FDA Guidance: Nonclinical Safety Evaluation of Reformulated Drug Products & Products Intended for Administration by an Alternate Route

October 29, 2015

Published on October 27, 2015, the guidance document outlines a number of recommendations for the nonclinical evaluation of previously approved drug substances when a new formulation or a new route of administration for a previously approved formulation is proposed by the sponsor. The guidance was published for those who are “involved in the development and review of new formulations of previously approved drug substances and proposals for existing formulations to be used by a new route of administration.”

The goals of the guidance are for FDA to:

  1. “Communicate to industry the FDA’s current thinking pertaining to safety data needed to support approval of these drug products.
  2. Increase uniformity within CDER on recommendations for the nonclinical development of reformulated drug products and products being used by an alternate route.”

Additionally, the Agency states that the guidance does not:

  • Excuse sponsors from providing nonclinical information that is required for drug products.
  • Fully address the complete safety evaluation necessary for excipients that are being used in a new formulation but have never before been used in an FDA-approved product.

Overview of Nonclinical Data

Nonclinical data is typically used to support the use of a drug product by a particular route of administration and reflects the planned duration of use. Frequently, the nonclinical data used in the approval of the initial formulation of a drug can also be used to support the safety of new formulations. However, this does not always work according to plan.

If a sponsor is introducing a new formulation that will be used in a different way than the initial product, the original information is not always sufficient to support the approval. According to FDA, “this is particularly true if the drug product’s route of administration is different or the duration of use changes markedly.” Sponsors may be required to prove that the toxicity of the new formulation remains fully characterized, in which case further nonclinical studies may be needed. In general, the more significant the difference(s) (e.g. new route, longer duration, etc.) between the new and initial formulations, the greater the chance that additional nonclinical data will be required.

The guidance provides sponsors with various general considerations as well as systemic toxicity and route of administration considerations, including:

General Considerations

FDA assumes that the safety evaluation of previously approved drug products was conducted in compliance with current standards. If not, this change may trigger the need for additional studies in order to address any deficiencies that may exist.

Toxicity information should be reviewed and sponsors should determine whether or not the existing data supports the suggested clinical use of the new formulation or new route of administration. FDA also recommends that sponsors and FDA’s reviewing division consult the following ICH guidances:

These guidances provide detailed information regarding the time frame in which to submit nonclinical data relative to clinical development and can be helpful to all parties involved.

Systemic Toxicity Considerations

According to FDA guidance, “the adequacy of the available systemic toxicity information should be evaluated based on a comparison of the systemic exposure obtained after administration of a proposed new formulation to the systemic exposure with use of the previously approved formulation.”

Information regarding the pharmacokinetics and absorption, distribution, metabolism, and elimination (PK/ADME) of the drug, in combination with any available human data, can be helpful in determining the additional nonclinical toxicity data is needed. As such, FDA recommends that the data is evaluated thoroughly. FDA also advises sponsors to examine the shape of the concentration/time curve in addition to the total area under the curve when conducting the PK/ADME comparison, and states that if the information for the new formulation or route is not available, simply assuming 100% bioavailability might be used to judge the adequacy.

Route of Administration Considerations

In addition to the considerations provided above, FDA says that the possible toxic effects of a particular route of administration should also be considered. A number of recommendations are provided, which are broken down into two categories:

  1. Considerations for All Routes of Administration
  2. Route-Specific Considerations

The Agency provides a number of recommendations for both, listing each possible route of administration and provides various considerations for each one. For more details view the guidance here.

Are you in the process of developing a drug that may be subject to the guidelines provided in the Agency’s recent draft guidance? We can help you achieve successful interactions with the Agency and get your product approved by the FDA. Contact us today to learn more about our services and how we can be of assistance to you.


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