The US Food and Drug Administration (FDA) does not formerly recognize non-biological complex drugs (NBCDs), with originators required to follow the new drug application (NDA) route and follow-on NBCDs using the generics – abbreviated new drug application (ANDA) – route .
However, like biologicals, NBCDs consist of different (closely related) structures that cannot be fully quantitated, characterized or described by (physico-)chemical analytical tools. The composition and quality of NBCDs are dependent on the manufacturing process and controls – just as is the case with biologicals. Therefore, approval of follow-on NBCDs via generics pathways may not be appropriate and use of biosimilars pathways for non-biologicals is also not appropriate.
In an effort to address this situation, on 24 March 2015, Michael Burgess a former physician and member of the House Energy and Commerce Committee introduced to Congress the Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015. The bill (H.R.1576) aims to investigate whether a new pathway – like that for biosimilars – needs to be introduced for complex drugs.
If passed, the bill would require the Government Accountability Office (GAO), and specifically the Comptroller General of the United States, to conduct a study to determine whether follow-on NBCDs can still be approved via the generic route or if they should follow the biologicals route. Experts believe they are more complex than generics, but less complex than biosimilars, possibly making both routes obsolete and highlighting the need for a specific route for these complex molecules.
The bill asks the GAO to take a critical look at FDA’s ‘current regulatory pathway for reviewing generic versions’ of NBCDs. Just some of the issues the GAO is being asked to look at include:
• What degree of characterization of the proposed generic version and the reference product should be required in order to determine the safety and effectiveness of the generic version.
• What degree of similarity should be required to deem that the active ingredient of the proposed generic version is the same as the active ingredient of the reference product.
• What types of evidence should be required to demonstrate that the proposed generic version is bioequivalent to the reference product.
• What requirements should be established with respect to the comparability of the manufacturing process for the proposed generic version and the manufacturing process for the reference product.
• Whether and to what extent clinical evidence is needed to demonstrate that there is no difference in immunogenicity between the proposed generic version and the reference product.
• Whether and to what extent other clinical evidence is needed to demonstrate that the proposed generic version is as safe and effective for patients as the reference product.
The GAO has a 2-year period from the passing of the bill within which to complete its study.
EU guidelines for follow-on NBCDs
1. GaBI Online – Generics and Biosimilars Initiative. Regulations for follow-on NBCDs [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 May 27]. Available from: www.gabionline.net/Non-Biological-Complex-Drugs/Reports/Regulations-for-follow-on-NBCDs