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

February 7, 2017

In October 2015, the FDA published a guidance document which outlines its recommendations regarding “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.”  In developing the guidance, entitled “Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route,” the Agency set out to accomplish the following goals:

  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.”


Typically, nonclinical data is used by sponsors to support the use of a drug by a particular route of administration, as well as the planned duration of use.  In a lot of cases, the nonclinical data used to support the approval of an initial formulation can also be used to support the safety of new formulation.  However, there are some situations where “these data may not be sufficient to support additional approvals because changes in the formulation could produce a new toxicity or more commonly because the new formulation will be used in a different way.”  Furthermore, FDA notes that “this is particularly true if the drug product’s route of administration is different or the duration of use changes markedly.”  In such circumstances, FDA may recommend that additional nonclinical studies be conducted to guarantee the toxicity of the new formulation is fully characterized.

The amount of additional data that is needed depends on the differences between the original and the new formulations.  As such, the Agency states that if the new formulation will be used similarly to the initial formulation, only a limited amount of additional nonclinical data will be needed.  However, if there are substantial differences between the formulations (e.g., new route, longer duration), “the need for additional nonclinical data becomes greater and additional nonclinical information may be needed even if no change is made in the composition of the formulation.”

FDA Recommendations & Considerations

General Considerations

FDA notes that the recommendations provided in its guidance “assume that the nonclinical evaluations of the previously approved drug products were adequate by current standards. If this is not the case, and the change in formulation or route of administration triggers the need for additional studies, then additional nonclinical studies might be recommended to address any preexisting deficiencies.”

FDA also advises sponsors to review any available toxicity information to determine whether it supports the proposed clinical use of the new formulation or new route of administration.  Furthermore, FDA recommends that sponsors refer to the ICH guidances (M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals or S9 Nonclinical Evaluation for Anticancer Pharmaceuticals) and consult the appropriate review division concerning when the nonclinical data should be submitted relative to clinical development.

Systemic Toxicity Considerations

All routes of administration can result in systemic exposure.  As such, FDA states that “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.”

Additionally, changes in the formulation can alter the pharmacokinetics of an active ingredient.  As such, if the available toxicity information is not sufficient, additional toxicity studies may be needed to “support the exposure associated with the new formulation or route or if a significantly different pattern of exposure results from the new formulation or route.”

When developing a new formulation, FDA recommends that sponsors evaluate the pharmacokinetics and absorption, distribution, metabolism, and elimination (PK/ADME) of the product.  Evaluating the PK/ADME data, as well as any human data that is available, can help sponsors determine what, if any, additional nonclinical toxicity data is needed.

Route of Administration Considerations

It is important that sponsors consider the possible toxic effects relevant to the particular route of administration.  When a new formulation has a new route of administration, information on toxic effects from the initial formulation may not be sufficient.  In addition, FDA notes that “even reformulations that do not change the route of administration might have local toxic effects not previously observed, because new combinations of active and inactive ingredients can produce additive or new effects.”

The guidance document provides additional general and route-specific recommendations.  For more information, view the FDA’s full guidance document.

This guidance contains a plethora of important information concerning what nonclinical data is needed to support the approval of a reformulated drug product, making it a critical for sponsors and industry professionals.  This guidance document is essential for sponsors when developing a new formulation of a previously approved drug, making it a must-have on our list of important guidance documents.

Ensuring that you have conducted all the necessary studies and collected all the required data can be a challenging and daunting task.  However, if done incorrectly or incompletely, it could end up costing you an extraordinary amount of time and money – two things that many of us cannot afford to lose.  Sometimes the high-cost of making a mistake is impossible to avoid, but in this case, it is not.  We can help ensure that your submission meets all of FDA’s requirements, helping you obtain the Agency’s approval in less time.  We have a proven track-record of helping our clients achieve a successful interaction with the FDA and we are qualified and capable of doing the same for your company.  To learn more about our services and how we can help you, contact us today.


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