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Presentation: Evaluation Panel Roadshow - Overview of Toxicology Evaluations

TGA presentations: Evaluation Panel Roadshow, November 2017

8 December 2017


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  • Presented by: Toxicology Section, Scientific Evaluation Branch
  • Presented at: Therapeutic Goods Evaluation Panel Information Sessions
  • Presentation date: November 2017
  • Presentation summary: Evaluation Panel Roadshow information for prospective evaluators for the TGA


Overview of Toxicology Evaluations

Toxicology Section, Scientific Evaluation Branch

Therapeutic Goods Evaluation Panel Information Sessions, November 2017

Slide 1 - What do we do?

  • Evaluate nonclinical (pharmacology and toxicology) data submitted to support clinical trials or registration of medicines (prescription, over-the-counter and complementary) and medical devices in Australia;
  • Report on the nonclinical data submitted; and
  • Assess and make recommendations for sections of the Product Information that contain nonclinical data, including Use in Pregnancy and pregnancy categorisation.

Slide 2 - Goals of nonclinical studies

  • To identify starting dose and dose escalation for clinical trials;
  • To identify potential target organs; and
  • To identify toxic effects that cannot be discerned from clinical studies

Slide 3 - Contents of an Evaluation Report

Cover page image of the contents of an Evaluation Report

Slide 4 - Evaluation Content – Main Body

  • Pharmacology
    • Primary Pharmacology
      • In vitro: Mechanism of action and potency;
      • In vivo: Efficacy in an animal model;
    • Secondary and Safety Pharmacology
      • Pharmacological effects other than primary therapeutic effects
      • Unwanted effects on major organ systems & exaggerated pharmacological effects

Slide 5 - Evaluation Content – Main Body

  • Pharmacokinetics (ADME)
    • Absorption (IV: Vd, Cl, t½; PO: Cmax, Tmax, F, single & repeated dose)
    • Distribution (organ concentration, autoradiography)
    • Metabolism (plasma, urinary, biliary & faecal metabolites)
    • Excretion (urine, faeces, expired air, carcass; time course)
    • Interactions (plasma protein binding, CYP450 drug interactions, transporters)

Are animals used in the studies good models for human?

Slide 6 - Evaluation Content – Main Body

  • Toxicity (1)
    • Acute/Single dose toxicity
      • Single dose, mortality & signs, 14 days observation
    • Repeat dose toxicity
      • Dose, duration, species, sample size, route, toxicokinetics;
      • Mortality, bodyweight gain, food & water consumption, clinical signs, ECG, ophthalmology, haematology, clinical chemistry, urinalysis, organ weight;
      • Includes detailed microscopic examination of an extensive set of tissues;

Slide 7 - Evaluation Content – Main Body

  • Toxicity (2)
    • Carcinogenicity
      • Near lifetime studies in two rodent species
      • Applicability to humans
    • Genotoxicity
      • Gene mutation
      • Chromosomal damage
      • DNA damage

Slide 8 - Evaluation Content – Main Body

  • Toxicity (3)
    • Reproductive and developmental toxicity
      • Fertility and early embryonic development
      • Embryo-foetal development (teratology)
      • Pre- and post-natal development
    • Local tolerance
      • IV, inhalation, eye, skin injection site effects after IV, IM, SC
    • Other Toxicity studies
      • Antigenicity/immunotoxicity
      • Studies with impurities

Slide 9 - Evaluation Content – Assessment Body

  • Integration & critical assessment of data

Scientific guidelines

  • Consider overall quality of submission
    • Highlight inconsistencies or concerns;
    • Deficiencies & their significance for human risk
    • Relevant studies not conducted;
    • Deficiencies in conducted studies;
    • Positive findings & their significance for human risk

Slide 10 - Recommendation

Registration/variation to existing registration:

    • supported;
    • supported with reservations or restrictions
      • (this may refer to recommended changes to the proposed Product Information);
    • not supported by nonclinical data

Slide 11 - Evaluation Content – Product Information

  • A concise summary of all information about the drug relevant to its clinical use
  • Sections containing nonclinical data
    • Pharmacodynamics/mechanism of action
    • Pharmacokinetics and drug interactions
    • Genotoxicity and carcinogenicity
    • Effects on fertility
    • Use in pregnancy (Aus categorisation: A, C, B1-B3, D, X)
    • Use in lactation
    • Interactions with other medicines

Slide 12 - Conclusions

  • Evaluation of nonclinical (toxicological) data is an integral part of prescription medicines registration;
  • Animal to human: Identification of potential adverse effects in humans;
  • Key areas of nonclinical toxicological concern;
  • See “real-life” evaluations in the Australian Public Assessment Report (AusPAR) for prescription medicines:

Australian Public Assessment Reports for prescription medicines (AusPARs)

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