Equivalence of complex drug products

Non‐Biological Complex Drugs/Reports | Posted 14/04/2017 post-comment0 Post your comment

Complex drug products and their generic (or follow-on) versions was the subject discussed at the New York Academy of Sciences symposium on Equivalence of Complex Drug Products: Scientific and Regulatory Challenges [1].


According to the Association for Accessible Medicine (AAM), formerly known as the Generic Pharmaceutical Association (GPhA), almost 90% of prescriptions in the US in 2015 were for generics. However, despite this success rate there are certain complex drug product categories, where the regulatory pathways for the introduction of generic (or follow-on) versions are under debate.

One of the main reasons for this debate is that demonstrating the therapeutic equivalence of generic complex drugs (of which many are follow-on non-biological complex drugs; follow-on NBCDs) to their brand-name counterparts has unique challenges not encountered with small, low molecular weight molecules in conventional dosage forms. This may be due to the fact that the active components of complex drugs are unknown, as are the critical attributes, i.e. the physical and chemical characteristics essential for efficacy and safety. Complex drugs are also difficult to fully characterize, and the products are very sensitive to changes in manufacturing, which is often proprietary.

Speakers present at the symposium spoke on various subjects including regulatory issues for follow-on versions of non-biological complex drugs, approaches to evaluate the equivalence of complex drugs and technical challenges to characterize complex drugs. In addition, presentations on the approval process for follow-on versions of doxorubicin-liposomes, glatiramer acetate and iron sucrose were also part of the programme.

Contributors related to the US Food and Drug Administration (FDA) explained complex drugs as those having complex active ingredients such as peptides, polymers, or complex mixtures; complex formulations and/or dosages such as liposomes, iron colloids, and long-acting injectables; complex routes of delivery such as locally acting drugs, ophthalmic drugs, suspensions, emulsions and gels; and/or complex drug-device combinations such as nasal sprays and inhalers.

In this definition of complex drug products FDA excludes biologicals. Also, the agency does not formerly recognize NBCDs. It requires originators to follow the new drug application (NDA) route and follow-on NBCDs to use the generics – abbreviated new drug application (ANDA) – route. It has, however, issued draft guidance documents for certain NBCD families, e.g. liposomes, different iron carbohydrates (iron sucrose, iron gluconate, ferumoxytol) and cyclosporine ophthalmic emulsions [2].

FDA has recognized the challenges associated with complex drug products and has included among its key provisions in the Generic Drug User Fee Amendments Reauthorization (GDUFA II) ‘meetings for complex products’ [3]. In this context, the agency has recently published a request for input in the Federal Register [4] and has announced a public workshop on 3 May 2017.

Related articles
Regulations for follow-on NBCDs

Status and regulatory issues surrounding follow-on NBCDs

1. The New York Academy of Sciences. Equivalence of complex drug products: scientific and regulatory challenges. 9 November 2016; New York, USA.
2. GaBI Online - Generics and Biosimilars Initiative. US guidelines for follow-on NBCDs [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Apr 14]. Available from: www.gabionline.net/Non-Biological-Complex-Drugs/Guidelines/US-guidelines-for-follow-on-NBCDs
3. GaBI Online - Generics and Biosimilars Initiative. FDA and industry agree on terms of GDUFA II reauthorization [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Apr 14]. Available from: www.gabionline.net/Policies-Legislation/FDA-and-industry-agree-on-terms-of-GDUFA-II-reauthorization
4. Federal Register. Generic Drug User Fee Amendments of 2012; Regulatory Science Initiatives; Public Workshop; Request for Comments; [cited 2017 Apr 14]. Available from: www.federalregister.gov/documents/2017/03/14/2017-04981/generic-drug-user-fee-      amendments-of-2012-regulatory-science-initiatives-public-workshop-request-for

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