Research with FDA regulated Drugs or Biologics
Any protocol involving human subjects and a drug or biologic as the object of the study falls under Food & Drug Administration (FDA) regulations. This applies regardless of whether the drug or biologic is already FDA approved. However, this does not include any marketed drugs used as part of routine medical practice.
Any protocol involving human subjects and a drug or biologic as the object of the study falls under Food & Drug Administration (FDA) regulations. This applies regardless of whether the drug or biologic is already FDA approved. However, this does not include any marketed drugs used as part of routine medical practice.
If your study includes an FDA-regulated drug or biologic, it must either be conducted under an IND (Investigational New Drug application) or determined to be IND Exempt.
Investigational New Drug Application (IND)
An Investigational New Drug Application (IND) is a request from a clinical study sponsor to the FDA for permission to administer an investigational drug or biological product to humans. Clinical studies are often conducted to gather safety and effectiveness information for these products.
Unless exempted, the sponsor must obtain FDA authorization by submitting an IND Application before conducting the study. This authorization is required before the interstate shipment and administration of any new drug or biological product that does not have an approved New Drug Application or Biologics Product License Application.
Note: If the use of the product is not exempt from the requirement for an IND, the IRB will not review the study, and research cannot begin until a valid IND is in effect. As the Principal Investigator (PI), you are responsible for providing the IRB with documentation confirming that a valid IND is in effect. A valid IND is in effect under either of these conditions:
- Thirty days after the FDA receives the IND application, unless the FDA notifies the sponsor that the investigations described in the IND are subject to a clinical hold, OR
- An earlier notification from the FDA that the clinical investigations under the IND may begin.
You should provide documentation from the FDA verifying the IND number and indicating that the study is safe to proceed (e.g., the FDA letter assigning the IND number and the "safe to proceed" letter). If the "safe to proceed" letter has not been received, the IRB will accept documentation from the sponsor indicating the FDA's confirmation that the study may proceed.
You must also provide the IRB with a copy of the Investigator Brochure (IB) or package insert for any investigational products at the time of the Initial Review and are responsible for reviewing and providing the IB with any updates. This is important for evaluating any new risks to research subjects.
If no IB exists for an investigational drug, you must include all relevant preclinical and clinical safety and efficacy data in the protocol to support the proposed use of the product in the research.
IND Exempt
Some clinical studies involving drugs or biologics may be exempt from IND requirements. However, IND-exempt studies are still regulated by the FDA and must meet all applicable requirements.
When a Study May Be IND Exempt
A study of a marketed drug may be IND exempt if all of the following are true:
- The drug is lawfully marketed in the U.S.
- The study is not intended to support a new indication, labeling change, or advertising claim
- The study does not increase risk (e.g., through dose, route, or population)
- The study complies with IRB (21 CFR 56) and informed consent (21 CFR 50) requirements
- The study is not intended to promote or commercialize the drug
If any of these criteria are not met, an IND is required.
Other IND Exemptions
Some additional types of studies may also be IND exempt:
- In vitro diagnostic biological products:
Includes blood grouping serum, reagent red blood cells, or anti-human globulin, when used only to confirm a diagnosis made by another established method and shipped in compliance with FDA requirements. - Placebo use:
A study using a placebo may be IND exempt if the study does not otherwise require an IND.
Investigator Responsibilities
When your research involves the clinical investigation of an IND Exempt product, you must provide written justification in the protocol for why the product is exempt from the requirement for an IND.
If the Office of IRB Operations (IRBO) does not concur with your determination that the product is exempt, they may require you to submit to the FDA for a formal determination prior to further review of the study. The FDA's determination as to whether the product is exempt or requires an IND is final.
If you seek guidance from the FDA to make these determinations, they will provide you with a determination letter. You should include this letter as part of your Initial Review Submission.
FDA Form 1572
Form FDA 1572, also known as the Statement of Investigator, is a document that is collected by the sponsor for studies conducted under an IND. This form is an agreement signed by the investigator, ensuring that they will provide specific information to the sponsor and comply with FDA regulations related to the conduct of a clinical investigation of an investigational drug or biologic.
By signing Form FDA 1572, you as the investigator affirm your qualifications to conduct the clinical investigation and confirm your awareness of your obligations. The obligations that you agree to by signing Form FDA 1572 include, but are not limited to:
- Conducting the Study: Conduct the study in accordance with the relevant, current protocol and only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects.
