By Penelope Przekop, MSQA, RQAP-GCP
The FDA’s goal is to ensure safety, not to give sponsors a compliance safety net. Its acceptance of arbitrary suspected, unexpected, serious adverse reaction (SUSAR) reporting timelines that allow for long gaps in sponsor processing and reporting would be counterproductive to its purpose and goals.
Yet, the FDA and other global regulators have decided that sponsors can ensure compliance through various acceptable processes. Although they issue guidance documents, regulators stop short of requiring sponsors to implement a detailed, prescribed process. For example, the FDA requires sponsors to report a SUSAR within 15 calendar days of sponsor awareness. If the SUSAR is life-threatening or involves a death, the requirement shortens to seven calendar days (refer to FDA 21 CFR Part 312.32). The FDA and other key global regulators also require PIs to inform sponsors immediately upon becoming aware of a serious adverse event (SAE) (refer to FDA 21 CFR Part 312.64). To be practical, a widely accepted industry standard evolved: Sponsors require PIs to inform them no later than 24 hours upon their awareness of a serious adverse event (SAE).
But out in the wild, what does that really mean?
How Clinical Research Professionals Determine Day Zero
Regulators require these events to be reported as quickly as possible after they have occurred because it is their responsibility to monitor the evolving safety profile of investigational products and, therefore, ensure the safety of clinical trial subjects and, ultimately, the public. The FDA depends on sponsors to partner in those goals and, therefore, have an attitude of urgency when it comes to SUSAR reporting. Developing processes and contractual agreements that allow for reporting timeliness is a sponsor responsibility, and the associated costs are simply the cost of doing business in the pharmaceutical industry.
In a recent (and unofficial) LinkedIn survey, I asked industry professionals, “How do you/your company interpret/define Day Zero for FDA SUSAR reporting? When does the clock begin to tick?”
The results were:
- 67% said Day Zero starts with principal investigator (PI)/clinical site awareness,
- 25% indicated Contract Research Organization (CRO)/sponsor awareness, and
- 8% indicated the determination of positive causality.
The results reflected differing interpretations, which aligns with what I and other quality assurance consultants have observed in recent years. Interestingly, the majority of respondents who considered PI/clinical site awareness as Day Zero had much longer and deeper industry experience and were currently employed by a big pharma company or had been during their career. This was not the case for the 33% who selected a different answer.
Multiple Handoffs Make SUSAR Reporting More Harrowing
Before the explosion of outsourcing, most pharma companies shared the goal of satisfying the numerous global reporting requirements, and so they built processes around the most stringent ones. Most companies considered their awareness as the start of the regulatory clock, or Day Zero. PIs were expected to report available information so that sponsors could assess expectedness and causality, and when applicable, report seven- and 15-day SUSARs on time.
Now that the number of sponsors and outsourcing companies have skyrocketed — and global regulations have not evolved at the same pace — confusion as to when the regulatory clock starts has surfaced. Our most detailed explanations of pharmacovigilance (PV) regulatory requirements and expectations are found in the Guideline on Good PV Practices in the European Union, commonly referred to as the EU PV Modules. However, the EU PV Modules are specific to marketed products. Regardless, in content related to solicited, interventional activities, the Modules relay that Day Zero is considered the date on which an organization becomes aware of a SUSAR — and that includes any personnel in that organization as well as third parties with contractual arrangements with that organization. Given that description, anyone within those organizations could be considered the point person for establishing Day Zero. In the clinical development space, we work with investigational products with developing safety profiles yet to be evaluated by regulators. This is all the more reason Day Zero must be considered the date on which a sponsor becomes aware, including both personnel and contracted parties. Years ago, the sponsor and the PI held the primary contract. Today, the various outsourcing scenarios have increased the number of handoffs when it comes to regulatory reporting. Sponsors must not overlook the fact that they not only have contractual agreements with vendors, but they also have them with PIs. When faced with various handoffs, some sponsors are choosing which to count and which not to count, rather than creating processes that allow for the most stringent interpretation of Day Zero, one that is supported by regulations, guidance, and logic when considering the shared primary goal: safety.
