The following are examples of general categories of studies of marketed cancer drugs that would likely not be exempt from IND regulation because of protocol-related issues.

#1

Studies of cytotoxic drugs are normally not exempt in patients for whom cytotoxic therapy would not be considered standard therapy and would require special justification. Any use of cytotoxic agents in nonmalignant disease (e.g., rheumatoid arthritis, multiple sclerosis) would, most likely, be considered to alter the acceptability of the risk of the agent.

#2

Studies of adjuvant chemotherapy (chemotherapy given after surgery to remove cancer) are likely not exempt for the following reasons:

• If the population studied has a low risk of cancer recurring after surgery, treatment with any toxic therapy may indicate a significantly increased risk.
• If standard adjuvant therapy is available and produces a survival benefit, substitution of new therapy for standard therapy poses a significant risk that the new therapy will not produce the same survival benefit.
• If adjuvant trials are properly designed, they usually will be able to demonstrate whether the new therapy is safe and effective, and such results may lead to a marketing application. All investigations intended to support marketing of a new product indication, significant change in product labeling, or a significant change in the advertising for a product require an IND. During FDA review of INDs intended to support marketing applications, the Agency will provide feedback about the acceptability of trial design for this purpose.

#3

Studies involving substitution of a new agent of unproven activity are generally not exempt in settings where standard therapy provides a cure or increase in survival. For instance, in the first-line treatment of testicular cancer, ovarian cancer, breast cancer, leukemia, and lymphoma, studies of new agents without proven efficacy would likely not be exempt. In this case, the critical judgment is whether it is ethical to withhold standard therapy while testing a new agent.

#4

Studies are generally not exempt in settings where animal studies should be conducted to determine a safe starting dose or schedule. For example:

• Initial studies of a marketed drug given by a new route of administration are likely not exempt.
• Unless adequately described in the literature, initial studies of new drug combinations should usually be performed under an IND because of the possible occurrence of synergistic toxicity. As noted earlier, synergistic toxicity may be anticipated when one agent interferes with the metabolism or elimination of the other agent; when both agents target the same metabolic pathway or cellular function; or when one agent targets signaling pathways that are reasonably expected to modulate sensitivity to the other agent.
• Initial studies in humans of changes in the schedule of drug administration should generally be submitted in an IND. Some drugs have demonstrated significantly greater toxicity when given by an alternative schedule (e.g., methotrexate demonstrates much more hematologic toxicity when given by prolonged administration compared to intermittent administration).
• Initial studies of drugs intended to be chemosensitizers, radiosensitizers, or resistance modulators should generally be submitted in an IND. Animal studies should be used to estimate the effect of the modulator on toxicity and to allow estimation of a safe starting dose in humans.

#5

Studies intended to support approval of a new indication, a significant change in the product labeling, or a significant change in advertising are not exempt.

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