The ICH S9 Guideline Q&A document was recently published in June 2018, designed to clarify some of the most common challenges experienced across industry when implementing ICH S9. Here, we highlight a few key areas selected on the basis of the advice sought by our customers during development of their anticancer pharmaceutical.
 
The finalization of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) S9 Guideline – Nonclinical evaluation for Anticancer Pharmaceuticals – in October 2009 was an important milestone in understanding anticancer therapy development.
 
The tripartite harmonized ICH guideline provides information for pharmaceuticals that are intended to treat cancer in patients with late-stage or advanced disease, including both small-molecule and biotechnology-derived pharmaceuticals, regardless of the route of administration. It gives us the type and timing of non-clinical studies in relation to the development of anticancer pharmaceuticals and references other guidance as appropriate.
 
Following a decade of questions and interactions with industry, a Q&A document was published in June 2018, designed to clarify some of the most common challenges experienced across industry when implementing ICH S9. It represents the current thinking of the U.S. Food and Drug Administration (FDA) and, as such, provides non-binding recommendations.
 
The Q&A document contains 41 questions that cover the full scope of ICH S9: studies to support non-clinical evaluation, non-clinical data to support clinical trial design and marketing, and other considerations. Here we highlight a few key areas selected on the basis of the advice sought by our customers during development of their anticancer pharmaceutical.
 
Are all initial development plans for anticancer pharmaceuticals covered under ICH S9?
 
Right from the start, the document provides clarification on a commonly raised question: Are all initial development plans for anticancer pharmaceuticals covered under ICH S9? ICH S9 makes clear that the intended treatment population is patients with advanced disease and limited therapeutic options. Question 1.1 of the Q&A document provides the further insight you need:
 
‘As most initial development programs are performed in patients (adult and pediatric) whose disease is resistant and refractory to available therapy, the nonclinical program described in ICH S9 is applicable. See also the answer to Question 2 (1.2). For other initial development programs in cancer that is not resistant and refractory, ICH S9 should be used as a starting point, and other studies added as appropriate with reference to ICH M3(R2) and S6(R1). In some situations where the development pathway is not clear, regulatory agencies should be consulted.’
 
In addition, while the guideline did not make reference to life expectancy, this has now been clarified – ‘… application of the guideline should not be based on an expectation of survival as measured in years.’ Finally, the Q&A document also makes clear that non-oncology therapeutics, even those for life-threatening disease with limited therapeutic options, are outside the scope of ICH9.
 
Which studies are required?
 
The requirement for planning additional toxicology studies (beyond “general” toxicology) is complicated, and there is often a temptation to cover a wide range of possibilities in the pre-clinical phase in order to avoid missing something.
 
Now, the Q&A document clarifies, for example, that inclusion of supportive care drugs such as antibiotics during toxicology studies can be considered appropriate when secondary infection due to immunosuppression is observed in the study; however, giving such care to all animals prophylactically is not recommended. In addition, the document suggests that when the anticancer pharmaceutical is shown to extend survival of patients, additional general toxicology studies are usually not warranted; when such studies are required, they could still be submitted post approval. These two points allow you to reduce the studies required prior to approval, by judicious application of the knowledge of their product to the development program.
 
Hidden under ‘Other considerations’ are a number of clarifications related to antibody–drug conjugates (ADCs) which, you need to take into account. These clarifications cover requirements for pilot studies on the different elements of the conjugated material, tissue distribution studies, plasma stability, dosing in pre-clinical studies and the approach to setting a first-in-human starting dose.

Given that nearly 250 ADCs are in the pipeline for the treatment of cancer, we anticipate that the points covered under “other consideration” may prove the most useful clarifications over the next decade.
 
What’s the outlook for oncology programs?
 
The ICH S9 Guideline Q&A is well timed. Targeted therapies account for around 87% of oncology drugs in development, and these small molecules, monoclonal antibodies and ADCs should reduce harmful side effects for healthy cells and achieve a better clinical effect. And 2017 was the year that the FDA first approved a cancer treatment based on a common biomarker, rather than the location in the body where the tumor originated. The clarification offered in the new Q&A help us all plan, design, execute and submit non-clinical studies to the FDA and other regulatory bodies around the world. www.envigo.com