- Supervision: Personally conduct or supervise the described investigation.
- Regulatory Compliance: Ensure that the FDA requirements relating to obtaining informed consent and IRB review and approval are met.
- Adverse Event Reporting: Report to the sponsor any adverse experiences that occur during the course of the investigation.
- Understanding Risks: Read and understand the information in the investigator's brochure, including the potential risks and side effects of the drug.
- Team Awareness: Ensure that all associates, colleagues, and employees assisting in the conduct of the study are informed about their obligations to meet the above commitments.
- Record Maintenance: Maintain adequate and accurate records in accordance with relevant federal regulations and make those records available for inspection as required by the FDA.
- Reporting to IRB: Promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others.
- Protocol Changes: Not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
FDA-specific reports required when a protocol is conducted under an IND
Direct communication with the FDA is typically initiated by, and is the responsibility of, the sponsor of the study. As the site investigator, you should submit the following reports to the sponsor to provide them with the information they need to submit the required reports to the FDA:
You should provide regular updates on the progress of the trial to the sponsor, who is responsible for collecting and evaluating the results. The sponsor is required to submit annual reports to the FDA on the progress of the clinical investigation. They may request additional information from you around the time of this submission and ask you to submit an annual progress report. The contents of this report are dictated by the sponsor.
The required timeframe for submitting these event reports should be outlined in the protocol, but it is often within 24 hours from the time the investigator is notified of the event. The sponsor will have their own deadline to determine if these events meet the criteria for required reporting to the FDA. They may request additional information after the initial report to complete their evaluation and submission. Events that need to be reported to the sponsor include:
- SAEs, whether or not considered drug-related, including those listed in the protocol or investigator brochure, along with an assessment of whether there is a reasonable possibility that the drug caused the event.
- The FDA requires that all serious events be reported to the sponsor regardless of the attribution by the investigator, as the sponsor has access to the complete set of aggregated safety data, allowing them to conduct a thorough investigation of any serious adverse reactions.
- Non-serious events that are events of special interest may also need to be reported to the sponsor expeditiously. The timetable for reporting these events should be specified in the protocol.
The sponsor is required to submit a final report to the FDA after completing an investigation. Therefore, the sponsor may ask you to provide an adequate investigator final report shortly after completing the investigation at your site. The content of this report is dictated by the sponsor.
By ensuring these reports are submitted in a timely and thorough manner, you help the sponsor meet their regulatory obligations to the FDA and maintain compliance with all relevant guidelines and requirements.
Sponsor vs. IRB Reporting Requirements
The reporting requirements for both the sponsor and the IRB should be clearly outlined in the protocol. There may be instances where events need to be reported to the sponsor but not to the IRB.
A common source of confusion relates to the reporting of SAEs, Serious Suspected Adverse Reactions (SUSARs), and Unanticipated Problems (UPs). For example, SAEs must be reported to the sponsor, but an SAE may not meet the criteria for reporting to the IRB if it is unrelated to the research and therefore not considered a UP. These terms are not interchangeable, and their definitions should be reviewed at the time of reporting to ensure the event is reported to the appropriate entity.
Key Definitions:
- Serious Adverse Events (SAEs): Any adverse event that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or results in a congenital anomaly/birth defect. SAEs must be reported to the sponsor, but they may not need to be reported to the IRB if they do not meet the criteria for a UP.
- Serious Suspected Adverse Reactions (SUSARs): An adverse reaction that is both serious and unexpected. SUSARs must be reported to the sponsor, as these events are suspected to be related to the investigational product.
- Unanticipated Problems (UPs): Any incident, experience, or outcome that is unexpected, related or possibly related to the research, and suggests that the research places subjects or others at a greater risk of harm than was previously known. UPs must be reported to both the IRB and the sponsor.
Ensure that the protocol specifies the reporting requirements and timelines for each type of event. Always review the definitions and guidelines to determine the appropriate reporting entity and comply with both sponsor and IRB policies.
Data from Withdrawn Subjects
- When a participant withdraws from a study conducted under an IND, the data collected on the participant up to the point of withdrawal remains part of the study database and may not be removed.
- You may not continue to access the participant's medical record or other confidential records for additional research purposes unless the participant has provided consent to do so.