(M1430-02-07) An Overview of Cross-Referencing Approaches to Support Generic Drug Approval

Purpose: In certain cases, an Abbreviated New Drug Application (ANDA) applicant may cross-reference in vivo bioequivalence (BE) studies submitted in another ANDA to support BE for its generic drug application. This study aims to elucidate the regulatory scenarios where such a cross-referencing approach may be applicable and to provide an overview of the related scientific considerations and supporting data from a BE perspective. It is important to note that there may be product quality as well as regulatory considerations for the acceptability of a cross-referencing approach which are not covered in this study.

Methods: A survey was conducted on the Agency’s Product Specific Guidance (PSG) database  to identify drug products for which a recommendation of a cross-referencing approach is available. Additionally, the Agency’s internal databases were examined to identify regulatory scenarios where a cross-referencing approach was applied. The analysis was focused on the underlying regulatory contexts, scientific considerations, and BE data necessary to support the application of a cross-referencing approach in regulatory submissions.

Results: As of March 2024, recommendations related to a cross-referencing approach were found in 23 PSGs and the application of this approach was found in 78 approved ANDAs. Our findings indicated that cross-referencing approaches to support BE in ANDAs can be broadly categorized into the following scenarios: (1) Prescription (Rx) to Over-the-Counter (OTC) Switch: The change in marketing status of a drug product from prescription to non-prescription is referred to as an ‘Rx-to-OTC switch.’ When there is an Rx-to-OTC switch, an ANDA applicant referencing the OTC Reference Listed Drug (RLD) may cross-reference the in vivo BE studies submitted in its corresponding Rx ANDA (i.e., its ANDA referencing the Rx RLD) provided that the Rx and OTC generic products: (i) have the same formulation composition (when same strength) or proportionally similar formulation compositions (in case of different strengths); and (ii) have comparable dissolution profiles. This scenario is depicted in Figure 1. (2) Sister Applications: Sister applications refer to submissions by the same applicant for the same drug, in the same dosage form, in the same or different strengths, with each application having a distinct RLD. For sister ANDAs, an applicant may submit the recommended in vivo BE studies in one ANDA and cross-reference those studies in its corresponding sister ANDA, provided that the drug products of the two ANDAs share the same formulation (when same strength) or proportionally similar formulations (in case of different strengths) and exhibit comparable dissolution profiles. This scenario is depicted in Figure 2. (3) Co-packaged Drugs: A co-packaged drug product consists of two or more separate drugs in their final dosage forms that are intended to be used together for a common or related therapeutic purpose and contained in a single package or unit. Generally, an applicant should demonstrate that the individual drugs in a generic co-packaged product are bioequivalent to the respective individual drugs of the co-packaged RLD product. However, if the co-packaged RLD product consists of approved individual drug products, then the applicant of the corresponding co-packaged ANDA may adopt the same approach (i.e., co-package approved individual generic drug products). When an ANDA is a co-package of approved generics, it may be possible for the co-package ANDA applicant to cross-reference the in vivo BE studies from the ANDAs under which the individual generic products were previously approved. This scenario is depicted in Figure 3.

Conclusion: Based on the survey of PSGs and the Agency’s internal databases, the cross-referencing approaches used in generic drug applications can be broadly classified into three categories. This high-level overview of the cross-referencing approaches describes additional options to facilitate generic drug development, as well as a means to reduce unnecessary human testing. When using a cross-referencing approach in an ANDA, applicants should consider the following factors: (i) For any drug product, refer to the PSG first to determine the applicability of a cross-referencing approach. If not stated in the PSG, the ANDA applicant may submit a controlled correspondence to the Agency requesting feedback on the proposed cross-referencing approach. (ii) In the cross-referencing scenarios discussed above, the products of the cross-referenced ANDAs, if and as applicable, should have the same manufacturing process, controls, and quality standards. (iii) The final acceptability of a cross-referencing approach in an ANDA is a review issue.

References: 1 https://www.accessdata.fda.gov/scripts/cder/psg/index.cfm
2 https://www.fda.gov/drugs/drug-application-process-nonprescription-drugs/prescription-nonprescription-rx-otc-switches
3 https://www.federalregister.gov/documents/2015/12/23/2015-32246/fixed-combination-and-co-packaged-drugs-applications-for-approval-and-combinations-of-active#:~:text=4.-,Co%2DPackaged%20Drug,a%20single%20package%20or%20unit

Acknowledgements: The abstract reflects the views of the authors and should not be construed to represent FDA's views or policies.

Figure 1: Cross-Referencing Approach in Rx-to-OTC Switch


Figure 2: Cross-Referencing Approach in Sister Applications


Figure 3: Cross-Referencing Approach in Co-Packaged Drug Products