Overview
Over the past five years, the U.S. Food and Drug Administration (FDA) has issued 61 warning letters to clinical investigators highlighting failures in regulatory compliance that can jeopardize participant safety and the credibility of research programs.
While the specifics of each case vary, three recurring issues surfaced:
- Failure to ensure investigations are conducted according to the investigational plan (21 CFR 312.60)
- Failure to submit an Investigational New Drug (IND) application when required (21 CFR 312.20 and 21 CFR 312.40)
- Failure to ensure proper Institutional Review Board (IRB) review and oversight (21 CFR 312.66)
The FDA issues warning letters when it identifies potentially significant violations of federal requirements. The recipient is given the opportunity to address the FDA’s concerns and must respond within a certain timeframe. Regulatory violations can have serious ramifications if not adhered to. Potential consequences may include, but are not limited to:
- Required corrective and preventive action (CAPA) plans
- Delays in research timelines and product development
- Damage to professional credibility
Since warning letters are publicly available, their impact extends beyond regulatory compliance and can influence long-term organizational outcomes.
The encouraging news is that each of these issues can be mitigated through stronger collaboration between clinical investigators and IRBs. This article explores these common findings and provides actionable steps investigators can take, in partnership with their IRBs, to avoid becoming the next recipient of a warning letter.
IRBs are often perceived as regulatory gatekeepers responsible for initial study approval. However, their role extends far beyond that of a gatekeeper. When engaged early, IRBs serve as strategic partners in maintaining FDA compliance throughout the lifecycle of a clinical investigation.
Additionally, IRBs play a key role in:
- Interpreting regulatory requirements, including IND determinations
- Monitoring ongoing studies through continuing review and amendment oversight
- Supporting investigator education
By leveraging IRB expertise early in study planning and maintaining open communication, investigators can proactively identify compliance risks and implement corrective measures before they escalate.
Conducting Studies According to the Investigational Plan (21 CFR 312.60)
Investigators are responsible for ensuring that studies follow the approved protocol. FDA warning letters frequently cite deviations such as ineligible participant enrollment, failure to obtain informed consent, or failure to abide by dosing regimens as stated in the investigational plan. The FDA has issued guidance documents, such as E6(R3) Good Clinical Practice (GCP) and Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects, which reinforce that investigators are ultimately responsible for protocol compliance and study oversight.
Unintentional protocol deviations can potentially occur due to:
- Protocol complexity
- Inadequate training across the study team
- Poor communication
The E6(R3) Good Clinical Practice (GCP) guidance highlights the increasing complexity of modern trials and the need for risk-proportionate approaches to study conduct and oversight.
Investigators can avoid this type of warning letter by engaging with their IRB. An IRB should be viewed as a collaborator rather than an entity that solely grants ethics approval. Investigators can be proactive with their IRB by:
- Sharing initial study design plans with their IRB to request guidance on areas prone to jeopardizing participant welfare
- Completing all training requirements necessary to conduct responsible human subjects research
- Understanding what constitutes a reportable event and a path towards corrective action
Failure to Submit an IND When Required (21 CFR 312.20 and 312.40)
Some investigators proceed with clinical studies involving investigational drugs without submitting an IND application. The FDA expectations around IND requirements and exemptions are detailed in guidance such as Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND and E6(R3) Good Clinical Practice (GCP). These documents clarify when an IND is required and reinforce the investigator’s responsibility to submit an IND before initiating their clinical study.
This often stems from a misunderstanding of whether a study qualifies for an IND exemption. Investigators may assume that using an approved drug automatically removes the need for an IND. However, this is not always the case. The Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND guidance highlights common areas of confusion, particularly around studies involving approved drugs used in new indications, different populations, or altered dosing regimens.
Investigators can work with their IRB in the following ways:
- Present the IND determination rationale before study initiation.
- Document the decision of an IND (even when not required) and share it with the IRB for audit purposes
- Ensure completion of training on IND requirements
Inadequate IRB Oversight (21 CFR 312.66)
The third primary issue that surfaces in FDA warning letters relates to failure to obtain proper IRB approval or maintain ongoing IRB oversight. This includes conducting research without approval, failing to submit the study for continuing review when approval has lapsed, or failing to report changes. FDA expectations for IRB oversight are outlined in Institutional Review Boards Frequently Asked Questions: Guidance for Institutional Review Boards and Clinical Investigators, E6(R3) Good Clinical Practice (GCP), and IRB Continuing Review After Clinical Investigation Approval: Guidance for IRBs, Clinical Investigators, and Sponsors. These guidance documents reinforce the requirement for both initial and ongoing IRB review of clinical research.
Issues of this nature can occur due to poor administrative oversight, inadequate tracking systems, and a lack of clarity about how investigators can ensure their studies don’t have a lapse in IRB approval. The FDA highlights that compliance failures often stem from ineffective systems for tracking approvals, managing ongoing reporting obligations, and documenting completion of continuing review.
Investigators can take the following actionable steps with their IRB:
- Establish clear lines of communication based on what the study team needs from the IRB. For example, there could be a designated person within an institution’s IRB that handles reliance agreements, which are typically needed for collaborative research.
- Coordinate a pre-study alignment meeting with the IRB to understand safety reporting expectations, documenting protocol amendments, and continuing review deadlines.
- Encourage a culture of transparency by keeping open dialogue with the IRB.
The Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring: Guidance for Industry and A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers: Guidance for Industry guidance documents emphasize the importance of supporting ongoing evaluation and quality management systems, including internal audits, to ensure compliance.
By strengthening investigator and IRB collaboration, organizations can move from reactive compliance to a more proactive, systems-based approach that reduces regulatory risk and enhances participant protections.
References and Additional Resources
- Assurance of IRB Review, 21 CFR § 312.66 (2002).
- General requirements for use of an investigational new drug in a clinical investigation, 21 CFR § 312.40 (2004).
- General responsibilities of investigators, 21 CFR § 312.60 (2023).
- Requirement for an IND, 21 CFR § 312.20 (1997).
- U.S. Food and Drug Administration (FDA). 2009. “Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects.” Accessed April 22, 2026.
- U.S. Food and Drug Administration (FDA). 2012. “IRB Continuing Review After Clinical Investigation Approval.” Accessed April 22, 2026.
- U.S. Food and Drug Administration (FDA). 2013a. “Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND.” Accessed April 22, 2026.
- U.S. Food and Drug Administration (FDA). 2013b. “Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring.” Accessed April 22, 2026.
- U.S. Food and Drug Administration (FDA). 2023. “A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers.” Accessed April 22, 2026.
- U.S. Food and Drug Administration (FDA). 2025a. “E6(R3) Good Clinical Practice (GCP).” Accessed April 22, 2026.
- U.S. Food and Drug Administration (FDA). 2025b. “Institutional Review Boards Frequently Asked Questions.” Accessed April 22, 2026.
