SAFETY LABELING TIDBIT - No. 21 (Mar 30, 2021): Criteria for “identified” and “potential” risks compared with the criteria for adding risks to labeling - Part 4 (read Parts 1-3 first): 2nd example for IDENTIFIED risk (ICH wording): “An adverse reaction observed in well-designed clinical trials or epidemiological studies for which the magnitude of the difference compared with the comparator group (…) on a parameter of interest suggests a causal relationship”. The corresponding example for POTENTIAL risk (ICH wording): “Adverse events observed in clinical trials or epidemiological studies for which the magnitude of the difference, compared with the comparator group (…), on the parameter of interest raises a suspicion of, but is not large enough to suggest, a causal relationship.” - - - For the most part, the difference mentioned in these examples is one in the % of patients with one or more events of interest. For labeling, absence of such a difference alone is by no means a sufficient reason to reject something as an adverse reaction, i.e., some potential risks of this type may very well be label-worthy. Continued in Part 5. More info in my book. See www.pharmiceutics.com for previous TIDBITS.

SAFETY LABELING TIDBIT - No. 22 (Apr 1, 2021): Criteria for “identified” and “potential” risks compared with the criteria for adding risks to labeling - Part 5 (read Parts 1-4 first): In a well-controlled trial, for a certain type of event, how large must a difference in the % of patients between drug and placebo arms be to consider it to constitute “adequate evidence of an association” and, therefore, to allow us to consider the type of event an IDENTIFIED risk for RMP purposes? With 100 patients per study arm, is a 30% difference good enough? Probably so. 10%? Maybe. 3%? Probably not. It depends on many things. And even if we ignored everything else relevant for such a decision (as suggested by this ICH example), it depends on how sure we WANT to be for proclaiming the evidence adequate.  - - - And the suspect events that do not make our subjective cut, those ending up being POTENTIAL risks? Can we stay silent about them in labeling? Well … that, too, depends - among other things on their potential relevance for the patient/user, which can significantly lower the threshold for including them in labeling.  More info in my book. See www.pharmiceutics.com for previous TIDBITS.

SAFETY LABELING TIDBIT - No. 23 (Apr 2, 2021): Criteria for “identified” and “potential” risks compared with the criteria for adding risks to labeling - Part 6 (read Parts 1-5 first): Going through the examples in the ICH definition and exploring whether only identified risks are label-worthy (Spoiler alert … The answer is NO). - - - Example of IDENTIFIED risk No. 3 (ICH wording): “An adverse reaction suggested by a number of well-documented spontaneous reports where causality is strongly supported by temporal relationship and biological plausibility, such as anaphylactic reactions or application site reactions” Corresponding example of POTENTIAL risk: “A signal arising from a spontaneous adverse reaction reporting system”. - - - Whether a “signal” will be accepted as AR for labeling will depend on the overall level of evidence for causation and how important it is to alert the user. It may end up being label-worthy not only if causality is STRONGLY supported by temporal relationship and biological plausibility. Think about potential reactions such as Lyell’s syndrome where it is crucial to discontinue any (potential) culprit drug as early as possible.  More info in my book. See www.pharmiceutics.com for previous TIDBITS.

SAFETY LABELING TIDBIT - No. 24 (Apr 5, 2021): ICH criteria for “identified” and “potential” risks compared with the criteria for adding risks to labeling - Part 76 (read Parts 1-6 first): Example of POTENTIAL risk No. 4 (ICH wording): “An event known to be associated with other active substances within the same class or which could be expected to occur based on the properties of the medicinal product.” Obviously, whether such things are label-worthy will depend on the overall level of evidence for causation (and applicability to our own product) and how important it is to alert the user. - - - INTERIM CONCLUSION from TIDBITS 18 - 24: There can be label-worthy instances in all categories of POTENTIAL risks that are represented by the examples in the ICH definition of “potential risk”. Such risks are especially likely to be label-worthy if they are of greater clinical relevance (aka “important”). That only IDENTIFIED risks are label-worthy is incorrect. - - - The next TIDBIT will be about an extra clause attached to the EU GVP definition of “identified risk”, which might cause someone to erroneously believe that only identified risks should be labeled. See www.pharmiceutics.com for previous TIDBITS.

SAFETY LABELING TIDBIT - No. 25 (Apr 6, 2021): ICH criteria for “identified” and “potential” risks compared with the criteria for adding risks to labeling - Part 8 (read Parts 1-7 first) = Looking at the extra clause attached to the EU GVP definition of “identified risk” : : : : That many potential risks are label-worthy can easily be verified by comparing section 4.8 (“Undesirable effects”) of the EU SmPC with the list of potential risks in the public RMP summary. However, if - as we see/know - section 4.8 indeed lists as adverse reactions (ARs) clinical manifestations of BOTH identified AND label-worthy potential risks, why has the EU GVP definition of IDENTIFIED risk the following additional clause attached? “ADVERSE REACTIONS included IN SECTION 4.8 of the summary of product characteristics (SmPC) ARE ALSO CONSIDERED IDENTIFIED RISKS, unless they are class-related reactions which are mentioned in the SmPC but which are not specifically described as occurring with this product (these would normally be considered as a potential risk).” Doesn’t this imply that only identified risks are accepted as ARs for labeling? - Cliffhanger … CONTINUED IN NEXT TIDBID. See www.pharmiceutics.com for previous TIDBITS.

