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New Nonclinical Guidance for 505(b)(2) Products: No Cause for Alarm

On October 15, 2015, the United States Food and Drug Administration (FDA) issued a new guidance for industry and review staff with more uniform recommendations for the nonclinical safety evaluation of approved drug substances that are reformulated or in which a new route of administration is proposed for a previously approved drug product. These products, approved through the 505(b)(2) pathway, represent the third category of drug products that lie between the generics and innovative/new chemical entities.

This guidance assumes that the active pharmaceutical ingredient (API) or drug substance has already been used in a previously approved drug product. As this relates to submissions through the 505(b)(2) regulatory pathway, the guidance does not obviate the need to provide complete nonclinical information for the proposed drug product. However, this information can be provided directly via the scientific literature and/or study reports and/or by relying on the findings of safety and effectiveness for a listed drug (LD) and establishing a clinical bridge to that LD. Consequently the recommendations in this guidance do not necessarily mean that additional studies beyond those scientifically justified or recommended in the International Conference on Harmonisation (ICH) guidances M3(R2) or ICH S9 would be required. Keep in mind, one of the stated goals of this guidance is to increase uniformity among all the divisions within the Center for Drug Evaluation and Research (CDER) on recommendations for the nonclinical development of these types of drug products.

In general, the nonclinical data used to support the approval of the initial formulation may be utilized to support the safety of a new formulation, but in some cases additional data may be needed to fully characterize the toxicity/safety of the new formulation or new route of administration. Sometimes the data that were adequate to support previously approved drug or LD are not adequate by current standards prompting the need for additional studies.

Specific considerations addressed in this guidance include those related to systemic toxicity and route of administration. Some of the recommendations are rather intuitive and are just good common sense.  For example, a change in formulation or route can change the pharmacokinetics of the API. So it follows that additional toxicity studies may be required to support the exposure that results from the new formulation or route. The guidance then provides a delineation of route-specific studies that may be required which are dependent on factors like systemic and local exposure, duration of treatment, and possible interactions with environmental conditions (eg, sunlight). Toxicology studies that will be used to support the clinical investigations of a new drug product should be conducted in accordance with good laboratory practice (GLP) regulations (see 21 CFR part 58).

Finally, this guidance does not fully address the complete nonclinical safety evaluation that may be required for a novel excipient being used in a reformulation. For complete recommendations one would want to consult the guidance for industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients.

In some cases, regulatory strategy is not vigorously addressed until the time for filing an Investigative New Drug (IND) application. Unfortunately at this point, data deficiencies that could be potential clinical hold issues are not identified until late in the development process. Likewise, a checkbox mentality towards the development process might have lead to the conduct of studies that were largely unnecessary. The potential nonclinical impact that a change in formulation or route of administration may have on the drug development program is just one more reason why one should think about the regulatory pathway and engage a regulatory strategist early in the drug development process.