We left our discussion in part 9 on the varying language in the ISL about specificity/selectivity, wondering how you can tell what really applies. We take note of an interesting distinction proposed by Mr. Idiot, but aren't sure it would be accepted.
I think that the ISL rules governing specificity are best understood in the context of our discussion of method validation. In this context, it is clear that selectivity must play a role in method validation, notwithstanding any permissive language we might find in ISL rules 18.104.22.168.1 and 22.214.171.124.2. It would make no sense to devote great effort to the determination of the accuracy of a test method, without devoting a roughly equivalent effort to determine that the method is measuring what it is supposed to measure. Understanding what we do about “fitness for purpose”, it would be impossible to argue that a test method lacking in selectivity could possibly be “fit for purpose.”
At the same time, it may be unreasonable to expect that WADA lab method validation should ensure complete selectivity. As we’ve stated repeatedly, the ISL is based on the assumption that standard methods are not available for doping testing, and that WADA labs will be required to develop their own test methods in house. It’s probably unrealistic to expect new and novel test methods to achieve perfect selectivity (notwithstanding the importance to the athletes being tested that the labs avoid making any mistakes). In addition, given that a urine sample is a complex matrix that might contain any number of unexpected substances, it might be impossible to prove that a lab method was capable of avoiding all possible interferences. Finally, we should recall that method validation is a finite effort, designed to determine fitness for purpose, but limited in important respects by factors of time and cost. Given all this, it seems most reasonable to define “specificity” for purposes of the ISL as a high degree of selectivity, but probably not as 100% selectivity.
But what of the difference highlighted above between the standards for avoiding (or limiting) matrix interference in ISL rules 126.96.36.199.1 and 188.8.131.52.2? Here on TBV, Mr. Idiot has advanced a good explanation for the difference in these standards. ISL 184.108.40.206.2 addresses the requirement to limit interference in testing for threshold substances, where the lab is required to measure the amount of the substance present in the standard. In contrast, ISL 220.127.116.11.1 governs the requirement to avoid interference in testing for non-threshold substances, where the lab is only required to determine the presence of the substance. Arguably, the standards for methods that need to measure the amount of a substance must be more exacting than the standards for methods that need only to detect the presence of a substance.
But I would caution against making too much of the difference in language between the standards in ISL rule 18.104.22.168.1 and 22.214.171.124.2. Recall what we’ve said so far about method validation. The goal of method validation is to ensure that a lab method is fit for purpose; a lab method that does not achieve good specificity (whether specificity is determined by avoiding interference or by limiting interference) is not fit for purpose. Moreover, given the unpredictability inherent in matrix interference (at least when dealing with a complex matrix such as urine), we can also expect that a lab will use the best means available to combat interferences, regardless of whether the lab is testing for a threshold or a non-threshold substance. At the same time, we expect labs to perform only a limited amount of method validation, so that method validation can be completed within a reasonable time and at a reasonable cost. In other words, we can predict that the main limitation on determining selectivity under the ISL will not be the standards set forth under ISL 126.96.36.199.1 and 188.8.131.52.2, but instead will be the limited effort required of labs under the ISL and ISO 17025 in performing method validation.
So, I think that the best way to understand the ISL rules on specificity is the way we’ve described above: under the ISL, specificity is a high degree of selectivity, but probably not perfect selectivity.
Up to the Introduction; back to part 9; on to part 11.