Determination Of Day Zero For SUSAR Reporting Becomes Inconsistent When Left Up To Individual Interpretation
Outsourcing has added handoffs between PI site and the sponsor: the vendor(s) to whom the sponsor has delegated authority. In doing so, it has introduced the following common scenarios for SUSAR reporting to the FDA:
- The PI site is notified of an SAE but doesn’t report it to the CRO for 10 days. The CRO considers its receipt of the information as Day Zero. It’s a life-threatening case, so the CRO submits the SUSAR to the FDA within seven days.
- The PI site is notified of an SAE but doesn’t report it to the CRO for 10 days. The CRO submits it to the sponsor’s pharmacovigilance function five days after their receipt. The sponsor counts its receipt of the information as Day Zero. It’s a life-threatening case, so the sponsor submits the SUSAR to the FDA by Day 7, per their calculation.
- The PI site reports an SAE to the CRO on the day it receives the information. The CRO and the sponsor go back and forth for eight days, finalizing the sponsor’s causality assessment. The CRO considers the day that the sponsor informs them of a positive causality determination as Day Zero. It’s a life-threatening case, and the SUSAR is submitted to the FDA within seven days.
The sponsors involved in all of the above scenarios believe that they have submitted the seven-day SUSARs on time per regulatory reporting requirements. Before you agree, consider how the points below provide logical justification that their interpretation does not put patient safety first nor does it jibe with the intent of the regulations for SUSAR reporting to the FDA.
If the three interpretations above were accurate, the only noncompliance would be the PIs in scenarios 1 and 2. However, this would also reflect poorly on the clinical trial management and oversight because the PI should be held accountable for reporting the SAE immediately, as required by the FDA. For this reason, it would not make sense that the CRO, which has been delegated by the sponsor to process and report SUSARs, to say, “The PI didn’t send it for 10 days, but it doesn’t matter because we submitted it within seven days of our receipt.” The FDA expects the sponsor or its delegated CRO to ensure that the PI submits the information immediately so that if it’s determined to be a SUSAR, it can be reported within the required timeline. PI receipt of the information should be viewed as Day Zero.
In scenario 2, aside from late reporting by the PI, the CRO hangs onto the report for five days. Perhaps it just takes that long due to the headcount they have. Perhaps the person assigned to that study was on vacation. According to their interpretation, that’s all fine. The CRO can send the information to the sponsor as soon as they can get to it because Day Zero isn’t until the sponsor has it. Sponsors are required to collect an FDA Form 1572 from each PI, which includes the PI’s commitment to report SAEs to the sponsor within 24 hours. The means that either the PI has to send it directly to the sponsor, which is not happening, or to the CRO as the sponsor’s delegate. The CRO is the sponsor delegate and therefore the clock continues to tick.
In scenario 3, the PI submits the information on the same day the information is received, yet the CRO and sponsor do not prioritize determination of causality. Perhaps the sponsor is a small company, and its physician is on vacation. It knows that it should probably have a backup but assumes the FDA will understand because it’s small, virtual, and fully outsourced. Besides, according to the Sponsor’s their policy, Day Zero doesn’t start until its physician returns to the office and officially determines positive causality. As noted above, the CRO is the sponsor’s delegate. The FDA requires that the sponsor, and therefore their delegate, have processes, including backups, to ensure on time reporting. In this case, the sponsor is out of compliance.
Day Zero Should Start With The Site
Global regulators take contractual agreements and delegation of authority seriously. Sponsors must demonstrate oversight by ensuring that their vendors conduct contracted sponsor activities in a compliant manner. Any outside, contracted party that assists a sponsor in executing a clinical trial is considered a representative of that sponsor. This includes PIs, CROs, and more. The best, most logical practice to ensure patient safety every time is to start the regulatory reporting clock for a potential SUSAR the day that the PI learns of the SAE. The PI must report the SAE to the sponsor immediately, or no later than 24 hours after receiving the information. The sponsor must then have processes in place to ensure that the SAE is assessed for expectedness and causality immediately, or within enough time to report it within seven to 15 days, if applicable. This is how pharma companies and regulators work together to ensure that the evolving safety profile of an investigational product is understood so subjects remain safe.
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 and serves as the Chief Compliance Officer for Engrail Therapeutics. She is the author of Six Sigma for Business Excellence (McGraw-Hill). 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. Her new book, 5-Star Career: Define and Build Yours Using the Science of Quality Management launches in November 2021 from Productivity Press.