Step 1: Determine if the study uses drugs/biologics

1. Use the footnotes in HRP-306 Drugs and Biologics Worksheet to determine if substances used in a study meet FDA’s definition of a “drug” or “biologic.”
   1. Foods and dietary supplements may be regulated as drugs if a study is evaluating their ability to cure, mitigate, treat, or prevent disease (for example, evaluating whether grape juice lowers cholesterol, or fiber reduces chronic diarrhea).
   2. Medical foods are not regulated as drugs but must meet certain FDA requirements. See FDA Frequently Asked Questions about Medical Foods.
   3. Medical gases such as oxygen and carbon dioxide are regulated as drugs. Medical gases used within their approved indications are likely to be IND exempt.
   4. A few products that seem like they should be classed as drugs are actually considered devices, such as saliva substitutes and artificial tears.

Step 2: Determine if IND regulations apply

2. If the study uses a drug/biologic, use section 1 and footnotes in HRP-306 to determine if Investigational New Drug (IND) regulations (21 CFR 312) apply to the use of that substance on the study.
   1. Consider all drugs/biologics used on the study, not only those that may be the focus of the research. Common examples include contrast agents for research MRI or CT scans, PET tracers, barium products for swallow studies.
   2. If the protocol specifies the use of a drug, IND regulations apply unless the drug is approved and its use on the study is completely up to the discretion of the practitioner. For example, if a protocol advises using topical anesthetic for a punch biopsy or an anti-emetic for managing study drug side effects per institutional practice, those drugs would not be subject to IND regulations.
   3. The deciding factor is whether the drug/biologic is administered in the course of medical practice as opposed to being administered as a result of the research study. Unlike devices, it doesn’t matter whether a drug/biologic is being evaluated for safety or efficacy. If the protocol dictates use of the drug as part of the study procedures, IND regulations apply.
3. For each drug/biologic to which IND regulations apply, consider whether an IND is required or if the drug/biologic meets criteria for IND exemption:
   1. Exceptions: Use of certain unapproved radioactive drugs may qualify for review by a Radioactive Drug Research Committee (RDRC) instead of an IND. Use of cold isotopes may fall under FDA enforcement discretion. Both of these situations are rare. Studies using these drugs are FDA regulated. See HRP-306 section 5 for details.
   1. The study involves a route of administration, dose level, or patient population that significantly increases the risks or decreases acceptability of the risks of the drug.
   2. The study is intended to support a new indication or other significant change in labeling for the use of the drug or a significant change in advertising.
1. An IND is required for any drug/biologic that is not FDA-approved.
2. An IND is required for an approved drug/biologic if:
3. Use section 5 in HRP-306 to determine if an approved drug/biologic meets criteria for IND exemption. For cancer drugs, see FDA Guidance: IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer.
4. Email FDA-Regulated-Research-Oversight@lists.wisc.edu and cc the study team if there are any questions about applying IND regulations. FDARROP will work with the study team, as necessary, to ensure sufficient and accurate information is provided regarding applicable FDA status and reporting requirements.

Resource: REGARDD IND Flowchart

Studies involving drugs and/or biologics can be scheduled for review at an IRB meeting when the following requirements are met in addition to other (not FDA-specific) review ready requirements.

1. ARROW application:
   1. If it is not already, the study must be assigned to the Health Sciences IRB. Only the HS IRB can review FDA-regulated studies. Use the “Reassign IRB” activity in the study workspace.
   2. UW-Madison personnel who hold an IND for the study should be included on the Study Team when they serve as study investigators as well as IND sponsors, which is the case in most investigator-initiated studies.
   3. Study Summary page should select “Drugs, biological agents, or nutritional supplements.”
   4. Drug and Device Documents page should provide:
   1. Investigator Brochure (IB) for each investigational agent.
   2. If an IB is not available, a document summarizing the agent’s pharmacological and toxicological effects, safety and effectiveness in humans, and potential risks and side effects
   3. Package insert for approved drugs/biologics to which IND regulations apply.  Approved drugs used completely at the discretion of the practitioner do not require a package insert (e.g., lidocaine for a blood draw).
   4. See FDA Regulations and IRB Review in the Investigator Manual for more information about IBs and package inserts.
   5. If an IND is required and will be held by a UW-Madison investigator, correspondence from the FDA that includes the IND number, such as FDA acknowledgement that an IND application has been received. This is required to validate the IND number, per HRP-306 section 3. (When the IND is not held by UW, the IND number must be imprinted on the Sponsor protocol or other documentation from the FDA.) Studies cannot be scheduled for IRB review until the IND number has been received.
   6. A response to the question as to whether the IND will be held by the UW investigator.
2. Protocol:
   1. For drugs/biologics that require an IND, the ICTR template provides more complete guidance than the Toolkit Biomedical Template. Use this template for reference to check for necessary information in the study protocol.
   2. For each drug/biologic used on the study, the protocol should identify whether it will be used under an IND or describe how its use meets FDA criteria for IND exemption. If what an investigator-initiated protocol asserts does not meet the criteria listed above, either the study team or the IRB staff member should email FDA-Regulated-Research-Oversight@lists.wisc.edu) for clarification. If staff send the email, please cc study team.
   3. The protocol should specifically describe why the study meets exemption criteria and accurately describe if any reporting requirements are applicable.
   4. The protocol should include a plan for drug/biologic storage, control, and dispensing, per HRP-306 section 4. An adequate plan will be consistent with the UW Control of Test Articles Used in Research policy.
   5. The IRB does not need to review IND monitoring plans.
   6. If the study will use a remote consent process, the protocol should confirm that the consent process will adhere to 21 CFR Part 11 requirements (see HRP-314 section 8).
   7. If the study proposes a waiver or alteration of consent or waiver of signed consent, the protocol should describe how the study meets criteria in HRP-410 section 2 and/or HRP-411 section 1.
3. Consent forms:
   1. Use HRP-314 Criteria for Approval Worksheet and HRP-502 Consent Template to ensure that the study consent documents include FDA-required information in addition to other required consent elements.
4. Report UW-held, IND regulated studies to FDARROP:
   1. Email FDA-Regulated-Research-Oversight@lists.wisc.edu(and cc study team) to inform FDARROP if any of the following apply:
      1. The study requires a new IND that will be held by a UW-Madison investigator.
      2. The study will be added to an existing IND held by a UW-Madison investigator (IND amendment).
      3. The study will use any drugs/biologics that appear to meet criteria for IND exemption.
   2. If you have consulted with FDARROP to determine how FDA regulations apply to a study, that consultation serves to report the study to FDARROP.
   3. Reporting to FDARROP ensures that FDARROP is aware of studies that require registration with the Oversight Program. See HRP-309 Ancillary Review Matrix for information. Once this email is sent, it is acceptable to check the box on HRP-306 (#6).

1. After an IND application has been submitted, the sponsor-investigator must wait 30 calendar days before initiating any clinical trials. During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.
   1. The IRB can approve studies without administrative hold before the 30-day time period has elapsed or the FDA indicates a protocol may proceed; however, the study team cannot begin study activities until after FDA approval. If the FDA requests changes, the study team must submit a change of protocol before conducting study activities.
2. Studies that require an amendment to an existing IND can be scheduled and approved with an assurance from the study team that they will submit an amendment to the FDA. Study activities may begin once the IRB has approved the protocol and the new protocol amendment has been submitted to the FDA.