SAFETY LABELING TIDBIT - No. 26 (Apr 7, 2021): ICH criteria for “identified” and “potential” risks compared with the criteria for adding risks to labeling - Part 9 (read Parts 1-8 first) = Looking at the extra clause attached to the EU GVP definition of “identified risk” : : : : The clause added to the EU GVP definition of IDENTIFIED risk (“ADVERSE REACTIONS included IN SECTION 4.8 of the summary of product characteristics (SmPC) ARE ALSO CONSIDERED IDENTIFIED RISKS, unless … “) is not meant imply that only identified risks are accepted as adverse reactions for labeling. It conveys that, once a potential risk has become labeled in section 4.8, it may become treated as an identified risk. It is not intended to invalidate the criteria (which are described in the definition and illustrated by examples) for sorting risks into “identified” and “potential”.  - - - FINAL CONCLUSION for TIDBITS 18 - 26:  Risks categorized as “potential” can be label-worthy. Their inclusion in labeling is more likely if they are of greater clinical relevance (aka “important”). Based on their nature and relevance, they may appear in the Adverse Reactions section and/or other label sections. See www.pharmiceutics.com for previous TIDBITS.

SAFETY LABELING TIDBIT - No. 27 (Apr 8, 2021): Getting our arms around the relevance of potential adverse reactions (ARs) as threshold-lowering factor for inclusion in labeling - Part 1 : : : : Analyzing regulations and reg guidance, we have seen that, for AR candidates of particular relevance, the “causality threshold” (”evidentiary standard”) for including them in labeling can be rather low (see TIDBITS 14-15). - - - Factors that constitute relevance include, for example, an event’s severity, potential irreversibility, potential impact on treatment compliance, and need for early intervention. - - - We have to look at relevance with the eyes of the user of our product (patient/consumer and healthcare professional). Relevance can also be public health relevance. - - - However, relevance will vary from user to user and - to a certain extent - can be “subjective”. So, when asking ourselves whether a potential AR deserves to be added to labeling, how can we validly determine the relevance of the AR candidate? Can we ever make it right for every user? - - - Continued in the next TIDBIT. More info in my book. See www.pharmiceutics.com for previous TIDBITS.

AFETY LABELING TIDBIT - No. 28 (Apr 9, 2021): Getting our arms around the relevance of potential adverse reactions (ARs) as threshold-lowering factor for inclusion in labeling - Part 2 : : : : Naturally, there can always be users saying that, for a particular potential AR, one should have lowered the threshold even further, i.e., alerted them sooner (evidence-wise). It is, nevertheless, important that we do our best to determine at which level of confidence in causation a potential AR deserves to be labeled. When, as part of this, assessing its relevance for the user we are informed by, e.g., our own perception of its relevance (beware of bias and a patronizing attitude), legal colleagues (to represent user viewpoints) and labeling precedents (possibly showing the position of reg agencies). - - - Reg agencies that act as advocates of our products’ users should also be the body in which authority is vested to determine when (evidence-wise) to add a potential AR to labeling.  However, to allow them to play that role effectively, they must be made aware of potential AR candidates for labeling rather early. And of course, reg agencies/reviewers, too, can be biased. See www.pharmiceutics.com for previous TIDBITS.

AFETY LABELING TIDBIT - No. 29 (Apr 12, 2021): Still “sitting on the fence”? : : : : Whenever the available evidence is not enough to make us rather confident that a product can cause a certain type of adverse event, we can find ourselves undecided whether to include it in labeling as adverse reaction - even if we take into account its relevance for the user. - - - In such situations, this is what I recommend doing to get off the fence, and in the right direction: Imagine you talk to THE PERSON YOU LOVE MOST ON EARTH (e.g., a spouse or child), and that person is ill, needs treatment and can choose between your product and other medicines.  She/he is medically educated and wants to make an informed benefit/risk decision. So, he/she is asking you whether there is, for your product, any not-(yet)-labeled, potential adverse reaction - whether major or minor. And begs you to respect her/his decision-making autonomy, i.e., not to withhold information because you think it shouldn’t make a difference for his/her decision. - - - If there were any potential adverse reaction you wanted to tell the person you love most on earth, shouldn’t it also be added to labeling? - - - More in my book. See www.pharmiceutics.com for previous TIDBITS.

SAFETY LABELING TIDBIT - No. 30 (Apr 13, 2021) : : : : COVID-19 vaccine risks - an opportunity to observe how challenging risk messaging can be … and how confusing, especially when filtered by outlets and pundits that - lacking information and PV/regulatory knowledge - distort the messages sent by companies/agencies. - - - FIRST: We may hear again the “obligatory” early statement that causality has not (yet) been established (or something to that effect). Correct and made for good reasons, but possibly misinterpreted as meaning that reported events can (still) be disregarded when weighing benefits and risks. - - - SECOND: We see this world of very public regulatory risk communication outside of (and before) labeling. For agencies that engage in such pre-labeling risk messaging, labeling is a more definitive step (“regulatory action”) that comes after further assessment. In general (i.e., not related to the current COVID vaccine scenario!), companies, to which the tool of public pre-labeling risk messaging is less available, may feel they cannot wait that long (duration-wise and/or confidence in causality-wise) until they propose a label update. - - - CONTINUED. See www.pharmiceutics.com for previous TIDBITS.