Adversity in Toxicology Studies Setting the NOAEL

Transcription

1 Adversity in Toxicology Studies Setting the NOAEL Regulatory Affairs & Drug Development : Current Thinking and Challenges April, 2017 Peter C. Mann, DVM, Dipl. ACVP, FIATP pmann@epl-inc.com

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3 Definitions of Adversity Although the concept appears simple, The definitions of Adversity/NOAEL are confusing, to say the least

4 Adverse Effect - Lewis A biochemical, morphological or physiological change (in response to a stimulus) that either singly or in combination adversely affects the performance of the whole organism or reduces the organisms ability to respond to an additional environmental challenge Lewis et al. Toxicol Pathol 2002

5 Non-Adverse Effect Lewis 2002 Contrasted to adverse effects, nonadverse effects can be defined as those biological effects that do not cause biochemical, morphological, or physiological changes that affect the general well-being, growth, development or life span of an animal. Lewis et al. Toxicol Pathol 2002

6 Adverse Effect Dorato 2005 In very broad terms, an adverse effect may be considered to be a change (biochemical, functional, or structural) that may impair performance and generally have a detrimental effect on growth, development or life span of a non-clinical toxicology model. More specifically, an adverse effect in a non-clinical toxicology study should be an effect that would be unacceptable if it occurred in a human clinical trial (FDA Guidance, 2002). Dorato and Englehardt, Reg Tox & Pharmacol 2005

7 Adverse Effect Dorato (cont) Toxicologists have not been consistent in applying judgment to determine if an observed effect in a non-clinical toxicology study is either adverse or acceptable. In practice, the judgment on the adverse nature of an observation in a non-clinical toxicology study is subject to discussion, challenge, and reinterpretation. The decision that an observation is adverse may be affected as much by public policy as by strict scientific interpretation

8 Adverse Effect Keller 2012 A change in morphology, physiology, growth, development, reproduction, or life span of a cell or organism, system, or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress, or an increase in susceptibility to other influences. Keller, et al. Tox Sciences, 2012

9 Adaptive Response In the context of toxicology, the process whereby a cell or organism responds to a xenobiotic so that the cell or organism will survive in the new environment that contains the xenobiotic without impairment of function. Keller, et al. Tox Sciences, 2012

10 Adaptive Response (cont) Adaptive responses to toxicant exposure may be characterized by reversibility Adaptive changes are often early homeostatic adjustments, (metabolism or gene expression/transcriptomic changes). Typically not considered to be precursors of functional impairment but rather a response that would return to a homeostatic condition.

11 Adaptive Response (cont) In some situations, a minor change may be sustained resulting in a new normal state where the cell/tissue/organism has adapted without adverse consequences, (P450 enzymes resulting in hepatocellular hypertrophy) and increased liver weight. These adaptive changes, in a different context, may be indicators of a potentially adverse outcome.

12 Biologically (Toxicologically) Significant Effect - Lewis A response (to a stimulus) in an organism or other biological system that is considered to have substantial or noteworthy effect (positive or negative) on the well-being of the biological system. Lewis, et al. Toxicol Pathol, 2002

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14 No Observed Adverse Effect Level (NOAEL) Dorato The highest dose/exposure that does not cause toxicologically relevant increases in the frequency or severityof effects between exposed and control groups based on careful biological and statistical analysis. While minimum toxic effects or pharmacodynamic responses may be observed at this dose, they are not considered to endanger human health or as precursors to serious events with continued duration of exposure.

15 NOAEL - Keller The highest exposure level at which there are no significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control. Significance is considered with regard to biological significance in the test species and may also incorporate statistical significance.

16 NOAEL - Keller (Cont) Some effects may be produced at this level, but they are not considered to be adverse or precursors to adverse effects. The perceived clinical relevance of a finding for humans should not be part of the decision-making process in allocating a NOAEL for a particular study but this should form part of the broader discussion of subsequent human hazard assessment. Keller et al. Tox Sciences 2012

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18 STP Draft Best Practices Paper on Adversity Recommended ( Best ) Practices for Defining and Communicating Adversity for Nonclinical Study Data Roy Kerlin (Chair), Brad Bolon, John Burkhardt, Sabine Francke, Peter Greaves, Vince Meador, and James Popp

19 STP Best Practices Paper Chose not to redefine Adversity or NOAEL Made a series of Recommendations for Defining and Communicating Adversity in Nonclinical Studies

20 STP Recommendations 1. The decision about whether or not a test article effect in a nonclinical study should be considered adverse or nonadverse should be unambiguously stated and clearly justified in the study report. 2. Adversity as identified in a nonclinical study should be applied only to the test species used within the study. 3. Undesirable effects on cells, tissues, organs or systems within the test animal should be assessed on their own merit.

