Single Dose Acute Toxicity Testing For Pharmaceuticals

1. Name of Guidance

Guidance for Industry: Single dose acute toxicity testing for pharmaceuticals

2. Status of Guidance: Draft/ Final Guidance

Final

3. When was the Guidance released?

August 1996

4. Link to the Guidance

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079270.pdf

5. Target audience

Companies designing their non-clinical safety plan.

6. Laws and Regulations Referenced (and what each Law states in relevant part)

No laws or regulations are referenced in this guidance. It does reference the guidance for how many animals should be used in these studies (Federal Register of

October 11, 1988, 53 FR 39650). This guidance, which was updated since the release of the FDA guidance document, provides alternative methods to the LD50 test that was used to find the dose that killed 50% (n>/=20) of animals within 14 days of a single dose.

7. Summary

Acute toxicology studies are preliminary drug development studies that provide information about target organs of toxicity, delayed toxicity, and appropriate doses for future studies. The study consists of a single dose (or multiple doses within a 24 hour period if a single dose is not feasible) of test article by 2 different routes of administration (unless the intended human administration route is intravenous, then only the IV route needs to be used in acute toxicity studies). The study should include a rodent and non-rodent species. Only 3-5 rodents should be used for the rodent study. Fewer non-rodents may be used. Animals are observed for 14 days following test article administration for signs of acute toxicity, dose response relationships, pharmacokinetics, clinical pathology, and histopathology.

8. Rationale

Acute toxicity studies provide basic safety information about an investigational chemical product early in the development process. The data generated are used to determine the maximally tolerated dose and design further non-clinical and clinical studies. The small number of animals used reduces the number of animals subjected to potential overt toxicities while still obtaining the necessary information.

9. Resulting Recommendations

Acute toxicology studies should be performed in a rodent and non-rodent species (n=3-5) early in development. LD50 calculations are no longer recommended.

10. Impact

This guidance changed the way in which acute toxicology studies were performed. It recommends the use a very small number of animals early in non-clinical development so future studies can try to avoid overt toxicities while providing valuable information about the toxicology of the test article.