Background

In the new draft guidance, content from the 2012 final guidance remains largely unchanged; however, the new draft guidance does not incorporate the investigator provisions of the 2012 final guidance. FDA said it intends to publish a separate draft guidance on investigator's responsibilities for safety reporting for human drug and biological products that are being investigated under an IND. When the new draft guidance and the forthcoming draft guidance on investigator's responsibilities for IND safety reporting are finalized, FDA will withdraw the 2012 final guidance; until then, however, the 2012 final guidance remains in effect.

Primarily, the new draft guidance responds to comments received on the 2015 draft guidance, which was concurrently withdrawn with the publication of the new draft guidance. The 2021 draft guidance focuses on the reporting of serious adverse events (SAEs) in the setting of a clinical investigation conducted under an IND, and specifically discusses:

1. Planned unblinding of safety data and implications for trial integrity;

2. Increased flexibility regarding the party reviewing aggregate safety information for IND safety reporting purposes;

3. Clarification regarding the scope and methodology of aggregate analyses; and

4. Clarification regarding the plan for safety surveillance, including what elements should be included in the plan.

IND safety reporting requirements

Pursuant to 21 CFR 312.32, a drug sponsor is required to review promptly all information relevant to the safety of the drug to comply with the IND safety reporting requirements and to improve the overall quality of safety reporting; in addition, they must evaluate all accumulating data at regular intervals to update safety information and to identify new safety signals. Under § 312.32(c), the sponsor is required to notify FDA and all participating investigators through an IND safety report (i.e., the 7- or 15-day expedited report) of potentially serious risks from clinical trials or any other source as soon as possible but no later than 15 calendar days after the sponsor receives the safety information and determines that the information qualifies for reporting in an IND safety report.

The new draft guidance notes, as previously indicated, that clinical trial sponsors must review and evaluate safety information from any source regardless of whether the data came from studies conducted under the IND to determine if there is a newly identified significant risk to trial participants. Sources the sponsor is responsible for reviewing include, among others:

• Animal or in vitro studies
• Clinical or epidemiological investigations
• Reports in the scientific literature, including unpublished reports of which the sponsor becomes aware
• Information presented at professional or scientific meetings (e.g., abstracts)
• Reports from foreign regulatory authorities
• Reports from commercial marketing experience, including outside the U.S.

The draft guidance emphasizes that monitoring the progress of safety investigations is necessary for sponsors to identify previously undetected potential serious risks; to update investigator’s brochures, protocols, and consent forms with new information on adverse events; and, when necessary, to take steps to protect subjects (e.g., modifying dosing, participant selection, or monitoring).

Safety surveillance plan

Toward the goal of complying with IND safety reporting requirements, the 2021 draft guidance employs a new term, “safety surveillance plan,” to describe how sponsors should employ a systematic approach to safety surveillance. FDA explains that a plan for safety surveillance should include descriptions of the following elements:

1. Clearly defined roles and responsibilities of the entities and participating individuals that have responsibility for any or all of following: reviewing, analyzing, and making decisions regarding IND safety reporting

2. A plan for regular review of SAEs and other important safety information, with unblinding as necessary for interpretation

3. A process for aggregate safety reviews

Compared to the previous guidance documents, the new draft guidance expounds significantly on the agency’s recommendations regarding this third bullet point, discussed more below.

Aggregate data analysis

Serious adverse events can be anticipated to occur in a clinical study population independent of drug exposure, including both events common in a study population, and events known to occur with drugs administered as part of a background regimen. As a result, FDA requires clinical trial sponsors to conduct analyses of aggregate data to identify imbalances that indicate which events may occur more frequently in the drug treatment group than in a concurrent or historical control group, and imbalances that suggest an increased rate of occurrence of serious suspected adverse reactions in the drug treatment group.

For purposes of IND safety reporting, a “suspected adverse reaction” means there is a reasonable possibility that the drug caused the event.” To interpret imbalances in aggregate data, clinical and statistical expertise will be needed to determine whether that reasonable possibility exists, based on the totality of available information. The new guidance offers many factors to consider when determining whether that “reasonable possibility” threshold has been met:

• The extent of the increase in incidence seen in the test group compared to the control groups
• Evidence of a dose response
• Temporal relationship
• Consistency of the increase in multiple trials
• Presence of a plausible mechanism of action
• Nonclinical evidence (e.g., from toxicology or pharmacology animal studies, genetic studies, or human genetic data) to support the finding
• Pharmacology of the drug (including results from receptor, transporter, or enzyme binding or activation studies, and animal models) and known class effects
• Pattern across the study population (for example, the event is observed more frequently in individuals likely to be susceptible to it)
• Occurrence of other potentially related adverse events

However, in the new draft guidance, FDA offers greater flexibility for this aggregate data analysis, recognizing that “[i]nterpreting imbalances may be particularly challenging for smaller programs where the number of events is small.” Here, FDA is acknowledging the challenges associated with sponsors differentiating between reactions that are caused directly by a drug and those that merely “result from chance” in small trials that see only a few adverse reactions. The agency adds, “[f]or drug development programs in rare diseases, external data sources used to establish anticipated adverse event rates are often limited.”

