Equivalence of complex drug products: advances in and challenges for current regulatory frameworks

Hussaarts, L.; Mühlebach, Stefan; Shah, Vinod P.; McNeil, Scott E.; Borchard, Gerrit; Flühmann, Beat; Weinstein, Vera; Neervannan, Sesha; Griffiths, Elwyn; Jiang, Wenlei; Wolff-Holz, Elena; Crommelin, Daan J.A.; Vlieger, Jon S. B. de

doi:10.1111/nyas.13347

Cited by 68 publications

(57 citation statements)

References 30 publications

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“…First, as explained in a recent publication coauthored by industry scientists, academic researchers, and regulators (including the FDA), the science is not advanced enough to adequately identify relevant CQAs that must be assessed to ensure the safety of a generic (7). Most nanomaterial-containing drug products do not consist of a homo-molecular pharmaceutical moiety, as multiple parts of the drug directly affect the treatment outcome.…”

Section: The Active Ingredients In Such Drug Products Arementioning

confidence: 99%

Reflections on FDA Draft Guidance for Products Containing Nanomaterials: Is the Abbreviated New Drug Application (ANDA) a Suitable Pathway for Nanomedicines?

Marden

Ntai

Bass

et al. 2018

AAPS J

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Abstract.The US Food and Drug Administration (FDA) recently released a draft guidance for industry titled BDrug Products, Including Biological Products, that Contain Nanomaterials.^The FDA's attention to the unique safety and efficacy aspects of drugs containing nanomaterials is commendable. This Draft Guidance succeeds in acknowledging the complexity of these products, as well as the challenges associated with approving safe and therapeutically equivalent complex generic versions. However, the challenge posed by the manufacturing process for drugs containing nanomaterials is insufficiently addressed. The critical quality attributes of such products cannot be properly defined, and therefore it is not possible to design informative comparative physicochemical assessments for equivalence. As a consequence, the 505(j) Abbreviated New Drug Application (ANDA) pathway, currently advised as the standard from the FDA, is not suitable for the approval of complex generic products. Drawing from the successful story of biologics, we propose instead a stepwise totality-of-evidence approach, demonstrating similarity and including clinical studies when deemed necessary, as an appropriate alternative to the 505(j) ANDA pathway.

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Section: The Active Ingredients In Such Drug Products Arementioning

confidence: 99%

Reflections on FDA Draft Guidance for Products Containing Nanomaterials: Is the Abbreviated New Drug Application (ANDA) a Suitable Pathway for Nanomedicines?

Marden

Ntai

Bass

et al. 2018

AAPS J

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“…Considering the significantly different pharmacokinetic profiles of different iron-carbohydrate complexes ( Table 1), these drugs are obviously not bioequivalent. 69 For conventional low-molecular-weight drugs that can be fully characterized (orange), demonstration of PE and BE is relatively simple. iron complexes, higher molecular weight (FCM vs. SFG and IS) correlates with longer terminal half-life.…”

Section: Differences In Efficacy and Tolerability Between Originator mentioning

confidence: 99%

“…For non-dextran-based i.v. The classification of some NBCDs such as albumin-bound nanoparticles and low-molecular-weight heparins (blue with a green outline) varies across different countries (figure reproduced from Hussaarts et al 69 ). Dextran/dextran-based complexes do not show such a correlation, having relatively long terminal half-lives regardless of molecular weight.…”

Section: Differences In Efficacy and Tolerability Between Originator mentioning

confidence: 99%

“…69,72,78,79 Thus, it has been suggested that for the marketing authorizations of NBCD follow-on products, similar requirements as for biosimilars and a stepwise approach should be used. 69,72,78,79 Thus, it has been suggested that for the marketing authorizations of NBCD follow-on products, similar requirements as for biosimilars and a stepwise approach should be used.…”

