The NOAEL and Study Directors, Pathologists, Sponsors, and Regulators


For many of us working as toxicologists, wearing the hat of study director/sponsor/regulator, we have come across interpretation of adverse effects and conclusion of No-Observed Adverse-Effect-Levels (NOAELs), which is the ultimate goal of a nonclinical study. As you all know, people may vary in their thought processes on the NOAELs based on the hats they wear. However, irrespective of the hat you wear, the derived study NOAEL value is totally based on the specific study data. In conclusion, data holds the key.

During the 2019 SOT Annual Meeting and ToxExpo, I was fortunate to attend an excellent Workshop Session titled “Adverse or Not Adverse? Thinking Process behind Adversity Determination during Nonclinical Drug Development.” This session focused primarily on the thought process of people working as study directors, pathologists, sponsors, and regulators on the adverse effects and their interpretation to derive the NOAEL value.

The best part of this Workshop, in my opinion, was having the study director, pathologist, and consultant, as well as the regulator, on the same dais.

This Workshop was endorsed by the Drug Discovery Toxicology and Biotechnology Specialty Sections as well as the Association of Scientists of Indian Origin Special Interest Group.

2019 Adverse or Not Adverse Symposium.pngThere are numerous definitions of NOAEL available across pages. Dr. Vijaykumar Kale, study director and Principal Investigator from Battelle Memorial Institute, chaired the session and introduced the session with a perfect definition of NOAEL proposed by Palazzi et al. that emphasizes the words “likely effects.” He further elaborated on the steps in determination of NOAEL in a toxicity study and its further application to determine first-in-human (FIH). The emphasis was on providing a justification to the derived NOAEL value, which is a key aspect looked at by the regulators.

This was followed by an excellent talk from Dr. John Kapeghian from Preclinical Safety Associates, who presented a study director’s perspective on determination of adversity and NOAEL from a study. He again emphasized on the word “likely” in the definition of NOAEL and its significance. Later, he focused on the types of NOAELs with respect to local versus systemic effects and also NOAELs with respect to sex and route differences. He further emphasized a key aspect of NOAEL that the derived value should always include data-driven rationale along with scientific judgment. He also touched upon the studies on oncolytics wherein derivation of a NOAEL would be difficult owing to the adverse effects observed even at the therapeutic doses. The take-home message for small molecules was determination of clinical dose using either one-tenth of the severely toxic dose in rodents and one-sixth of the highest non-severely toxic dose in nonrodents in accordance with ICH S9. In clinical settings, the adverse effects from nonclinical studies should be evaluated in terms of their monitoring in human trials. Later, a total of five case studies were presented and discussed. These case studies presented unique situations wherein differences of opinions in study director, sponsor, and/or reviewer were highlighted.

The pathologist’s role starts from the termination of the in-life phase of the study. In fact, pathology is the heart of any nonclinical safety study in deriving the NOAEL value. Any toxicity study would, of course, be with some or the other pathological effects. Here, Mr. Bhanu Singh from Janssen Research & Development presented a very nice perspective of a pathologist in determining adversities in the nonclinical toxicology studies. The key message from the presentation was differentiation of observed effects as adaptive versus adverse, which plays a prime role in deriving the NOAEL dose. Mr. Singh initiated the discussion by presenting various factors like lesion severity, functional effects, adaptation, and lesion reversibility, which together determine the adversity of an observed effect. At the same time, it is equally important to understand some of the factors that should not be considered in adversity determination, like the clinical pathology biomarkers. This aspect was very effectively presented by Mr. Singh. Furthermore, as a pathologist, he discussed that the key question a pathologist always asks to himself is if the lesion observed is an artifact or real, followed by the immediate next question of if the effect observed is test article related and adverse/nonadverse. This was elaborated perfectly by the pathologist himself. Later, the communication of adversity was presented, with an emphasis on the clarity of adverse and nonadverse effects and justification of NOAEL in the report. Mr. Singh stressed the fact that the determination of NOAEL strictly lies with the study director based on the weight of evidence and not the pathologist. Furthermore, case studies on a titanium dioxide inhalation study and a 14-day oral rat study for a small molecule were presented.

After the completion of the entire nonclinical program, it is submitted to the regulators for their review and approval. In a same fashion, the last lecture of the Workshop was delivered by Dr. Ilona Bebenek from the US Food and Drug Administration on “A Regulatory Perspective of Determining Adversity and Translating Findings from Nonclinical Studies.” Dr. Bebenek initially presented her views on the needs and applications of the NOAEL dose from clinical and nonclinical perspectives. Later, she focused on the aspects to be taken care of in classifying a finding as adaptive or adverse, which was very informative. She stressed the fact that the NOAEL determined from a study should have a proper rationale rather than being vaguely stated as species difference or within the historical range. Each and every effect should provide a proper justification. She further stressed the fact that the regulators evaluate the effects observed in terms of relevance in humans, safety margins, and monitoring in the clinical settings. She also stated that there may be disagreements in the NOAEL values proposed by the sponsors and regulators wherein the most conservative NOAEL value selection is the way to proceed further. This was followed by a presentation of various examples, which presented various study data scenarios, and how the final NOAELs was concluded.

The session concluded with Dr. Bebenek’s presentation followed by panel discussion, which turned out to be a very healthy and productive interaction between the speakers and the audience toxicologists.

One statement I would like to make here is that this is one of the best sessions of SOT 2019, with around 100+ participants. It was a great session to understand the differences in adverse versus nonadverse effects as well as the thought processes of the study toxicologist, pathologist, and regulator on the determination and interpretation of NOAEL. As a study director and project toxicologist myself, I was enlightened from attending this session, and I am sure that everybody who attended this session gained a lot from the expertise of the speakers and case studies discussed.

This blog was prepared by an SOT Reporter. SOT Reporters are SOT members who volunteer to write about sessions and events they attend during the SOT Annual Meeting and ToxExpo. If you are interested in participating in the SOT Reporter program in the future, please email Giuliana Macaluso.

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