Thank you very much. This is very interesting discussion.
I believe that this NIH definition does not refer to all types of trials, it's specific to the clinical efficacy endpoints mostly for Ph III including registrational studies and does not pertain to early phase studies especially FIH.
First, clinical endpoints don't always measure clinical benefit, this is the efficacy term. In the example FIH the primary clinical endpoints are assessments of safety (ECG, vital signs, clin labs, etc) to support primary clinical objective to assess safety and tolerability of the new compound. This is not directed to clinical benefit especially when the study participants are healthy normal volunteers.
Clinical endpoints are not always supported by the statistical calculations - same example FIH study is exploratory and sample size is based on historical preferences and practical considerations and to much lesser extent statistical model. Ph II studies are frequently exploratory and also do not have sample size based on the statistical power, it allows to determine the extent of effect and doses for future definitive studies.
Clinical endpoints are not always already validated especially for new drug and FIH study, they can be explored and need to relate to the properties of the new drug in the early studies.
Concerning immunogenicity in FIH studies - even though there is a lot of information on immunogenicity in general now, for a new biologics this is a first opportunity to evaluate if the new drug is immunogenic. In a way it's part of safety assessment and I've seen immunogenicity analyzed under safety.
The obstacle of course is small sample size and relatively shorter duration of the treatment which may not allow to detect true frequency of ADAs .
However. as this is a first chance to evaluate and potentially correct immunogenicity issues with a new drug (for example adjust the acceptance criteria for particle contamination), I think it should be a secondary objective and measured in every FIH study for new biologic, not only for the reasons of PK.
Frequency of immunogenicity - even though it's hopefully a rare event, the samples from all subjects need to be tested to assess it.
The NIH definition refers to events which can be registered when they occur but do not require separate testing of all patients or testing is done as a part of already planned assessments. If an additional assessment requires specialized effort it's likely to be a part of secondary objective.
Original Message:
Sent: 3/3/2023 2:19:00 PM
From: Vibha Jawa
Subject: Immunogenicity as en exploratory vs secondary endpoint?
Posting a discussion from Johanna Mora
Would you help me improve my understanding on how to correctly assign IMG as a secondary vs. exploratory objective? Throughout my career, I have supported studies where immunogenicity is an exploratory objective, we used a validated method and reported in the CSR, in order words, treated as we would a secondary objective. Recently, when questioned about this, I was not able to properly justify why it was not a secondary objective. In other cases, based on immunogenicity risk assessment, we have purposely placed immunogenicity under exploratory objectives because we do not intend to analyze unless we see an unexplained change in PK/safety. That aligns with this NIH reference (Endpoint (nih.gov)) see below. Also, for programs in life cycle management, exploratory makes sense, since there is so much data on IMG. For a FIH, can you think of why you would place under exploratory? Any other thoughts? Thanks so much for sharing your experiences.
From the NIH link: Exploratory endpoints may include clinically important events that are expected to occur too infrequently to show a treatment effect or endpoints that for other reasons are thought to be less likely to show an effect but are included to explore new hypotheses.
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Johanna Mora Ph.D.
Bristol-Myers Squibb
Princeton NJ
[email protected]
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Vibha Jawa
Executive Director
Nonclinical Disposition and Bioanalysis
Bristol-Myers Squibb
Princeton,NJ
[email protected]
Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
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