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FDA published in December 2012 a final guidance on IND and BA/BE reporting along with a brief Q&A accompanying it. See: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf and www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM332846.pdf respectively.

The Q&A is short and not too useful but the final guidance runs 32 pages and is a very useful read.  It summarizes FDA’s requirements and thinking on SAE reporting in clinical trials.  The section on BA/BE reporting is at the end and is rather brief.

The document is largely without surprises though a few things actually did surprise me.  We will review the key points here and in the next posting.  It is a long document (over 30 pages) and many worthwhile points are made.  The routine safety reporting requirements we will presume you are aware of and will not discuss unless there is something important to note.

FDA notes clearly up front that 21CFR320 (the IND safety reporting regulations) were changed to avoid excess reporting of individual cases where there is not enough evidence to suggest a reasonable possibility that the drug caused the AE.  FDA notes that there is often over-interpretation of the regulatory phrase:  “reasonable possibility that that the AE may have been caused by the drug” which means associated with the use of the drug.  FDA points out several times that single case reports are usually not useful and should not be reported as 15 day IND safety reports.

Suspected Adverse Reactions

Several standard definitions are noted.  The only one to emphasize here is “suspected adverse reaction”.  This is any AE for which there is a reasonable possibility that the drug caused the AE and where “reasonable possibility” means there is evidence to suggest a causal relationship between the drug & AE.  There are basically three types of suspected ARs:

Here is FDA’s diagram from the appendix of this guidance:

Editorial comment: What FDA is saying here is that they don’t want excessive reporting of cases that are not really suspected of being due to the drug.  They imply (softly) in several areas that companies sometimes do excessive reporting to cover themselves.

Well yes indeed.  The problem from the company’s point of view is that if they get it wrong and don’t report some cases that turn out to be drug related and/or if they override an investigator’s causality (see below) they will get no sympathy or succor from FDA, the press, patients or attorneys…

Having been burned several times over the years, my view is still to be conservative and over-report (or at least require really compelling reasons and data to not report).


FDA acknowledges here that the US requirements differ from ICH E2A.  Specifically, the FDA requires the sponsor to determine causality (with consideration of the investigator’s opinion) whereas the E2A proposal is that both the investigator and the sponsor determine causality.  In the latter case, usually the most conservative call is used (that is, if one says related and the other unrelated, the case is considered unrelated).


Again the FDA notes that “anticipated” AEs based on the disease or patient population under study are NOT used to determine expectedness.  Rather the specific AEs listed in the IB seen with the drug are used.


In a somewhat surprising note that I’m sure was missed by many folks (myself included), the FDA requirement for “important medical events” is clarified:  FDA uses “and” rather than “or” for important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definition.

FDA accepts both the ICH (“or”) and FDA definition (“and”).

Editorial Comment: The FDA definition seems more restricted than the ICH definition requiring that the patient be jeopardized AND require medical or surgical intervention.  In practice, this probably doesn’t matter as almost all patients in such situations would require some sort of medical intervention – even if it is just observation.  It also doesn’t mean that they will actually get the intervention, only that they “may require” it.

Review of Safety Information

FDA spells out the information that must be reviewed.  This is not an inclusive list but seems to me to cover pretty much everything a company or investigator might run into regarding the drug:

In regard to the scientific/medical literature: “The sponsor should conduct literature searches regularly with a frequency appropriate to the drug or study design to seek safety information”.

Editorial Comment: No surprises here.

Investigator Notification

The sponsor must notify FDA & “all participating investigators” of an IND safety report (7 or 15 day report) no later than 15 calendar days.  No surprise.

Clarification of “all participating investigators” is given: All investigators to whom the sponsor is providing drug under any of its INDs or under an investigator’s IND.

Editorial Comment: This may be a surprise to some readers as not all companies send the 15 day reports to investigators in ALL their INDs or to investigator initiated studies that the company has supplied drug for.

Analysis of Similar Reports

This analysis, required for 15 day expedited reports, should be based on information from all other INDs held by the sponsor and any other relevant information known to the sponsor. In addition, the suspected AR should be examined in the context of other related AEs including those in placebos, comparators and those in pre- and post-marketing studies.

Editorial Comment: FDA seems to want some context for the analysis of similar events.  If there are, say, a dozen other myocardial infarctions in patients taking the study drug in other INDs but also in the comparators, this should be noted.

Review of the Safety Database

Sponsors should conduct ongoing safety evaluations, including periodic review and analyses of their entire safety database, not only for IND safety reporting purposes, but also to update investigator brochures, protocols, and consent forms with new safety information.

Editorial Comment: Call it what you will: signaling, trend analysis, life cycle risk management.  It has to be done.

Investigator Initiated Studies (IISs)

The investigator is held to the same regulations as corporate sponsors including reporting on the scientific literature and foreign commercial marketing experience.

But “FDA recognizes that a sponsor-investigator may not have access to complete safety data…but sponsor-investigators are responsible for evaluating all safety information available to them… To protect human subjects, we recommend that entities that provide drug to or receive drug from other entities share safety information with each other.”

Editorial Comment: Reading through the somewhat obscure language in the last sentence, this means that pharma companies “helping” in or involved with IISs should supply the investigator with the IB, safety updates etc.  It’s not clear all companies do this and it’s certainly not clear that all investigators fully comply with IND maintenance and reporting.

Serious & Unexpected Suspected ARs

This refers to what most others (and occasionally FDA itself!) call SUSARs (Suspected Unexpected Serious Adverse Reaction).  However, FDA does not officially use the term SUSAR.

FDA reiterates that the sponsor must consider the investigator’s causality assessment (which is obligatory for the investigator) but that the sponsor may override that judgment and should submit “an IND safety report only for those events for which the sponsor determines that there is a reasonable possibility the drug caused the event, regardless of the investigator’s causality assessment.“ The investigator assessment should be in the safety report as well as the sponsor’s.  If the investigator does not supply an assessment (even though it is required) the sponsor assessment is then used.

Editorial Comment:  This has produced a lot of consternation amongst sponsors.  Many companies do not feel they should override an investigator assessment (lack of trained staff, not right to disagree with the investigator, the sponsor override may appear self-serving, there may be potential legal jeopardy).  No easy answer on this.  I personally take a very conservative viewpoint and prefer to overreport than underreport using the most conservative assessment– not the position the FDA wants.  Note that this may then produce a safety report for other regions (EMA, Canada, etc.) but not for the US FDA.  This violates one of the “fundamental rules” of drug safety: Say the same thing to all regulators at the same time.

We are only about a third of the way through the guidance.  More in the next posting.

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