21 STP Recommendations (cont) 4. Communication of what is considered adverse and the NOAEL should be consistent within and between study subreports and the overall nonclinical study report. 5. The basis for setting a NOAEL for a test article should be stated in an overview document based on data from multiple studies. 6. The NOAEL should either be deleted from data tables or linked to the appropriate explanatory text within study reports an overview documents

22 STP Recommendations (cont) 7. Communication of adverse findings and the NOAEL should include direct interaction between staff within different contributing scientific disciplines of the sponsor institution 8. Study toxicologists, pathologists and other contributing scientists who interpret data from nonclinical studies should be active participants in assessing and communicating human risk 9. All available data from nonclinical studies must be evaluated together to define any potential toxicities and to predict human risk

23 INTERPRETATION OF TOXICOLOGICAL DATA: A STRUCTURED APPROACH Interpretation of multi-endpoint toxicology studies is not straightforward Comprehensive assessment of toxicology data involves: Expert opinion and judgment to integrate complex and diverse information Recognition that effects may represent a continuum Recognition that there are areas that are open to interpretation where weight of evidence and overall level of concern may be more appropriate and informative than a judgment that an effect is adverse or not

24 DIFFERENTIATION OF ADVERSE FROM NON ADVERSE EFFECTS No alteration in function of organism or organ Adaptive response Transient Limited severity or below level of concern Effect not a precursor or part of continuum Secondary to other adverse effect Consequence of experimental model

25 NOAEL IS STUDY SPECIFIC NOAEL is context-driven Every study must be treated separately NOAEL is determined by the findings in that particular study only. Cannot use the results of one study as a surrogate for an entire program Results from several studies may be combined in filing documents to give overall picture of adversity

26 DETERMINATION OF NOAEL IS A COLLABORATIVE EFFORT Although anatomic pathology findings are often key to determining NOAEL, they are not the only relevant endpoints. Clinical findings, clinical pathology findings are often key to determining NOAEL Determination of NOAEL should be a collaborative effort by all relevant investigators.

27 Approach to Classification - Dorato

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30 CASE STUDIES

31 14-Day Oral Rat, 28-day recovery Dose (mg/kg) Organ/Diagnosis Terminal Females Adrenal (n): Necrosis, diffuse, severe Angiectasis, diffuse, moderate to severe

32 14-Day Oral Rat,28-day recovery Organ/Diagnosis Terminal Females Dose (mg/kg) Liver (n): Hypertrophy, centrolobular, diffuse, moderate Infiltrate, lymphohistiocytic, multifocal, minimal

33 Single Dose, Oral Rat Dose (mg/kg) Organ/Diagnosis Terminal Females Liver (n): Single Cell Necrosis, mutifocal, minimal to moderate AST and ALT elevated 4-6x

34 14-Day Oral Dog No clinical signs or gross lesions Dose (mg/kg) Organ/Diagnosis Brain (n): Inflammation, acute Inflammation, subacute

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36 CHRONIC PROGRESSIVE NEPHROPATHY A Study in Context

37 Rat Kidney Control Low Mid High Chronic Progressive Nephropathy

38 Kidney, Chronic Progressive Nephropathy

39 Kidney CPN Thickened Basement Membranes

40 Kidney Tubular basophilia / early CPN

41 What strain of rat? Common spontaneous change in SD rats Less common in Wistar

42 Sprague Dawley Rat Kidney Control Low Mid High Chronic Progressive Nephropathy

43 Other Factors Length of Study? Age of rats? Severity of change

44 Sprague Dawley Rat Kidney Control Low Mid High Number (20) (20) (20) (20) Chronic Progressive Nephropathy % Incidence Control Low Mid High Number (65) (65) (65) (65) Chronic Progressive Nephropathy % Incidence

45 Sprague Dawley Rat Kidney 90 day study Control Low Mid High Number (20) (20) (20) (20) Chronic Progressive Nephropathy % Incidence year study Control Low Mid High Number (65) (65) (65) (65) Chronic Progressive Nephropathy % Incidence

46 Sprague Dawley Rat Kidney 90 day study Control Low Mid High Number (20) (20) (20) (20) Chronic Progressive Nephropathy % Incidence

47 Sprague Dawley Rat Kidney 90 day study Control Low Mid High Number (20) (20) (20) (20) Chronic Progressive Nephropathy % Incidence minimal mild moderate

48 Sprague Dawley Rat Kidney 90 day study Control Low Mid High Number (20) (20) (20) (20) Chronic Progressive Nephropathy % Incidence minimal mild moderate Severity Average

49 Relevance of Change CPN is a spontaneous change in aging rats Some strains have a higher incidence CPN may be exacerbated by treatment Although CPN may be an adverse effect in a rodent study, there is no equivalent change in humans

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52 References Dorato, M.A. and Engelhardt, J.A. The no-observed-adverseeffect-level in drug safety evaluations: Use, issues, and definition(s). Regulatory Toxicol. Pharmacol. 42, , Keller, DA, Juberg, DR, Catlin N, Farland,WH, Hess,FG, Wolf,DC and Doerrer NG. Identification and Characterization of Adverse Effects in 21st Century Toxicology. Toxicol Sciences 126(2), , 2012

53 References Kerlin R (Chair), Bolon B, Burkhardt J, Francke S, Greaves P, Meador V, and Popp J. Recommended ( Best ) Practices for Defining and Communicating Adversity for Nonclinical Study Data (Draft), 2014 Lewis, R.W., Billington, R., Debryune, E., Gamer, A., Lang, B. and Carpanini, F. Recognition of adverse and nonadverse effects in toxicity studies. Toxicologic Pathology 30, 66-74, 2002.