FDA Guidance of June 2021 Strengthens Guidance on Safety SurveillanceJPCC Associates

In June, the FDA issued a new draft guidance that provides expanded recommendations regarding how Sponsors should manage safety data during clinical trials.

This draft guidance for industry (Sponsor Responsibilities - Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies - June 2021) confirms that the Sponsor safety reporting requirements are in alignment with the December 2012 guidance (Safety Reporting Requirements for INDs and BA/BE Studies.) A previous draft guidance from December 2015 (Safety Assessment for IND Safety Reporting) was withdrawn upon publication of this one.

What are the key takeaway points?

Plan for Safety Surveillance (PSS)

Sponsors should have a systematic, documented approach for reviewing safety data (i.e., PSS) for each trial. It should address the following points:

• Clearly defined roles & responsibilities for management of safety data (reviewing, analyzing, decision-making and reporting)

• Unblinding of safety data for signal interpretation

• Identification of anticipated events in the trial population, including any events that the Sponsor does not plan to report, regardless of the Investigator’s opinion of causality

• Monitoring of the incidence rates of all events

• Frequency of internal aggregate safety reviews

• Planned assessments of non-trial safety data (e.g., results from other completed trials for similar drugs/class effects) that may impact subject safety

The PSS should be periodically reviewed to ensure the approach for reviewing safety data remains up to date with evolving safety data. The PSS and the documentation of its timely execution should be available during an inspection.

Unblinding of Safety Data and Aggregate Analyses

Investigational New Drug (IND) reports (SUSAR) should be unblinded when they qualify for expedited reporting, but SAEs (SUSARs and non-SUSARs) are rarely unblinded during signal detection reviews initiated by the Sponsor. When most of the safety data remains blinded, aggregate analyses become complex and have limited value. The draft FDA guidance outlines options for unblinding data when needed for aggregate analyses:

• Unblind SAE Regularly: Regularly unblind SAE to assess meaningful differences between the active drug and comparator groups (e.g., every six months or after enrollment of X number of participants)

• Create Unblinding Triggers: If the rate of an AE exceeds the expected background rate for the event, the relevant cases could be unblinded to conduct an analysis. Another trigger could be a set number of SAE received for a specific event (e.g., event experienced by more than X participants)

Review of unblinded data can be conducted by external parties, such as a Data Monitoring Committee (DMC), but the draft FDA guidance also allows for analysis of unblinded data by internal personnel who are uninvolved in the overall conduct or analysis of the trial.

Suspected Adverse Reaction Definition

The FDA expanded its definition of Suspected Adverse Reactions, stating that when invasive procedures are required due to participation on the clinical trial, the FDA may request that Sponsors report SAE related to such procedures, even if the investigational product was not administered.

Unexpected Definition

The definition of what is “unexpected” is reinforced and addresses some of the other types of reports that should be expedited, such as increased frequency or significant findings from animal studies.

Causality Assessment

The draft guidance confirmed that both Sponsors and Investigators must assess seriousness, the Sponsor making the final decision for IND reporting, even when there is a disagreement between the Sponsor and the Investigator.

Reporting Activities for Marketed Comparator Products

• If the Sponsor is not the New Drug Application (NDA) or Biologics License Application (BLA) holder, the Sponsor should forward the report to the NDA or BLA holder, manufacturer, packager, or distributor of the marketed drug.

• If the Sponsor is the NDA or BLA holder, the Sponsor must submit safety information from the clinical trial per post-marketing safety reporting requirements (314.80 or 600.80).

• If the drug is not approved and not marketed in the US, but is approved outside of the US, the Sponsor must submit an IND safety report.

  
  

Conclusion

The FDA has been consistent in its vision of signal detection and IND reporting for many years. This draft guidance provides additional concrete elements that should help Sponsors to meet FDA regulations and expectations. The recommendation to develop a PSS reflects good pharmacovigilance practices that many companies (but not all) already have in place.

Are you in compliance regarding these recommendations?

• Do you have a PSS/safety monitoring plan for each of your investigational (and marketed) products?

• Do you haven documentation on file showing you have executed surveillance activities as outlined in your plan?

• Do your standard operating procedures/processes allow for unblinding of data to make important safety decisions?

• How do you manage your unblinding process for signal interpretation?

Even if the FDA guidances are not enforceable during inspections, they reflect best business practices and provide a solid framework towards best pharmacovigilance practices. A thorough review of the full draft guidance is recommended.