Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route

Blog #3

Name of Guidance: Guidance for Industry and Review Staff: Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route

Status of Guidance: Draft

Release Date: 7 March 2008

Link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079245.pdf

Target Audience: Individuals/companies developing non-clinical safety evaluation plans for currently approved drug products reformulated for a new, unapproved, route of administration.

Laws and Regulations Referenced: Good Laboratory Practices (21 CFR part 58). GLPs are the general regulations that apply to the conduct of all nonclinical studies to be submitted for evaluation by the FDA. GLPs set standards for operations, animal care and use, documentation, key personnel, and quality assurance.

Summary: This guidance provides recommendations for nonclinical safety evaluations on approved drug products reformulated for a new, unapproved, route of administration. Regardless of the change in formulation, acute and repeat dose toxicity studies should be performed in at least one appropriate species using the new route of administration. These studies should also include pathology. New formulation methods that dramatically alter the route (for example, oral instead of IV) and/or duration of dosing require more additional nonclinical safety evaluations than less significant reformulations.

The guidance assumes that the drug product has a previously established safety profile. If deficiencies are found in the previous assessments, more studies may be needed.

Rationale: Although a complete nonclinical safety package would have been completed for the original drug formulation, it cannot be assumed the safety profile would remain the same if delivered into the body differently. Alternate routes of administration can change exposure profiles. Therefore, nonclinical evaluations should focus on establishing the pharmacokinetics and absorption, distribution, metabolism, and elimination of the drug in the new formulation.

Differences in the bioavailability and excretion between routes of administration can also have effects on the toxicological profile of the drug, which need to be evaluated. Target organs of toxicity and local tolerance should be evaluated for each new route of administration before performing clinical trials to have a clear understanding of the new impacts of the new route.

Resulting Recommendations: For the subcutaneous, intramuscular, oral, and rectal routes, only the acute and repeat dose toxicity studies should be needed. The repeat dose toxicity studies should be conducted for at least the term expected in clinical use. The following routes of administration should include the acute and repeat dose toxicity studies as well as what is additionally noted. The photoirritation and photocarcinogenic potential of dermal patches and ointments should be evaluated. If use is intended to treat a chronic condition, carcinogenicity studies may also be needed. Dermal irritation and delayed contact hypersensitivity should be evaluated for the otic, dermal, vaginal, and intra-oral routes. Reproductive and developmental toxicity studies should be performed for the itracavernosal, intraurethral, intravesicular, and vaginal routes. If the drug is to be delivered by inhalation or intranasally, inhalation studies should be conducted as well as carcinogenicity studies of intended for chronic exposure. The ocular route should be evaluated for ocular and systemic pharmacokinetics. The effects of the drug on the inner ear should be evaluated for otic drugs. Epidurals should be carefully evaluated in at least 2 species for neurotoxicity and pharmacokinetics of the cerebral spinal fluid.

Impact: Reformulations can greatly increase the profitability of a currently approved drug. However, depending on the intended route of administration, the nonclinical evaluations needed to assess the safety of the new route can be costly and extensive. These evaluations are essential for assessing the toxicological potential of the drug when it is delivered in a new way. The extent of the evaluations need to be carefully considered prior to and during the development of the new delivery method.