By Penelope Przekop, MSQA, RQAP-GCP
This article is a follow-up to Why Clinical Site Awareness Should Be “Day Zero” For SUSAR Reporting.
There is no logic to support that a regulatory agency responsible for patient/consumer safety would agree that the timeline for suspected, unexpected, serious adverse reaction (SUSAR) reporting begins with sponsor awareness regardless of when the PI became aware. As noted in the first article on SUSAR reporting, doing so would sanction gaps between PI and sponsor awareness, regardless of length, as long as the sponsor reports within the required seven or 15 days (depending on the situation) of their awareness.
Part 1 of this article, published on May 3, 2023, explained that the FDA’s goal is to ensure safety not to provide a compliance safety net to sponsors by enabling arbitrary rules around SUSAR reporting timelines. The article included real-world scenarios that demonstrated why sponsor policies and procedures should establish PI (aka clinical investigator site) awareness of a serious adverse event (SAE) as “Day Zero.”
Following publication of Part 1, a few readers raised points to justify using sponsor awareness as Day Zero for SUSAR reporting, regardless of when the PI becomes aware. Part 2 addresses those points and why they miss the mark.
Justification 1: Any late reporting by the investigator does not interfere with or shorten the sponsor’s timelines.
The sponsor has overall responsibility for the conduct of a clinical trial. One reader proposed that basing Day Zero on PI awareness would shift responsibility for meeting Day 7/Day 15 SUSAR reporting obligations entirely to the sponsor. This seemed unfair to the reader when considering that both the PI and the sponsor should only be held accountable for their own delays or failures.
ICH E6 codifies FDA, EMA, and Japan alignment regarding investigator and sponsor responsibilities. Per ICH E6 (R2) 4.11.1 and R3 draft 2.7.2 (b), all) SAEs should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., investigator's brochure) identifies as not needing immediate reporting. The reader pointed out that sponsors should, and often do, require PIs to report SAEs within 24 hours of awareness. We all know that there are 24 hours in a day; that day is Day Zero. The “immediately or within 24 hours” policy adopted by many sponsors is reasonable and still supports PI reporting within a 24-hour period post awareness (Day Zero). This is one of the most important commitments PIs make to a sponsor. Regulators require the sponsor:
- to ensure that PIs are qualified and that they follow all applicable regulations as well as the protocol. (ICH E6 R2 5.6.1 and 5.6.3 and R3 draft 3.7.1 and 3.9.2),
- to be responsible for the ongoing safety evaluation of the investigation product(s) (ICH E6 R2 5.16.1 and E3 draft 3.13), and, per ICH E6 R3 draft 3.9.1 and 3.9.5, that the processes, information, and data generated are of sufficient quality to ensure reliable trial results, trial participant safety, and appropriate decision-making,
- to select qualified monitors who, among other tasks, are to determine whether adverse events are appropriately reported within the time periods required by the protocol, GCP, and the applicable regulatory requirement(s), and
- to determine the root cause of each late SUSAR (aka noncompliance) and take appropriate corrective and preventive action.
The sponsor is held responsible for late SUSAR reporting, regardless of the reason for the lateness. If the cause is PI late reporting or failure to report (the monitor identifies an SAE that was not reported), the sponsor takes the hit (meaning the lateness is included in sponsor metrics for on-time SUSAR reporting) and must take action to ensure that the noncompliant PI is brought into compliance. This has been confirmed during hundreds of regulatory inspections and is clearly communicated in the FDA Compliance Manual for Inspection of Sponsor and Contract Research Organizations. If a sponsor believes that they are not going to be cited by the FDA, or any other major regulatory health authority, for having late cases because they were late from the PI, they are mistaken.
Justification 2: Both parties (investigator and sponsor) work within their own universe and in their own quality management systems (QMS).
