IHC Guidelines

Question 1

Conventional approaches to toxicity testing of pharmaceuticals may not be appropriate for biopharmaceuticals. In developing a monoclonal antibody in accordance with ICH S6 guidelines, what is the first consideration when designing IND-enabling in vivo safety studies?
A. selecting a dose level producing clear toxicity
B. assuring the test article is non-immunogenic
C. understanding the mode of action
D. choosing a relevant test species

Answer 1

D. choosing a relevant test species

Explanation and Reference:
Preclinical safety testing should consider: (1) Selection of the relevant animal species; (2) age; (3) physiological state; (4) the manner of delivery, including dose, route of administration, and treatment regimen; and (5) stability of the test material under the conditions of use in that order. Reference: ICH S6, Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals, July 1997, pp.2-8. (specifically Section 1.2, Para 2)

Question 2

What IND-enabling preclinical studies are recommended in the ICH S6 and M3 guidelines for both monoclonal antibody and small molecule pharmaceutics?
A. immunogenicity studies
B. tissue cross reactivity studies
C. pharmacokinetic and toxicokinetic studies
D. in vitro genotoxicity studies

Answer 2

C. pharmacokinetic and toxicokinetic studies

Explanation and Reference:
Single and multiple dose pharmacokinetics, toxicokinetics, and tissue distribution studies in relevant species are recommended for both types of programs. Immunogenicity and tissue cross reactivity would be unusual for a small molecule and genotoxicity studies are generally not applicable to biotechnology products. ICH guidelines S6 (Section IV.B.(4.2.1) and IV.G.(4.7) and M3; also Hayes 6th, pp. 332-333, 355

Question 3

What are the primary purpose and limitation of juvenile toxicology studies for pharmaceutical and biotechnology products?
A. they are required for all new drug but not pesticide registration
B. they assess safety and efficacy but not risk
C. they assess the safety but not efficacy of a product .
D. they assess the efficacy but not safety of a product

Answer 3

C. they assess the safety but not efficacy of a product .

Explanation and Reference:
Juvenile toxicology studies may be requested by the FDA to evaluate safety under pediatric conditions. Hayes 6th, pp. 362-363

Question 4

To demonstrate definitively that a chemical has the potential to act as a teratogen in rats, when during gestation would you expose the dam?
A. during organogenesis
B. pre and post fertilization of the female
C. during the implantation period
D. throughout the entire gestation period

Answer 4

A. during organogenesis

Explanation and Reference:
Teratogens are most effective when administered during organogensis (Day 7 to 17 in the rat). C&D 8th, p. 36 and ICH S5(R3), 2020, Annex 1: In Vivo study designs, Section 1.1.2.3, Table 3

Question 5

What actions must be included when assessing embryo-fetal developmental toxicity under ICH S5?
A. examination of weanlings for gross and visceral abnormalities
B. treatment of male and female rodents for 60 days to assure implantation
C. assessments of resorptions, fetal body weights, and fetal malformations
D. assessments of neurobehavioral deficits incurred during prenatal exposure

Answer 5

C. assessments of resorptions, fetal body weights, and fetal malformations

Explanation and Reference:
These are needed to determine extent of unsuccessful implantations, predictive in fetal toxicity, and diagnostic for teratagens. ICH S5(R3), 2020, Annex 1 In Vivo study designs, Section 1.1.2.3, Table 3

Question 6

The potential for xenobiotic-induced embryo-fetal developmental toxicity is best evaluated during what gestational period in the rat (where conception=gestation day 0)?
A. gestation days 0-21
B. gestation days 6-17
C. gestation days 0-5
D. gestation days 6-21

Answer 6

B. gestation days 6-17

Explanation and Reference:
Gestational days 6-17 is the primary period of organogenesis in rodents. This is the period of development that is highly sensitive to teratogenesis. C&D 9th, pp. 554-55 (Table 10-4) and pp. 568- 570 and Table 10-7; also ICH S5 (R3) 2020 Section 1.1.2.3, Table 3.

Question 7

What actions must be included when assessing embryo-fetal developmental toxicity under ICH S5?
A. examination of weanlings for gross and visceral abnormalities
B. treatment of male and female rodents for 60 days to assure implantation
C. assessments of resorptions, fetal body weights, and fetal malformations
D. assessments of neurobehavioral deficits incurred during prenatal exposure

Answer 7

C. assessments of resorptions, fetal body weights, and fetal malformations

Explanation and Reference:
These are needed to determine extent of unsuccessful implantations, predictive in fetal toxicity, and diagnostic for teratagens. ICH S5(R3), 2020, Annex 1 In Vivo study designs, Section 1.1.2.3, Table 3

Question 8

For most systemically administered drugs, what measure is used to convert the animal dose to a human equivalent dose (HED)?
A. mg/m2
B. Cmax
C. AUC
D. mg/kg

Answer 8

A. mg/m2

Explanation and Reference:
mg/m2 is the recommended conversion, the other values should be adjusted depending on toxicity observed in animal studies. FDA Guidance (2010) M3(R2), Table 3

Question 9

Data from standard toxicology studies conducted with pharmaceuticals are evaluated for signs of immunotoxic potential. According to ICH S8, what is evidence of immunotoxic potential?
A. alterations in immune system organ weights and/or histology
B. decreased incidence of infections
C. hematological changes such as erythrocytopenia/erythrocytosis
D. mild thymic atrophy accompanied by decreased food consumption and a significant decrease in body weight gain

Answer 9

A. alterations in immune system organ weights and/or histology

Explanation and Reference:
Changes in the hematology panel would not suggest mild changes in the immune system; therefore, it would be a very insensitive high-level index of immunotoxicity. Similarly, mild thymic atrophy could be caused by many things including stress. In animals showing decreased food consumption and body weight, thymic atrophy would be a common finding and not indicative of immunotoxicity. Finally an increased incidence of infections would suggest immunocompromise; however, a decreased incidence of infections has little meaning in a preclinical safety study. The correct answer (B), changes in immune system organ weights and histology, would be routinely measured in a preclinical study and would require further immune system testing. ICH S8 Harmonized Tripartite Guideline Immunotoxicity Studies for Human Pharmaceuticals S8, 15 September 2005, Section 2.1.1 page 3.
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