available to those developing biopharmaceuticals. The philosophy of the original S6 remains the same, with some useful direction and best practice in many areas. The positive impact upon speed of product development is sure to be seen in the coming years.

Key Points

Clarification

of species selection, study design, immunogencity, reproductive and developmental toxicity and assessment of carcinogenic potential. biopharmaceuticals.

Refocus on the philosophy of pre-clinical safety of Based on best procedures following fourteen years
of working within the ICH S6 frame work.

References
1. ICH Harmonised Tripartite Guideline - Preclinical Evaluation of Biotechnology-Derived Pharmaceuticals Parent Guideline dated 16 July 1997 Current Step 4 Addendum dated 12 June 2011 incorporated at the end 2011. Safety S6(R1) version of June

Impact upon the 3Rs

One clearly stated purpose of the addendum is to reduce the use of animals in accordance with the 3Rs (reduce/refine/replace) principles. There are clearly many opportunities in the addendum to reduce the numbers of animals used in the development of biopharmaceuticals.

The use of only one relevant species for longer term toxicity studies rather than the conventional two. The use of recovery groups on a reduced number of toxicity studies and/or treatment groups. Limit to a maximum of six months duration for chronic studies.