The assessment of causality – whether the supplement caused the adverse event (AE) – is a very important part of the safety assessment. Although the lawyers out there would argue that it’s very difficult (if not impossible) to prove that a supplement caused an event, there are some factors strongly in favor of causality. These include:
- Did the event happen in close proximity to taking the supplement? This may be minutes or hours, but certainly within a reasonable time since taking the supplement.
- Does the AE make sense? (a.k.a., biologic plausibility). Fat burners tend to have ingredients that stimulate the sympathetic part of our nervous system, and frequently are associated with rapid heart rate, high blood pressure, or palpitations, to name just a few. If these AE occur, this makes “sense”, given the mechanism of action of the supplement.
- Does the same AE happen a second time? (a.k.a., positive re-challenge). This is the most powerful factors suggesting causality. If an AE happens twice in a row, especially if it is severe, it makes sense to not try it again, and, of course, to report the AE to the manufacturer.
- Has it ever been reported in published literature or with a similar product? In my opinion, there is a reporting bias in the literature about AE associated with dietary supplements. By this I mean that if a physician has a patient who experiences an AE with a dietary supplement, then s/he is more likely to report it to the company compared with a drug (even if the AE is identical!). But if someone has taken the time to report an AE in a publication, and it makes sense, then it is more likely to be causally related to the product.
So what’s the value in carefully investigating causality? First of all, you get valuable information about your product, which is important, because you as the manufacturer are responsible for assuring the safety of your supplements. If you discover that one of your supplements consistently causes adverse events, you might either modify your label, withdraw the product, or decide to reformulate or re-engineer your supplement, in order to minimize the AE.
Secondly by noting the causality in your AE narrative, you’re writing to a standard that the FDA reviewer is accustomed; i.e., the same standard that pharmaceutical and biologics companies adhere to when they send in an AE report.
Finally, while you’re investigating potential causality for an AE in a user of one of your products, realize that you may find alternative causes for the event, which may be more likely to have caused the AE. This is important, and you would note this in the causality assessment.
Sometimes, the event is not consistent with your product’s safety profile, but the timing (i.e., occurred shortly after taking the supplement) makes it difficult to rule out a causal relationship. In that case, write, “The event is not consistent with the known AE profile of the supplement, and in the opinion of the manufacturer, this event is not related to supplement use. However, the temporal relationship makes it impossible to rule out the product as a potential contributor to the event.”
|Key Learning: Perform and clearly document a thoughtful causality assessment for every serious adverse event reported to you. A careful assessment gives you valuable information about your product, which may lead to changes in labeling or manufacturer. In addition, FDA expects you to assure the safety of your product, and this is one important way to do that.|