Skip links

Advantages of the 505(b)(2) Pathway in Nonclinical Development

The 505(b)(2) new drug application (NDA) pathway can provide unique advantages from the nonclinical development perspective that can save significant time, money, and resources. Compared to the 505(b)(1) NDA pathway, which is more standardized and follows the general guidance provided by the International Conference on Harmonisation [1], the nonclinical development program under the 505(b)(2) pathway can be highly variable and dependent on the types of changes to the new drug product compared to the listed drug (LD) along with how robust the nonclinical database is for the LD.

FDA guidance provides general information and recommendations on the types of nonclinical studies that may be required for reformulated drug products and drug products administered by an alternate route. Although this guidance is very helpful, 505(b)(2) drug development programs may require more limited or more comprehensive nonclinical programs. The nonclinical requirements can be dependent on the drug product formulation, clinical indication, clinical population, specific FDA review division requirements, and other factors.

To illustrate the nuances in 505(b)(2) nonclinical development, below are examples of several specific changes to a drug product that qualify it for the 505(b)(2) pathway, along with nonclinical programs that were required to support the NDA. As a general concept, in addition to the specific considerations listed below, systemic and sometimes local exposure to the drug from the new drug product typically need to be equal to or less than exposure to the LD in order to rely on the nonclinical information in the LD-approved labeling.

Some examples of those drug product changes:

Different form of the drug substance (active ingredient)

If the LD is a racemic mixture and the new drug is a single enantiomer, comparative nonclinical toxicity testing is often required to ensure that the enantiomer does not exhibit greater toxicity than the racemic mixture. If the new drug is a different salt form of the LD, some salts (e.g., hydrochloride, sodium, potassium) may require no-to-limited nonclinical studies to support their safety, while others (e.g., strontium) can raise concerns with the agency and lead to targeted nonclinical studies to justify the safety of the salt itself. Furthermore, prodrugs often require nonclinical studies to demonstrate that the prodrug breaks down quickly and is not detected at appreciable levels systemically. Depending on the route of administration, local toxicity assessments may be required for prodrugs.

Excipient qualification

If the excipients in the new drug product are listed in the FDA’s Inactive Ingredient Database (IID) for the given route of exposure, and the amounts in the new drug product are at or below IID maximum potency levels, additional nonclinical qualification of the excipients is typically not required. However, if a given excipient is not listed in the IID, if it is listed but not for the new route of exposure, or if it is proposed to be dosed at levels higher than the maximum potency level in the IID, nonclinical testing will likely be needed to qualify the excipient. In addition, nonclinical studies may be needed if there were any unexpected or potential interactions between the excipients, degradants, and/or impurities. The nonclinical testing can range from including appropriate control groups in any new toxicity studies to a full nonclinical program to qualify the safety of the excipient as outlined in the FDA’s excipient guidance.

Changes in the route of administration

Changing the route of administration often requires nonclinical studies to demonstrate at least the local safety of the new route of administration. Systemic safety may also be required depending on differences with the LD (e.g., route-specific metabolic differences).

Different dosing regimen

Nonclinical testing may be needed if the clinical exposure for the new regimen is higher than the exposure for the LD dosing regimen. However, it may be possible to leverage existing toxicity studies, even if they did not use the new dosing regimen, since they often use a maximum tolerated dose or maximum feasible dose that may support different dosing regimens.

New clinical indication

When a new drug product has a new clinical indication and the route of exposure, dose, dosing regimen, and duration of use are similar for the new indication and the LD’s indication, no new nonclinical studies may be needed. However, if there are any differences from the approved indication (e.g., going from an acute to chronic dosing indication), nonclinical studies of appropriate duration would likely be required.

Overall, for a 505(b)(2) NDA, the nonclinical program is highly dependent on the drug product and requires extensive expertise and insight to understand the potential differences between the new drug and the LD that need to be addressed nonclinically. Furthermore, it requires accurate understanding of the 505(b)(2) pathway and strategic input when designing appropriate nonclinical programs that will meet applicable regulatory requirements and be accepted by the FDA to support IND-enabling initial clinical trials, ongoing clinical trials, and an eventual 505(b)(2) NDA.

To learn more about how Premier Consulting can assist with your nonclinical strategy, contact us.


William Salminen, PhD
Director of Scientific and Regulatory Affairs

[1] International Conference on Harmonisation (ICH): “Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2),” June 11, 2009.