Non-clinical studies for initiating phase 1 studies in oncology: Small molecules vs. biologics

1. Non-clinical studies for initiating phase 1 studies in oncology: Small molecules vs. biologics David Ross, M.D., Ph.D. Office of Oncology Drug Products Center for Drug Evaluation and Research U.S. Food and Drug Administration

2. Questions to be answered before initiating a Phase 1 study in patients with cancer • What are the potential toxicities? • How should we monitor for these toxicities? • In terms of risk to the patient: • What is an acceptable starting dose? • What is an acceptable duration of dosing? • What is an acceptable dosing schedule?

3. What types of pharm/tox studies are generally needed to initiate a Phase 1 study in patients with cancer?

4. What types of pharm/tox studies are generally needed to support a proposed starting dose in a Phase 1 study in patients with cancer?

5. What types of pharm/tox studies are generally needed to support a proposed duration of dosing (ICH M3)?

6. What types of pharm/tox studies are generally needed to support a proposed dosing schedule in a Phase 1 study in patients with cancer?

7. Why do these differences exist? • Toxicology testing in one species for biologics • “Safety evaluation programs should normally include two relevant species. However, in certain justifiable cases, one relevant species may suffice (e.g., when only one relevant species can be identified or where the biological activity of the biopharmaceutical is well understood).” (ICH S6) • “Toxicity studies in non-relevant species may be misleading and are discouraged.” (ICH S6) • Biologic dose selection based on biologically active dose • Cytotoxic effective dose near MTD • Biologic toxicities are extension of pharmacologic activity • Biologic dosing schedule driven by pharmacology and immunogenicity

8. What data are generally needed to continue dosing in a Phase 1 study in a patient with stable disease? Monitoring scheme Non-clinical data Disease/disease setting Clinical toxicity data Response data

9. Summary • A number of fundamental differences exist between small molecules and biologics • These differences are reflected in the non-clinical testing strategy for biologics • Guidance documents recognize these differences, and support a different testing strategy for biologics • Continued dosing in stable disease depends on a variety of factors

10. Question 1 • For most drug development programs, FDA recommends that the duration of non-clinical studies match the duration proposed for the clinic, an approach supported by the ICH M3 Guidance document. However, an abbreviated duration of non-clinical testing is generally acceptable for small molecule drugs under development as anti-tumor therapies. An abbreviated dosing duration has also been proposed for selected biological products intended as anti-tumor treatments. Please discuss scenarios where the duration of non-clinical studies: • may be abbreviated relative to the clinical duration. • should match the duration of the proposed clinical study. In your response, please address the anticipated non-clinical parameters (e.g., PK/PD, toxicity profiles) that should be considered in determining the minimum duration of toxicity testing.

11. Question 2 • The FDA has received applications that do not provide adequate non-clinical data to support continuation of dosing for an extended duration in a phase 1 clinical study. Please discuss the following: • In what clinical setting and/or patient population (e.g., refractory disease, indolent disease status, no prior treatments) would the risk of continued treatment in the absence of long-term non-clinical safety data be considered acceptable? • Where extended non-clinical safety data are unavailable for long-acting biologic therapeutics (e.g., monoclonal antibodies), FDA believes that continued dosing in the phase 1 study is appropriate only in patients who have demonstrated an acceptable benefit:risk (e.g., objective tumor responses or symptomatic improvement). Should extended non-clinical testing be available prior to allowing continued dosing in patients who have not had clear evidence of benefit? Please discuss the following scenarios: the patient with stable disease, the patient with progressive disease. [Voting] • How should patients who continue dosing in the absence of supporting non-clinical data be informed of the limitations of the non-clinical data and potential risks? Should they sign a new consent form, and if so, what should be conveyed (e.g., the lack of information about cumulative/delayed onset toxicity, the lack of information on how best to monitor patients, the potential for irreversible toxicity)? What additional information should the sponsor obtain during the clinical study to minimize the risks to the study subjects in the absence of supporting non-clinical safety data (e.g., interim reports of ongoing non-clinical studies)?