By Rose Pagano and Suzanne M. Sensabaugh, MS, MBA


The S9 Nonclinical Evaluation for Anticancer Pharmaceuticals Guidance (ICH S9) has resulted in confusion and challenges amongst its users. S9 Nonclinical Evaluation for Anticancer Pharmaceuticals Questions and Answers Guidance for Industry is intended to aid in the implementation of ICH S9 and help with the reduction, refinement, and replacement of animals.

ICH S9 nonclinical program is applicable to the majority of initial development programs for both adult and pediatric patients suffering from diseases that are resistant and refractory to available therapies. For programs where the cancer is not considered to be resistant or refractory, ICH S9 can be used as a starting point and ICH M3 and S6 may serve as good references. Always consult with FDA if the development pathway remains unclear.

Many have interpreted the ICH S9 guidance as applying to people with life expectancies around three years. However, the guidance does not make reference to the number of years patients are expected to live and how that should dictate drug trials. Utilizing this guidance should not be dictated on life expectancy, but rather on the resistant and refractory nature of the cancer.

It is important to note that using the principles of ICH S9 for non-oncology therapies for diseases that are life-threatening and have limited drug treatments goes outside the scope of the document. ICH M3 would be a good guidance to reference for these situations.

Additionally, the Q&A clarifies that if an anticancer pharmaceutical is proven to extend survival of patients, then typically general toxicology studies are unnecessary. Clinical safety data are meant to assess human risks more so than those generated by further animal studies. Additional toxicology studies other than general toxicology may be required depending on the situation, and these studies should be submitted after approval of the anticancer drug.

Also, the document explains that additional toxicology studies are not warranted when moving therapeutic development from an approved indication in oncology or from an unapproved indication with a sufficient nonclinical and clinical safety database to an unapproved oncology indication that is serious but not life-threatening. Again, clinical safety data for a patient population for an approved indication are most beneficial in an unapproved indication.

Furthermore, clinical trials in the adjuvant or neo-adjuvant setting are also covered under ICH S9. This document is a good starting point for drugs used in these settings even when there is not a detectable residual disease.

The Q&A guidance goes on to state that scientific assessment of recovery potential should be given in general toxicology studies to support clinical development, but recovery groups do not need to be included in all general toxicology studies. These data can be generated through the understanding that a certain effect is seen as reversible or non-reversible or by having a recovery period in at least one study. Recovery in 3-month studies is only necessary if there is a concern in short-term toxicology or from clinical studies that recovery animals could answer.

If there is a situation where the only relevant species is a non-human primate (NHP), a weight-of-evidence assessment of reproductive risk should be given. If the weight-of-evidence assessment  indicates risk, then a NHP study is not necessary. An NHP study for analysis of a hazard to embryofetal development should not be a default approach.

Nonclinical studies on abuse liability are usually unnecessary to support clinical trials and the marketing of pharmaceuticals for patients with advanced cancer. Likewise, for biopharmaceuticals, tissue cross reactivity studies are not required for an initial first-in-human study or later in development,  unless there is specific cause for concern. If there is no pharmacologically relevant species, human tissue cross reactivity and other methods may be a potential route of investigation for the first-in-human study.

All things considered, this Q&A guidance answered many of the commonly asked questions concerning the initial ICH S9 guidance and is useful for applicants under these protocols.


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Nitisha Pyndiah - Biotech Consulting Services

Suzanne M. Sensabaugh has advanced the development of over 130 biologics, biosimilars, and combination products since 2009. She can be reached at