PittPRO IND Determination

Steps to Determine if the Use of an FDA-approved Drug/Biologic in Research Needs to be Conducted under an IND

REMINDER: Verify the drug/biologic’s approved indication by reviewing the current version of the FDA-approved package label (i.e., package insert). 

The investigator must review the FDA criteria below to make an initial determination whether the study can be conducted without an IND. A clinical investigation of a marketed drug is exempt from the IND requirements if all of the criteria for an exemption in § 312.2(b) are met:

  1. The drug product is lawfully marketed in the United States.
  2. The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication and there is no intent to use it to support any other significant change in the labeling of the drug.
  3. In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.
  4. The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
  5. The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
  6. The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the investigation is not intended to promote or commercialize the drug product).

One of the most difficult issues in assessing whether an IND is needed is determining if the risk associated with the product is significantly increased (or the acceptability of the risk significantly decreased). The FDA offers guidance on Determining Whether Human Research Studies Can Be Conducted Without an IND. 

Investigators should carefully consider the risk implications of any conditions of use in the study that deviate from the conditions of use described in the drug’s labeling, with particular attention to the following:

Route of Administration: A change in the route of administration can introduce a significant new risk. For example, there could be a significant increase in risk if a drug marketed for oral administration is converted to a dosage form that is to be administered by injection or an intravenous, intrathecal, or inhalation route. These other routes of administration introduce concerns with increased local concentrations, sterility, pyrogenicity, hypersensitivity (e.g., airway reactivity), variations in metabolism, and other issues not present with oral administration that can significantly increase the risk, or decrease the acceptability of the risk, associated with use of the drug.
Dose: Increases in dose, frequency, or duration of administration, compared to labeled dosing regimens, can significantly increase the risk in a study using a marketed drug. It is also possible that a decrease in dose could significantly increase risk. For example, administering a sub-therapeutic dose of an antiviral drug to study subjects could induce resistance in the subjects, thus rendering a subsequent therapeutic dose of the drug ineffective in treating the virus. The significance of changes in dose (in particular, increases in dose) can vary across therapeutic areas. In clinical settings, use of higher doses than are recommended in labeling may be much more likely to significantly increase the risk or decrease the acceptability of the risk.
Patient Population: The acceptability of known and unknown risks can vary across different treatment populations. The population chosen for study could be at increased risk compared to the approved use population for a variety of reasons, such as increased age, different disease or stage of disease, concomitant illness, decreased renal or hepatic function, or concomitant therapy. When use of the drug in a specific patient population decreases the acceptability of the known risks, the study would have to be conducted under an IND.

When using these criteria, it is sometimes difficult for an investigator to determine whether an IND is required. Thus, it is important to consult with HRPO or the Office of Investigator-Sponsored IND and IDE Support (O3IS) during the planning phase of the study to assist with this decision.  Investigators may be instructed 1) that an IND is not necessary based on the criteria noted above, 2) that a request for an IND exemption  should be sought from the FDA, or 3) that an IND application should be submitted.

If the investigator makes an initial determination that the study can be conducted without an IND, an appropriate justification will need to be uploaded into the Drug Section of PittPRO. If there are publications that support the justification, include those as well.

It is important to note that individuals who hold an Investigator-Initiated IND are also subject to the requirements of being a sponsor. This includes additional responsibilities with respect to monitoring, accountability, and reporting to the FDA (for more information please contact IND and IDE Support at IIS@pitt.edu).