Examples
Worked examples
- Is an instance
A sponsor confirms a SUSAR from one trial site meets ICH E2A's serious/unexpected/suspected criteria and, alongside its expedited regulatory report to FDA/EudraVigilance, sends a Dear Investigator Letter to every other participating site summarizing the event, whether it changes the product's known risk profile, and whether any protocol or consent-form action is required at that site.
- Is an instance
A sponsor issues a safety-driven protocol amendment (e.g. a new contraindication or a revised dosing cap) together with a cover letter to all investigators explaining the change, attaching the updated Investigator's Brochure, and instructing sites to submit both to their IRB/REB before the amendment takes effect locally.
Counter-examples
Looks similar, but isn't
- Not an instance
A routine periodic safety update (e.g. an annual DSUR submitted to regulators on a fixed schedule, with no single new finding requiring immediate site-level action) is not itself a Dear Investigator Letter, even though its underlying data may later prompt one if the sponsor's safety review concludes new information needs to reach sites promptly.
- Not an instance
An investigator's own internal adverse-event log or a site's routine correspondence with its IRB is not a Safety Letter — the term specifically denotes the sponsor-to-investigator notification, not site-generated or site-internal documentation.
Editorial commentary
Why the artifact is distinct from the regulatory report
It is easy to conflate a Dear Investigator Letter with the regulatory filing that often accompanies it, but they serve different audiences and different obligations. An IND Safety Report (21 CFR 312.32) is a sponsor-to-regulator submission with its own expedited timelines — 7 calendar days for fatal/life-threatening SUSARs, 15 days for other qualifying SUSARs, measured from sponsor awareness. The Dear Investigator Letter is the parallel sponsor-to-investigator communication: it may summarize the same underlying event, but it is written for site staff who need to decide whether the new information changes anything at their site — consent form language, eligibility criteria, dosing, or monitoring — not for a regulatory reviewer assessing an expedited safety signal.
The two obligations run on different clocks and can exist independently of each other. A sponsor can owe FDA an IND Safety Report without every underlying event rising to the level that warrants a standalone Dear Investigator Letter to all sites (some safety information is more efficiently rolled into a routine DSUR update or an Investigator’s Brochure revision); conversely, a sponsor may proactively notify investigators of an emerging trend across several lower-grade events even before any single event meets the SUSAR threshold that triggers expedited regulatory reporting.
What a Dear Investigator Letter typically contains
- A clear statement of materiality. Whether or not the new information is judged significant enough to influence the risk-benefit assessment of the investigational product or the conduct of the trial — sponsors commonly state this explicitly, even when the answer is “no new action required,” so investigators and IRBs have a documented basis for their own review.
- A description of the new safety information — the event or finding, and how it relates to what is already documented in the current Investigator’s Brochure or product labeling.
- Any required action at the site level: a consent form update, a protocol amendment, revised eligibility or monitoring instructions, or simply an acknowledgment that no action is needed.
- Attachments where relevant — an updated Investigator’s Brochure section, a revised protocol amendment, or the safety report itself.
The IRB reporting duty it triggers
Receipt of a Dear Investigator Letter is not, by itself, an end point — it starts a downstream obligation at the site. The investigator’s role is to forward the letter (and any attached safety report) to their IRB/REB/EC as soon as practicable, per that IRB’s own reporting policy. This connects to two related but distinct regulatory concepts already covered on CASRAI:
- UPIRSO (21 CFR 56.108(b)) — the IRB’s own obligation to have written procedures for prompt reporting of unanticipated problems involving risks to subjects or others. Not every Dear Investigator Letter describes a UPIRSO: FDA and OHRP guidance is explicit that a safety report or safety letter does not automatically meet the unanticipated-problem definition. Many institutions have written local policy specifying exactly when a Dear Investigator Letter must be submitted to the IRB as a reportable event — commonly when it meets the UPIRSO definition, or when it triggers a sponsor-required protocol or consent change.
- IRB Reportable Events — the broader institutional category (which subsumes UPIRSO but also covers lower-severity items) that most sites use operationally to route incoming safety letters through IRB review, regardless of whether the specific letter turns out to meet the UPIRSO threshold.
Because the underlying institutional policy varies, the practical takeaway for multi-site trial coordination is that a Dear Investigator Letter is rarely the end of the paper trail at a given site — it is the input that starts each site’s own local determination of whether IRB notification, a consent re-approval, or a protocol amendment submission is required, on that IRB’s own timeline rather than the sponsor’s regulatory-reporting clock.
Related terms
See also SUSAR, Serious Adverse Event (SAE), Development Safety Update Report (DSUR), UPIRSO, and IRB Reportable Events.
Machine-readable encodings
Use in your systems
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"description": "<p>A <strong>Safety Letter</strong> — almost universally called a <strong>Dear Investigator Letter (DIL)</strong> in practice — is the direct, investigator-facing document a trial sponsor sends to every participating site in a multi-site clinical trial when new safety information emerges that could affect subjects' welfare, the risk-benefit assessment of the investigational product, or how the trial is conducted. It is the notification artifact itself: the letter (or attached safety report) an investigator physically receives, reads, and is expected to act on — distinct from the underlying regulatory reporting mechanisms (an <a href='/dictionary/term/suspected-unexpected-serious-adverse-reaction-susar'>IND Safety Report</a> to FDA, or a periodic <a href='/dictionary/term/development-safety-update-report-dsur'>DSUR</a>) that may trigger it.</p><p>Under US law, the obligation traces to <strong>21 CFR 312.55 (\"Informing investigators\")</strong>, which requires a sponsor to keep every participating investigator informed of new observations on the drug — particularly adverse effects and safe use — \"as the overall investigation proceeds,\" and specifically to ensure investigators are promptly informed of significant new adverse effects or risks. The regulation names periodically revised <a href='/dictionary/term/investigational-new-drug-ind'>Investigator's Brochure</a> updates, reprints of published studies, and \"reports or letters to clinical investigators\" as acceptable means of distribution — the Dear Investigator Letter is that last category in standard industry practice. ICH E6(R2) Sections 5.16–5.18 place the parallel expectation on sponsors internationally: ongoing safety evaluation, and prompt notification of investigators, IRBs/ECs, and regulators when new information could affect the conduct of the trial or the risk to subjects.</p>",
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