The 505(b)(2) New Drug Application (NDA) pathway can provide unique advantages from the nonclinical development perspective that can save significant amounts of 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 Harmonization (ICH) M3, the nonclinical development program under the 505(b)(2) pathway can be highly variable and dependent on the types of changes of the new drug product compared to the Listed Drug (LD) along with how robust the nonclinical database is for the LD.
Previously, we have discussed the FDA guidance that 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 (link here). 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 upon the drug product formulation, clinical indication, clinical population, specific FDA review Division requirements, and other factors. Therefore, to help understand 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 needs to be equal to or less than exposure from the LD in order to rely upon the nonclinical information in the LD approved labeling.
Examples of 505(b)(2) Nonclinical Development
Different form of the drug substance (active ingredient)
If the LD is a racemic mixture and the new drug is a single enantiomer, then 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 none to limited nonclinical studies to support their safety; whereas, 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.
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, then additional nonclinical qualification of the excipients is typically not required. However, if a given excipient is not listed in the IID, or if it is listed in the IID 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 the 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 (MTD) or Maximum Feasible Dose (MFD) which 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, then 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), then nonclinical studies of appropriate duration would likely be required.
Overall, for a 505(b)(2) NDA, the nonclinical program is highly drug product-dependent and requires extensive expertise and insight to understand the potential differences between the new drug product 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 initial clinical trials (i.e., IND-enabling), ongoing clinical trials, and an eventual 505(b)(2) NDA.
If the reader is interested in seeing more real-world examples of 505(b)(2) nonclinical programs, a paper was recently published in Drug Discovery Today that provides a more comprehensive overview and examples of 505(b)(2) nonclinical development.
To learn more about ways Camargo can assist your program with nonclinical strategy, contact us.
Zhen Gao, PhD, Research Scientist, Camargo Pharmaceutical Services
William Salminen, PhD, Director of Scientific and Regulatory Affairs, Camargo Pharmaceutical Services
 International Conference on Harmonisation (ICH): “Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2)”, 11 June 2009.