A critical question in determining whether a study is exempt involves the criterion: "the investigation may not significantly increase the risk associated with use of a drug product." The question of increased risk is determined by assessing the deviation in the planned investigation from the use described in the approved label. In oncology, modifications of labeled dosing recommendations are common and occur as part of oncologists' clinical practice. As outlined below, oncologists are familiar with evaluating the risk of off-label dosing regimens for cancer drug and biological products.

• Treatment with cancer drugs may be associated with significant risk from known toxicity. Because effectiveness is often related to dose, a dose close to the maximal tolerated dose is often selected for studies of cancer drugs. This same dose usually becomes the recommended dose in labeling when the new cancer drug is approved with the knowledge that the dose may be altered if it is not tolerated by a patient. Because it is not generally possible to have maximal efficacy in a population without inducing toxicity in some patients, it is not uncommon to observe severe or even lethal side effects from cancer drugs in some patients. In general, these circumstances mean that the toxicity, even potentially lethal toxicity, of cancer drugs is described in approved labeling.
• Off-label therapy with cancer drugs is common in practice. When there is no established therapy for a cancer, or stage of cancer, it is common for oncologists to try different regimens or combinations of established drugs. There is substantial off-label use in situations where satisfactory treatment was not available, and lower rates of off-label use when there was an effective therapy. In their daily practice, many oncologists treat cancer patients with regimens that include off-label use of drugs. They evaluate the published data and past clinical experience to assess the risk of such treatments. Such treatment of individual patients with approved drugs within their clinical practice does not require an IND.
• In many cases, drug administration to patients with similar off-label regimens in the context of an investigation seems to involve no increased risk to patients, and an investigator could conclude that such a study would not significantly increase the risk associated with the labeled use of a drug product and the study could be conducted without an IND. Oversight by an IRB and informed consent in compliance with parts 56 and 50, respectively, would be required as usual. On request, FDA will advise on the applicability of the IND exemption to a planned clinical investigation.

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