Section: Regulatory Considerations Of Intravenous Iron Products In Thmentioning

confidence: 99%

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Differences between intravenous iron products: focus on treatment of iron deficiency in chronic heart failure patients

et al. 2019

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Iron deficiency is the leading cause of anaemia and is highly prevalent in patients with chronic heart failure (CHF). Iron deficiency, with or without anaemia, can be corrected with intravenous (i.v.) iron therapy. In heart failure patients, iron status screening, diagnosis, and treatment of iron deficiency with ferric carboxymaltose are recommended by the 2016 European Society of Cardiology guidelines, based on results of two randomized controlled trials in CHF patients with iron deficiency. All i.v. iron complexes consist of a polynuclear Fe(III)‐oxyhydroxide/oxide core that is stabilized with a compound‐specific carbohydrate, which strongly influences their physico‐chemical properties (e.g. molecular weight distribution, complex stability, and labile iron content). Thus, the carbohydrate determines the metabolic fate of the complex, affecting its pharmacokinetic/pharmacodynamic profile and interactions with the innate immune system. Accordingly, i.v. iron products belong to the new class of non‐biological complex drugs for which regulatory authorities recognized the need for more detailed characterization by orthogonal methods, particularly when assessing generic/follow‐on products. Evaluation of published clinical and non‐clinical studies with different i.v. iron products in this review suggests that study results obtained with one i.v. iron product should not be assumed to be equivalent to other i.v. iron products that lack comparable study data in CHF. Without head‐to‐head clinical studies proving the therapeutic equivalence of other i.v. iron products with ferric carboxymaltose, in the highly vulnerable population of heart failure patients, extrapolation of results and substitution with a different i.v. iron product is not recommended.

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“…Biologicals, referred to as biologics in some countries, are the prime example of complex medicinal products. However, there are also nonbiological complex products, such as iron–carbohydrate drugs, liposomal drugs, glatyramoids, and, most recently, nanomedicines, and discussions are currently ongoing regarding the regulatory oversight of all these medicines and especially their subsequent or follow‐on versions, as exemplified by a meeting held at the New York Academy of Sciences in November 2016 . While the regulatory pathway for authorization of generic versions of small molecule drugs has been well established, guidance on the regulatory oversight of complex drug products is still evolving.…”

Section: Introductionmentioning

confidence: 99%

WHO standards for biotherapeutics, including biosimilars: an example of the evaluation of complex biological products

Knežević

Griffiths²

2017

Annals of the New York Academy of Sciences

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The most advanced regulatory processes for complex biological products have been put in place in many countries to provide appropriate regulatory oversight of biotherapeutic products in general, and similar biotherapeutics in particular. This process is still ongoing and requires regular updates to national regulatory requirements in line with scientific developments and up-to-date standards. For this purpose, strong knowledge of and expertise in evaluating biotherapeutics in general and similar biotherapeutic products, also called biosimilars, in particular is essential. Here, we discuss the World Health Organization's international standard-setting role in the regulatory evaluation of recombinant DNA-derived biotherapeutic products, including biosimilars, and provide examples that may serve as models for moving forward with nonbiological complex medicinal products. A number of scientific challenges and regulatory considerations imposed by the advent of biosimilars are described, together with the lessons learned, to stimulate future discussions on this topic. In addition, the experiences of facilitating the implementation of guiding principles for evaluation of similar biotherapeutic products into regulatory and manufacturers' practices in various countries over the past 10 years are briefly explained, with the aim of promoting further developments and regulatory convergence of complex biological and nonbiological products.

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Equivalence of complex drug products: advances in and challenges for current regulatory frameworks

Cited by 68 publications

References 30 publications

Reflections on FDA Draft Guidance for Products Containing Nanomaterials: Is the Abbreviated New Drug Application (ANDA) a Suitable Pathway for Nanomedicines?

Reflections on FDA Draft Guidance for Products Containing Nanomaterials: Is the Abbreviated New Drug Application (ANDA) a Suitable Pathway for Nanomedicines?

Differences between intravenous iron products: focus on treatment of iron deficiency in chronic heart failure patients

WHO standards for biotherapeutics, including biosimilars: an example of the evaluation of complex biological products

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