Messy Rules For Non‐Biological Complex Drugs Under Fire
Executive Summary
Calls are mounting for the EU to make the centralized procedure mandatory for follow-on versions of non‐biological complex drugs and for better regulatory alignment with the US and other countries.
Pressure is building on the EU to reform the way in which follow-on versions of non‐biological complex drugs are regulated throughout Europe, where approaches for authorizing NBCDs lack consistency and among other things could introduce unpredictability for manufacturers.
The number of follow-on NBCDs is expected to surge in the coming years as market exclusivities start expiring for more originator products.
There is still no formal authorization framework for originator or follow-on NBCDs in Europe and this needs to change, according to speakers at last month’s Regulatory Affairs Professionals Society (RAPS) 2019 Europe conference in Brussels.
The current situation whereby marketing applications for follow-on NBCDs are mostly submitted to national regulatory agencies for review and approval under any one of Europe’s non-centralized procedures is not good enough, said Pieter Stolk and Bert Leufkens.
It can lead to heterogeneity in the regulatory approach, involve different evidence requirements, and result in varying outcomes when assessing these drugs, Stolk and Leufkens warned. For some product classes this has already resulted in safety and efficacy implications, they said.
The EU centralized approval procedure should be made mandatory for complex products such as NBCDs, nanosimilars and their follow-on versions, said Stolk, a program manager at Lygature, a not-for-profit organization that aims to accelerate the development of new medical solutions by driving public-private collaboration between academia, industry and society.
“We will see more NBCD products [of] increasing complexities,” added Leufkens, who for a decade chaired the Medicines Evaluation Board in the Netherland and is now a professor at Utrecht University and a member of the Scientific Leadership Team at Lygature. The pressure for regulatory consistency and predictability for these drugs is increasing, he said.
Stolk and Leufkens also warned that the problem of inconsistent regulatory approaches for NBCDs was not exclusive to Europe. For example, there are also inconsistencies in the US, they said, adding that there was also a need for better regulatory alignment at the global level.
The pair have published a study to help support their case.
First Of A Kind Findings
NBCDs include liposomal formulations, iron sucrose and glatiramoids and are more similar to biologics than they are to small molecule drugs, Stolk said. The products are complex, heterogeneous, dependent on robust and well-controlled manufacturing processes, and it is very challenging to ensure the creation of identical copy versions, he explained.
Unlike originator biologics and biosimilars, for which consistent regulatory pathways exist, NBCDs and their follow-on products are not recognized as a distinct category of medicines and there is no rule that they have to be evaluated via a particular authorization procedure.
A study by Stolk, Leufkens and colleagues recently highlighted the lack of regulatory consistency when it comes to the approval of follow-on NBCDs in Europe. The study, published in the May issue of the European Journal of Pharmaceutical Sciences, for the first time explored which follow-on products were approved in the EU as of 2018 and which regulatory pathways were involved for individual NBCD products, and NBCD classes.
It found that as of November 2018, a total of 85 NBCD follow-on products were available in the EU. Of these, 83 were authorized via a non-centralized procedure – mostly through the decentralized procedure (DCP), followed by national procedures and, to a lesser extent and in particular for “older” products, the mutual recognition procedure (MRP). Two products were approved via the centralized procedure, having been reviewed by the European Medicines Agency. There were also three informed consent applications from innovator companies of glatiramer acetate and sevelamer carbonate, shortly after the approval of the first follow-on versions.
By contrast, of the 25 originator NBCDs that were found to be approved in the EU, 11 were authorized through the centralized procedure, nine through national procedures, six through the MRP and two through the DCP.
The study also found that the follow-on products were approved via one of Europe’s three different abridged application procedures, which can involve different evidence requirements. Some 48 follow-on NBCDs were approved via the generic application procedure (Article 10(1) of Directive 2001/83/EC), 32 were authorized via the hybrid application procedure (Article 10(3)), and five enoxaparin follow-on versions were approved via the biosimilar application procedure (Article 10(4)).
“The observed heterogeneity carries the risk of lack of predictability for NBCD developers and many other uncertainties for stakeholders,” the study authors said.
Regulators in Europe use a “case-by-case” approach to assess follow-on NBCDs, Leufkens observed. While using such an approach is “not essentially wrong,” it could lead to differences in the rigorousness of regulating these products, depending on the competent authority approached.
There is “a clear lack of convergence” that makes it challenging to guarantee a “sustainable systems approach,” Leufkens said.
The extent to which the different regulatory approaches might impact safety and efficacy evaluations is “unknown and needs to be further investigated,” said the study authors. “However, the experience with iron sucrose follow-on products and the recently observed compositional differences within the glatiramoid product class highlight the public health relevance and importance to further evaluate the present regulatory system in the EU for NBCDs.”
Another finding from the study relates to hybrid/biosimilars pathways. According to Leufkens, these involve higher product development costs and are being increasingly used for follow-on NBCDs, driven by certain products, including glatiramer and sevelamer.
The study says the approval of the iron sucrose follow-on product Sucrofer via the hybrid application procedure in June 2018, in contrast to earlier approvals via the generic pathway, was a particularly interesting example that illustrates an apparent change in the regulatory approach for approving NBCD follow-on products.
A more consistent approach for regulating NBCDs in the EU could be achieved by building on the EMA guidance documents on nanomedicines and providing an outline on appropriate regulatory pathways for specific NBCD product classes (eg, generic or hybrid application), Leufkens said.
A mandatory centralized pathway should also be considered, he added. “Like biotechnology-derived products or advanced therapy medicinal products, NBCDs could also benefit from a mandatory centralized procedure, as this will guarantee consistency in the scientific evaluation of follow-on products.”
Another benefit of the centralized procedure would be the guarantee of centralized safety monitoring and the obligation for the use of a single brand name throughout the EU.
Call For Global Alignment
As for the need for global alignment for follow-on NBCDs, Stolk gave the RAPS conference delegates examples of such products where requirements in the US and the EU differed.
For instance, he said, Momenta Pharmaceuticals’ Glatopa (glatiramer acetate injection) was approved by the US Food and Drug Administration in 2015 via a generics application based on sameness defined by the FDA, without clinical studies. Meanwhile, the EMA approved Synthon’s glatiramer acetate in 2016 via a hybrid application that included one Phase III study.
In addition, the Stolk and Leufkens study noted that the US Government Accountability Office had previously published a report showing that the unclarity and inconsistency of the regulatory approach for NBCDs in the country could create setbacks for generic drug developers and therefore could delay or prevent the introduction of much needed equivalent follow-on products.
“Since the GAO report was published, the FDA has released a number of product specific guidance documents on NBCD products,” Stolk told the Pink Sheet. The fact remains, however, that “it’s a case-by-case approach that does not yet seem to lead to an overarching solution based on scientific discussions amongst stakeholders and other regulatory agencies.”
As for the future, the EMA, for its part, mentions complex generic medicines in its Regulatory Science to 2025 strategic reflection document. It says there is a need to support international harmonization of regulatory science standards for complex generic medicines addressing bioequivalence, waivers and modeling.
This recognition by the agency “is to be applauded since it may prevent additional global divergence in the evaluation of these complex generic medicinal products,” Stolk said.
He noted that Lygature manages a Non-Biological Complex Drugs Working Group that was jointly established by a number of organizations in 2009 to stimulate discussion on the safety and efficacy of NBCD innovation and follow-on products.