In a recent webinar, Advarra regulatory experts discussed the must-haves of FDA and Common Rule reporting requirements. They reviewed the basics of what must be reported to whom—and when—for sponsors and investigators involved in IND studies, as well as requirements for identifying, reviewing, and reporting unanticipated problems and noncompliance to IRBs and Common Rule departments or agencies. Due to time constraints we weren’t able to answer all audience questions during the Q&A period, so our experts have answered some of the most popular questions in this blog.

Q: Suppose Dr. Smith is sponsor-investigator on Study 123 with Drug A. In another study (Study 456) with Drug A, Dr. Smith serves only as an investigator. In Study 456 she receives an outside safety report (OSR) related to Drug A; this has already been reported to the FDA by the sponsor of Study 456. As sponsor-investigator of Study 123, does Dr. Smith need to report the same adverse event (AE) that was collected as part of Study 456 to the FDA?
A: If the OSR contains information that would qualify for reporting under 21 CFR 312.32, then yes, the sponsor-investigator would have to report the information to the sponsor-investigator’s own IND.

Q: Aren’t reports required within 3 days for serious and unexpected AE?
A: A 3-day timeframe is no longer included in the investigational new drug (IND) regulations on safety reporting. IND safety reporting requirements and the submission timeframe were revised in September 2010. Under the current regulations for IND safety reporting (21 CFR 312.32):

  • The sponsor must notify FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later than 7 calendar days after the sponsor’s initial receipt of the information.
  • The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines the information qualifies for reporting.

For more information, see FDA Guidance on Expedited Safety Reporting Requirements for Human Drug and Biological Products.

Q: If a person serving as sponsor-investigator receives funding to run the trial from a pharmaceutical company, does that present a conflict of interest?
A: Funding to support research is typically not considered a conflict of interest (COI). For example, where an investigator conducts research funded by his/her institution, that is not considered a financial COI—that is simply funding of the research.

Q: Who do I contact with general questions regarding any FDA specific report?
A: For general questions on making an FDA required report about drugs or biologics:

Q: Where can I find the definition of “legally marketed”? There is sometimes confusion about what “legally marketed” means.
A: FDA Guidance “Determining Whether Human Research Studies Can Be Conducted Without an IND” explains what is meant by a drug product that is lawfully marketed in the United States.

Q: Is the sponsor required to monitor a study if the study is exempt from IND requirements?
A: The monitoring requirement under the IND regulations does not apply to IND exempt studies. However, a party other than the FDA might still require the sponsor to monitor the study. For example, a grant provider could impose monitoring requirements as a condition of the grant.

Q: How would you suggest submitting an IND application with more than one drug under an IND protocol?
A: You may include the drug names in the section for drug name on the Form FDA 1571 (Investigational New Drug Application).

Q: When should the IRB report events or determinations to the FDA?
A: FDA regulations require that the IRB promptly report the following to FDA:

  1. Any unanticipated problems involving risks to human subjects or others;
  2. Any instance of serious or continuing noncompliance with these regulations or the requirements or determinations of the IRB; and
  3. Any suspension or termination of IRB approval.

FDA regulations do not define “promptly.” IRBs may want to include their own definition of that word in relevant written procedures.

Q: What is best practice for IRBs in terms of reviewing AEs at continuing review?
A: FDA guidance on IRB Continuing Review After Clinical Investigation Approval and Adverse Event Reporting to IRBs may help an IRB in making some of these decisions.

Q: For studies subject to both the Common Rule and FDA oversight, do you have to report unanticipated problems involving risk to subjects or others (UPIRTSOs) to FDA and relevant Common Rule department or agency?
A: Yes, in accordance with the relevant requirements in the Common Rule and FDA regulations.

Q: If the research is funded or supported by HHS, do we only need to report to OHRP?
A: Not necessarily. If the research is funded or supported by HHS but is also being done under an IND, then OHRP (Common Rule) and FDA reporting requirements would both apply.  Where the regulations differ, the regulations that offer the greater protection to human subjects should be followed.

Q: Who within an institution should handle/act on reports of noncompliance?
A: The Common Rule and FDA regulations require that IRBs follow written procedures for ensuring prompt reporting of serious or continuing noncompliance. Beyond that, neither specifies who within an institution should handle or act on reports of noncompliance. Given that institutions’ organizational structures can vary, the decision on who should carry out those activities should be considered within each institution.

Q: Under the revised Common Rule, what role does the local IRB play for studies approved by a central IRB? Who is responsible for submitted unanticipated events under the Common Rule to the federal government?
A: The local IRB’s role can vary. In research subject to the Common Rule, the responsibilities of the local IRB and the central IRB must be documented (see 45 CFR 46.103[e]). While the revised Common Rule does not require that this be documented in a written agreement, it most often is.

The reliance agreement (or other documentation) between the relying and reviewing IRB will identify which entity is responsible for reporting events to the government.

Q: Could you provide examples of an UPIRTSO?
A: For HHS regulated research, examples would include events that are unexpected in nature, related to participation in the research, and resulted in new circumstances that increased the risk of harm to subjects. OHRP lists some specific examples in its Guidance on Unanticipated Problems Involving Risks & Adverse Events.

For FDA-regulated studies, an example of a UPIRTSO could be an AE observed during the conduct of a study if the AE were unexpected and serious, and would have implications for the conduct of the study (e.g., requiring a significant, and usually safety-related, change in the protocol such as revising inclusion/exclusion criteria or including a new monitoring requirement; informed consent; or investigator’s brochure).  In FDA Guidance on Adverse Event Reporting to IRBs, FDA provides a list of AEs that FDA believes should be considered as unanticipated problems that must be reported to IRBs.

For more information on reporting requirements for FDA and Common Rule agencies, watch the webinar The Must-Haves of FDA and Common Rule Reporting Requirements.

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