Guidance for Industry
`
`Single Dose Acute Toxicity Testing
`for Pharmaceuticals
`
`Center for Drug Evaluation and Research (CDER)
`
`August 1996
`
`PT 1
`
`Sandoz Inc.
`Exhibit 1048-0001
`
`JOINT 1048-0001
`
`

`
`GUIDANCE FOR INDUSTRY
`
`SINGLE DOSE ACUTE TOXICITY TESTING FOR
`PHARMACEUTICALS
`
`I.
`
`INTRODUCTION
`
`Acute toxicity studies in animals are usually necessary for any pharmaceutical intended for human
`use. The information obtained from these studies is useful in choosing doses for repeat-dose
`studies, providing preliminary identification of target organs of toxicity, and, occasionally,
`revealing delayed toxicity. Acute toxicity studies may also aid in the selection of starting doses for
`Phase 1 human studies, and provide information relevant to acute overdosing
`in humans.
`
`II.
`
`DEFINITION
`
`Acute toxicity is the toxicity produced by a pharmaceutical when it is administered in one or more
`doses during a period not exceeding 24 hours.
`
`III. TESTING PROCEDURES
`
`The test compound should be administered to animals to identify doses causing no adverse effect
`and doses causing maj or (life-threatening) toxicity. The use of vehicle control groups should be
`considered. For compounds with low toxicity, the maximum feasible dose should be administered.
`
`Acute toxicity studies in animals should ordinarily be conducted using two routes of drug
`administration: (1) The route intended for human administration, and (2) intravenous
`administration, if feasible. When intravenous dosing is proposed in humans, use of this route alone
`in animal testing is sufficient.
`
`1This guidance was originally published as a part of a proposed implementation document entitled "U. S.
`FDA’s Proposed Implementation of International Conference on Harmonisation (ICH) Safety Working Group
`Consensus Regarding new Drug Applications." The Agency has revised t~ais guidance based on comments it received
`on the proposed implementation. This approach, designed to facilitate the early stages of pharmaceutical development,
`is not and ICH consensus position although it is considered to be in general agreement with the ICH position on acute
`toxicity testing. This guidance was published in t~ae FederalRegister on August 26, 1996 (61 FR 43934). Although
`this guidance does not create or confer any rights for or on any person axed does not operate to bind FDA or the industry,
`it does represent the Agency’s current thinking on single dose acute toxicity testing for pharmaceuticals. For additional
`copies of l~ais guideline, contact l~ae Drug Information Branch, HFD-210, CDER, FDA, 5600 Fishers Lane, Rockville,
`MD 20857 (Phone: 301-827-4573) or the Max~nfacturers Assistance and Communication Staff (HFM-42), CBER, FDA,
`1401 Rockville Pike, Rockville, MD 20852-1448. Send one self-addressed adhesive label to assist the offices in
`processing your request. An electronic version of this guidance is also available via Internet using the World Wide Web
`(WWW) (connect to the CDER Home Page at http://w~wv.fda.gov/cder and go to l~ae "Regulatory Guidax~ce" section).
`
`Sandoz Inc.
`Exhibit 1048-0002
`
`JOINT 1048-0002
`
`

`
`Studies should be conducted in at least two mammalian species, including a nonrodent species
`when reasonable. The objectives of acute studies can usually be achieved in rodents using small
`groups of animals (for instance, three to five rodents per sex per dose). Where nonrodent species
`are appropriate for investigation, use of fewer animals may be considered. Any data providing
`information on acute effects in nonrodent species, including preliminary dose-range finding data
`for repeat-dose toxicity studies, may be acceptable.
`
`IV. OBSERVATION
`
`Animals should be observed for 14 days after pharmaceutical administration. All mortalities,
`clinical signs, time of onset, duration, and reversibility of toxicity should be recorded. Gross
`necropsies should be performed on all animals, including those sacrificed moribund, found dead,
`or terminated at 14 days.
`
`In addition, if acute toxicity studies in animals are to provide the primary safety data supporting
`single dose safety/kinetic studies in humans (e.g., a study screening multiple analogs to aid in the
`selection of a lead compound for clinical development), the toxicity studies should be designed to
`assess dose-response relationships and pharmacokinetics. Clinical pathology and histopathology
`should be monitored at an early time and at termination (i.e., ideally, for maximum effect and
`recovery).
`
`V. NOTE: ANIMAL PROTECTION
`
`Studies should be designed so that the maximum amount of information is obtained from the
`smallest number of animals. Calculating lethality parameters (e.g., LD<INF>50) using large
`numbers of animals, as was done previously, is not recommended (see the Federal Registerof
`October 11, 1988, 53 FR 39650).
`
`To avoid causing excessive pain or tissue damage in the animals, pharmaceuticals with irritant or
`corrosive characteristics should not be administered in concentrations that produce severe toxicity
`solely from local effects.
`
`Sandoz Inc.
`Exhibit 1048-0003
`
`JOINT 1048-0003