Summary of a workshop on nonclinical and clinical immunotoxicity assessment of immunomodulatory drugs

Figures & data

Table 1.  Immunomodulators and clinical immunotoxicology Workshop plenary presentations.

Topic	Author (Affiliation)
Current Strategies for Evaluating Immune Status and Perceived Gaps – Nonclinical (Industry and Regulatory Perspective)	Dr. Kenneth Hastings (Food and Drug Administration)^a
Current Strategies for Evaluating Immune Status and Perceived Gaps – Clinical (Industry and Regulatory Perspective)	Dr. Ian Gourley (Wyeth Research)
Clinical Immunology Assessment in Relation to Drug Development	Dr. Ronald Harbeck (National Jewish Medical and Research Center)
Results of HESI ITC Immunomodulators Survey	Dr. Ellen Evans (Schering-Plough Research Institute)

^aDr. Hastings is currently at Sanofi-Aventis.

Table 2.  Clinical endpoints for assessing immunodeficiencies.

Antibody Deficiency	T-Cell/B-Cell Deficiency	Complement Deficiency	Phagocyte Deficiency
Immunoglobulin isotypes^a	CBC with differential^b	CH50 and AH50	CBC with differential^b
Vaccine titers (e.g., tetanus, diphtheria)	Immunophenotyping^c	C3 and C4	Nitroblue tetrazolium test
B-cell enumeration	Immunoglobulin isotypes^a	Complement activity	Dihydrorhodamine test
IgG subclasses	Vaccine titers (e.g., tetanus, diphtheria)	C1 inhibitor	Chemotaxis assay
B-cell proliferation (e.g., pokeweed mitogen)	Skin testing		Oxidative burst
Memory B-cells (e.g., CD27/IgD)	T-cell proliferation (e.g., mitogens, recall antigens^d)		Phagocytosis assay
	Cytokines		Flow cytometry (e.g., CD11/CD18)

^aNormal levels of immunoglobulins (e.g., IgM, IgG, IgA and IgE) do not rule out an antibody deficiency.

^bComplete blood count with evaluation of leukocyte subpopulations. A normal CBC does not rule out a lymphocyte subset deficiency.

^cAnalysis of lymphocyte subsets (e.g., CD3, CD4, CD8 and CD19).

^dExamples of recall antigens used in the clinical setting are Candida and tetanus.

Table 3.  Breakout session discussion topics and questions.

Topic 1: Causes-for-concern and expectations for specialized immunotoxicity testing

•What causes-for-concern would require additional nonclinical immunotoxicity testing?

•What are the expectations of clinicians for nonclinical testing to assess immunotoxicity in humans?

•What causes-for-concern would require specialized immunotoxicity testing or monitoring in humans?

Topic 2: Specialized immunotoxicity assessment

•What specialized immunotoxicity testing is needed in nonclinical studies based on mechanism or target?

•What specialized immunotoxicity testing is needed clinically?

•If signs of immunotoxicity are seen in nonclinical studies, are additional immunotoxicity studies in animals needed or can risk be assessed in humans?

•Give examples of safety endpoints (e.g., biomarkers) translated to clinical trials to assess immunotoxicity.

Topic 3: Nonclinical and clinical testing methods/technology and scientific knowledge

•What are the key gaps?

•Where should we focus to fill these gaps?

Topic 4: Timing for immunotoxicity testing

•What is the timing of nonclinical immunotoxicity studies in relation to clinical programs? What is needed before FIH (nonclinical), FIP and Phase 3 (large population)?

•What is the timing of immunotoxicity testing clinically? What is needed before Phase 3 (large population)?

Topic 5: Use of immunotoxicity data in decision making and risk assessment

•How is nonclinical data used to make decisions in the clinic and to communicate risk?

•How is clinical data used to make decisions? Which tests/endpoints lead to useful information?

•How do regulatory agencies view immunotoxicity data for risk assessment in humans?

Topic 6: Host resistance

•Would you use a host resistance model to predict human risk? How do you select the appropriate model and how is the data used in risk assessment?

•What is the role of host resistance in risk assessment?

•What is currently being done to monitor infections in humans? What else can be done? Is it necessary to conduct host resistance studies nonclinically, or can you get answers to host resistance from clinical endpoints?

Topic 7: General principles to guide immunotoxicity evaluation of immunomodulatory drugs

Table 4.  Gaps and areas of controversy in nonclinical assessment of immunomodulators.

•Lack of consensus on the causes-of-concern or triggers that would warrant additional nonclinical immunotoxicity studies and on the types of tests that should be used

▪Lack of consensus on the added value of nonclinical TDAR or other immune function assays for drugs that are known to suppress or enhance the immune response

▪Lack of consensus on the use and relevance of host resistance models

•Translation of nonclinical immunotoxicity findings (hazard identification) to risk assessment in humans.

▪Understanding the clinical impact of nonclinical immunotoxicity findings

•Need for new assays or improvement of current assays

▪Alternatives to the host resistance assays

▪Animal models of cell-mediated immune responses

▪Predictive cytokine release assays

Table 5.  Research gaps in clinical assessment of.

•Situations that trigger the need for clinical assessment of immunotoxicity (e.g., TDAR / vaccine challenge studies) and how these data will be used in the risk assessment process are unclear

•Lack of consensus on the types of clinical assay that should be conducted and when during clinical development

•Need for better approaches to capture infection data (e.g., specific details, better tracking) and better methods to characterize infection rates (e.g., biomarkers)

•Robust assay that can reliably assess innate (other than standard ex vivo assays such as phagocytosis or NK assays) and adaptive immune function (especially T-cell-mediated function).