Accordingly, FDA says it will focus on the company’s “process and reasoning” in cases where the agency and the sponsor reach different conclusions. FDA advises in the draft guidance that the first step in preparing for an aggregate analysis of anticipated events is developing a list of these events in the protocol or in the safety surveillance plan, and documenting a plan for monitoring these events.

Unblinding of safety data

Aggregate data analyses are not required when SAEs are informative enough as single cases because they are “uncommon and known to be strongly associated with drug exposure.” The new draft guidance clarifies that for these cases, the “blind should ordinarily be broken for these types of IND safety reports.” Unblinding a study means investigators and/or participants become aware of which treatment an individual participant is receiving.

The 2015 draft guidance had recommended unblinding a study to allow a comparison of event rates and detection of numerical imbalances across treatment groups to identify important safety information. Similarly, FDA’s 2012 guidance said the “blind should ordinarily be broken for IND safety reports submitted to FDA and all participating investigators.” In response, comments on the 2015 draft guidance had expressed concern that unblinding a study could cause problems. Nevertheless, FDA continues to request in the new draft guidance that sponsors unblind a drug trial if it needs to analyze whether there was an adverse reaction they need to report to the FDA.

FDA writes that it doesn’t think “that unblinding single or small numbers of serious and unexpected adverse event cases will compromise trial integrity, in part because such unblinding should be infrequent.” FDA defends this position by writing in the new draft guidance: “Knowledge of the treatment received is necessary for…determining whether it is a suspected adverse reaction,” and is necessary to “maintain trial integrity.” The 2021 draft guidance goes further in laying out an “unblinding trigger approach,” whereby, the agency says, an unblind analysis must occur if and when a sponsor determines that “the results of the overall blinded analyses demonstrate that rate of events in the pooled treatment groups substantially exceeds the predicted rate.”

Safety assessment committees

Another notable difference between the 2015 draft guidance and the 2021 draft guidance is the omission of new guidance regarding the role of “safety assessment committee” (SAC), which was charged in 2015 with overseeing the evolving safety profile of the investigational drug by evaluating, at appropriate intervals, the cumulative serious adverse events from all of the trials in the development program, as well as other available important safety information (e.g., findings from epidemiological studies and from animal or in vitro testing), and performing unblinded comparisons of event rates in investigational and control groups.

The 2015 draft guidance had indicated a sponsor should report potential serious risks within 15 calendar days if an SAC identified information that would require IND safety reporting; however, there is no mention of an SAC – or of a similarly responsible committee, aside from a data monitoring committee (DMC) – in the 2021 draft guidance.

Entitles that review aggregate data for IND reporting

In a new section in the 2021 draft guidance, FDA discusses “Entities That Review Aggregate Data for IND Safety Reporting,” clarifying that clinical trial sponsors may choose to designate an entity to review the accumulating safety information in a drug development program (e.g., over time in a late-stage clinical trial, across trials, across INDs for the same drug) and to make a recommendation to the sponsor regarding whether the safety information must be reported. The new draft guidance purports to offer “flexibility” to the sponsor in determining which entity or entities should perform this function.

However, the draft guidance clarifies that the entity reviewing aggregate data for IND reporting should have knowledge about the investigational drug; the disease being treated, including the epidemiology of the disease; and the characteristics of the study population (e.g., natural history of the disease being treated, background rates of anticipated adverse clinical events). The reviewing entity should also be “qualified by training and experience to make clinical judgments about the safety of the drug.” The new guidance further recommends the use of a data monitoring committee (DMC) for this role, noting that sponsors may also consider a triage approach in which more than one entity participates in the review.

BA and BE study reporting

New in the 2021 draft guidance, FDA clarifies that, for a bioavailability (BA) or bioequivalence (BE) study conducted to support changes to an already approved NDA or abbreviated new drug application (ANDA), SAE reports must be submitted to FDA and should be submitted to the FDA Adverse Event Reporting System (FAERS). Electronic submissions can also now be submitted to the HHS Safety Reporting Portal (SRP). These reports include Bioavailability/Bioequivalence Safety Reports, Follow-up Bioavailability/Bioequivalence Safety Reports, and 7-day Bioavailability/Bioequivalence Safety Reports.

Flowcharts

The new draft guidance contains several new appendices to help clinical trial sponsors ascertain their responsibilities for safety reporting, including flowcharts for:

• Determining whether an adverse event meets criteria for IND safety reporting to FDA and investigators

• Submitting safety reports for control drugs, including when the IND Sponsor is not the NDA or BLA holder of the control drug vs. when the IND Sponsor is also the NDA or BLA holder of the control drug

• The two approaches to aggregate analyses: the unblinding trigger approach and the analyses of all events by treatment group

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FDA will accept comments on the new draft guidance until September 27, 2021. If you may wish to submit a comment or have any questions about the agency’s requirements related to safety reporting or safety assessments, please contact any of the authors of this alert or the Hogan Lovells attorney with whom you generally work.

Authored by Heidi Gertner