The following are examples of general categories of studies of marketed cancer drugs that would likely be exempt from IND regulation based on protocol-related issues.

• Single-arm, phase 2 trials using marketed drugs to treat a cancer different from that indicated in the approved labeling and using doses and schedules similar to those in the marketed drug labeling are usually exempt. An exception may exist when standard therapy in the population to be studied is very effective (e.g., is associated with a survival benefit); in that case, use of another regimen may expose patients to the risk of receiving an ineffective therapy and an IND would be necessary.
• Phase 1 oncology trials of marketed drugs may be considered exempt if such therapy is appropriate for the patient population (i.e., if patients have residual cancer) and if there is no effective therapy (i.e., therapy producing cure or a documented increase in survival) that the patients have not yet received. It remains the investigator’s responsibility to use starting doses that appear safe based on approved labeling or detailed literature reports, use incremental changes in dose or schedule, and carefully evaluate toxicity prior to dose escalation.
• The study of new combinations of drugs would not ordinarily constitute a significant risk if these combinations have been described in the professional medical literature. Even when the regimen described in the literature does not use exactly the doses planned for study, incremental differences in doses from those described in the literature would not normally pose a significant risk and would not require an IND. Because of the danger of synergistic toxicity (i.e., enhanced effects from the combination) occurring with a new drug combination, if there are no data from the literature on its safety, the initial study of a new drug combination should ordinarily be performed under an IND. 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. If it is determined that synergistic toxicity is likely, animal studies should be considered for determining a safe starting dose for the drug combination in humans.
• Studies of new routes or schedules of administration not described in the approved labeling are generally exempt if there is sufficient clinical experience described in the literature documenting safety to determine that treatment is safe. On the other hand, initial experience with a new route of administration should be based on studies in animals, and an IND should be submitted.
• Studies of high-dose therapy in cancer patients are likely to be considered exempt if the studies use adequately evaluated regimens that appear to have an acceptable therapeutic ratio for the population being studied. Similarly, phase 1 studies involving incremental changes from such well-described regimens are generally exempt.

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