On 16 May 2018, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted the ICH S9 guideline on non-clinical evaluation of anti-cancer pharmaceuticals (Step 5)1. This guideline aims to assist in the design of non-clinical studies for the development of anti-cancer pharmaceuticals. It provides recommendations for non-clinical evaluations to support the development of anti-cancer pharmaceuticals in clinical trials for the treatment of patients with advanced disease and limited therapeutic options, while avoiding unnecessary use of animals, in accordance with the 3R principles (reduce/refine/replace), and other resources.
The ICH S9 Guideline: Non-clinical Evaluation for Anti-cancer Pharmaceuticals reached Step 4 in November 2009 and the guideline was a significant advance in promoting anti-cancer drug development. Since reaching Step 4, all the parties using the guideline have experienced some challenges around implementation.
For this reason, an Implementation Working Group (IWG) was formed in October 2014, by the International Council for Harmonization (ICH), to develop Questions2 and Answers to provide additional clarity around anticancer pharmaceutical development, as described below –
Why is non-clinical evaluation of anti-cancer pharmaceuticals needed?
Because malignant tumors are life-threatening, the death rate from these diseases is high. Since existing therapies have limited effectiveness, it is desirable to provide new, effective anti-cancer drugs to patients more expeditiously. There have been no internationally accepted objectives or recommendations on the design and conduct of nonclinical studies to support the development of anti-cancer pharmaceuticals in clinical trials for the treatment of patients with advanced disease and limited therapeutic options. Non-clinical evaluations are conducted to:
- identify the pharmacologic properties of a pharmaceutical,
- establish a safe initial dose level for the first human exposure, and
- understand the toxicological profile of a pharmaceutical (e.g., identification of target organs, exposureresponse relationships, and reversibility).
In which type of studies and population will the principles of ICH S9 be applied?
- This guideline applies on both small molecule and biotechnology-derived pharmaceuticals (biopharmaceuticals), regardless of the route of administration.
- This guideline describes the type and timing of non-clinical studies in relation to the development of anti-cancer pharmaceuticals in patients with advanced cancer, whose disease is refractory or resistant to available therapy, or where current therapy is not considered to be proving beneficial.
- If the First in Human (FIH) study is conducted in a patient population with resistant and refractory disease, will subsequent Phase I studies in a different cancer, but still a resistant and refractory population, still be covered under S9? In some situations where the development pathway is not clear, regulatory agencies should be consulted.
- The guideline also prescribes further non-clinical data to be collected during continued clinical development in patients with advanced cancer. When an anti-cancer pharmaceutical is further investigated in cancer patient populations with long expected survival, the recommendations for and timing of additional non-clinical studies depend upon the available non-clinical and clinical data and the nature of the toxicities observed.
Is the use of the Highest Non-severely Toxic Dose (HNSTD) selected as an appropriate starting dose applicable to biopharmaceuticals?
The HNSTD may be appropriate in determining a starting dose of a biopharmaceutical (e.g., when drug is not an immune agonist) taking into consideration differences in binding affinity between animals and humans and pharmacological properties of the biopharmaceutical (including Antibody Drug Conjugates (ADCs)).
Does the ICH S9 Guideline apply to the drug itself having no anti-tumor activity, such as an enhancer, that is intended to be developed as the pharmaceutical combined only with the certain anti-tumor pharmaceutical for the treatment of patients with advanced disease in late stage development?
Yes, these pharmaceuticals are within the Scope of S9 if they are intended to treat cancer. Data to show that the enhancer is non-active should be provided. General toxicology, safety pharmacology, and reproductive toxicology assessments should be done for the combination. The enhancer alone may have a more limited safety assessment either as an arm in the general toxicology combination study or as a standalone general toxicology study of up to one-month duration.
If a drug with an impurity is first developed for patients with late-stage disease, and later moves to a different population with longer expected survival, how should the impurities in the drug be managed?
When an anti-cancer pharmaceutical is further investigated in cancer patient populations with longer expected survival, ICH Q3A/B and ICH M7 should both be considered for the control of impurities.
Are there any nonclinical studies to support trials in paediatric populations?
The general paradigm for investigating most anti-cancer pharmaceuticals in paediatric patients is first to define a relatively safe dose in adult populations and then to assess some fraction of that dose in initial paediatric clinical studies. The recommendations for non-clinical testing outlined elsewhere in this document also apply for this population. Studies in juvenile animals are not usually conducted in order to support inclusion of paediatric populations for the treatment of cancer. Conduct of studies in juvenile animals should be considered only when human safety data and previous animal studies are considered insufficient for a safety evaluation in the intended paediatric age group.
The guideline states that data to support a rationale for the combination should be provided prior to starting the clinical study. What comprise "data to support a rationale for the combination study"?
A scientific rationale should be provided to justify a combination clinical study. Data demonstrating increased anti-tumor activity by combined pharmaceuticals in pharmacology studies (e.g., animal tumor models, in-vitro or in-vivo studies based on mechanistic understanding of target biology) should be provided to support rationale for the combination, if feasible. This data could be from in-house studies or the scientific literature.
Note-This ICH S9 Guideline does not apply to pharmaceuticals intended for cancer prevention, treatment of symptoms or side effects of chemotherapeutics, studies in healthy volunteers, vaccines, or cellular or gene therapy. If healthy volunteers are included in clinical trials, the ICH M3 guideline should be followed. Radiopharmaceuticals are not covered in this guideline, but some of the principles could be adapted.
Footnotes
2 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2018/05/WC500248965.pdf
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