Information needed to conduct first-in-human oncology trials in the United States: a view from a former FDA medical reviewer.

Any drug product not previously authorized for marketing in the United States requires the submission of an Investigational New Drug application (IND). Although the IND submission is regulated by law (21CFR 312), there are several issues that are not covered in the law or U.S. Food and Drug Administration (FDA) guidances that are important for a successful IND submission. For oncology products, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S9 guidance (still in draft) is the most relevant. The most difficult issues to solve in an IND are chemistry, manufacturing and control information, and pharmacology and toxicology. In the United States, pivotal toxicological studies are done in two species: one rodent (i.e., rats) and one nonrodent (i.e., dogs). The safe starting dose is based on toxicological findings observed in the most sensitive species. Most first-in-humans studies in oncology include patients with advanced and/or metastatic disease, as serious to severe side effects of anticancer therapies are often less threatening to advanced cancer patients than their disease, and acceptable levels of toxicity are higher. For other indications (adjuvant therapy, chemoprevention, or healthy volunteers), first-in-human studies need to follow ICH M3 guidelines as the risk to benefit ratio in those subjects and/or patients without evidence of tumor is different. The division welcomes submissions before the IND, also known as pre-INDs, particularly for products with "atypical issues."