Neither the FDA nor ICH requires PIs to have quality management systems (QMS). Regulators are clear regarding documentation of PI site staff training records, qualifications, delegation of authority, etc., and the sponsor requirements to monitor these aspects and much more.
Clinical research is the sponsor’s universe, and every PI site selected to participate in a clinical trial is part of that universe. The sponsor is the legal entity requesting market approval. During pre-approval inspections, regulators inspect the sponsor and key clinical sites (selected by the regulator based on their criteria). The FDA considers all inspection results when making conclusions about how the study was conducted. A sponsor mindset that excludes investigator sites from their universe is a dangerous one.
Justification 3: The sponsor is responsible for assessing if the event meets the criteria for causality.
Regulators require a causality assessment from both the PI and the sponsor. The FDA bases reportability on the sponsor’s causality assessment; however, not all regulators have this approach. The European Medicines Agency (EMA) bases reportability on the PI’s causality assessment. For this reason, any sponsor that has clinical sites outside of the U.S. must consider PI awareness as Day Zero. This regulatory requirement drives policies and procedures for all Big Pharma companies and has been the long-held approach for them.
Justification 4: Complexity of global trials makes compliance unmanageable.
One reader suggested global time zones may cause seven-day SUSAR reporting to be unmanageable if PI awareness is considered as Day Zero.
A different reader shared that “regulatory health authority expectations and requirements for SUSAR reporting do not change based on:
- the organization, size, maturity/expertise, and resources of the sponsor,
- the outsourcing model used in the clinical trial,
- holidays or absences (e.g., vacation, sick leave, business trips, etc.) of the personnel responsible for SAE or SUSAR processing and reporting, or
- the complexity of reporting pathways and (electronic) tools used for transmitting safety information.
“As a result, processes for SUSAR handling must be crystal clear, documented in writing with clearly assigned responsibilities including pathways and timelines, have sufficient backups lined up to ensure at any time that the reporting obligations can be assumed within the specified timelines.”
This is correct, and time zone differences can be added to the list above. Individuals or companies that decide to be part of the pharma industry must accept that it is a highly regulated and complex one to step into. As a sponsor, your company is accepting all of the responsibilities noted above and more.
Justification 5: There is a perfect versus compliant world.
One reader surmised that in a perfect world the PI would report an SAE on the day it was received, which would then be the same date that the sponsor would become aware, and that this could be Day Zero. The reader further explained that in a compliant world, the sponsor has one additional day, giving them 8/16 days for SUSAR reporting.
The regulatory requirement is 7/15 days not 8/16 days. In our industry, a compliant world is a perfect world and is exactly what regulators expect. Attempts to justify noncompliance by stating that it’s not possible in a perfect world will not fly.
The compliant, perfect, and right thing to do is:
- consider PI awareness as Day Zero,
- hold PIs responsible to report SAEs immediately, or no later than within 24 hours,
- report SUSARS within 7/15 days of PI awareness,
- include all causes of sponsor lateness of SUSAR reporting in timeliness metrics, and
- identify root cause of each late report and apply appropriate corrective/preventive actions that will bring everyone into compliance and lead to 100% on-time SUSAR reporting.
About The Author:
Penelope Przekop is a corporate quality management expert. Throughout her 30+ year career, she has worked with numerous Fortune 100 pharma companies, including Pfizer, Merck, Lilly, and Glaxo Smith Kline, and held leadership positions at Novartis, Covance, Wyeth, and Johnson & Johnson. She is the founder and CEO of PDC Pharma Strategy, a firm that provides corporate compliance, quality assurance, and pharmacovigilance consulting and services. She is an author whose books include Six Sigma for Business Excellence (McGraw-Hill) and 5-Star Career: Define and Build Yours Using the Science of Quality Management (Productivity Press). Przekop earned a BS in biology from Louisiana State University and an MS in quality systems engineering from Kennesaw State University. She is a graduate of the Smith College Program for Women’s Leadership and the Rutgers University Senior Leadership Program for Professional Women.