In clinical trials, investigational products that meet the definition of a drug or biologic, as defined by FDA, generally need to be under an Investigational New Drug (IND) application for FDA supervision of the development process. This is true both for products that have never been approved by FDA, and for approved products that are being investigated in a patient population, route, or dosing regimen that is not included in the current marketing approval/ approved product label.
FDA regulations include certain criteria for “exemption” from the IND requirement, including
For marketed (approved) drugs
- The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug.
- If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product
- The drug must not be a new chemical entity
- The drug must not be radioactively labeled or cytotoxic
- The dosing for both the investigational and reference drug must follow the approved drug label for the reference product
Radioactive or Cold Isotopes
- The product is only used for basic research
- The dose studied is not known to cause pharmacological effects in humans
Whether an investigational product qualifies for an IND exemption also takes risk into consideration. FDA provides the requirements at 21 CFR 312.2(b)(1)(iii) which states:
“The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.”
The risk assessment is based on the known risks from the label indication, route, dose, and timing. The IRB uses the US Package Insert (USPI) as its primary source for determining if the proposed use qualifies for an IND exemption. When assessing whether off-label use (i.e. outside of FDA approved USPI indications) of a drug d constitutes a “significant increase in risk”, the IRB is tasked with answering two questions:
- Does the research use of the drug increase known risks or raise the potential for unknown risks significantly?
- Does the research use of the drug adversely affect the relationship of risks and potential benefits compared to approved uses of the drug such that the risks are less acceptable?
The use of a new route of administration or dosage level may immediately confer unknown risks to a degree that the risks are significant or lessen the acceptability of the risks. Substantially different patient populations from those in the indication may also confer additional, significant known risks or increase the chance for unknown risks significantly.
In order for the IRB to better assess the risks, decreasing the unknown factor is valuable. Providing literature documenting the risks of use or similar information can support a request for IND exemption. Similarly, addressing the differences between the USPI approved population and those to be studied and how the risks and acceptability of the risks are addressed is necessary. Claims based on current standards alone without addressing the risks and acceptability of risks is a reasonable clinical approach but does not address the regulatory requirements.
Therefore, when submitting a proposal for a drug study to the IRB, requesting and exemption from the requirement to obtain an IND, the protocol should provide a clear analysis of risk in the context of FDA regulations: “The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.”