Introduction

The Centre for Drug Evaluation (CDE) – the technical review body under the China Food and Drug Administration (CFDA) – released the Technical Guideline for the Research, Development and Evaluation of Biosimilars (Tentative) on February 28 2015. This long-awaited guideline outlines the regulatory framework for biosimilars, aiming to address clinical needs for biologics in China by improving the accessibility and affordability of innovative products. Both domestic and foreign biologics manufacturers have been closely following the guideline and its implementation, as it presents an alternative option for launching biologics in China.

The newly released guideline sets out:

  • the definition of 'biosimilars' and their reference products;
  • the basic principles underlying the technical review;
  • the criteria for comparability; and
  • the conditions under which extrapolations of indications are permissible.

Pursuant to the guideline, a biosimilar drug should in principle have the same amino acid sequence as the reference product. Similarly to the US and EU regulatory authorities, the CDE expects a detailed structural and functional characterisation of the biosimilar drug when comparing it to the reference product. The CDE also takes a similar step-wise approach to examine comparability through comparative pharmacology data, non-clinical studies and clinical studies.

Differences from US and EU regimes

Despite sharing the same principles for technical reviews, the guideline presents notable differences from the US and EU regimes. First, biosimilars are not assigned to a separate abbreviated approval pathway in China; rather, they are subject to the same approval pathway as that used for innovative biologics. Second, the CDE does not accept an innovative biologic approved by foreign regulatory authorities as a reference product. The reference product can be pending for CFDA approval during early stages of the biosimilar development process, but must be approved by the CFDA when comparative clinical studies are conducted. Finally, first-to-market biosimilars are not entitled to regulatory exclusivity in China. These differences are elaborated in the comparative overview below.

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Overall regulatory approach

The guideline serves as standalone technical guidance; it is not derived from any overarching law (eg, the Drug Administration Law) or regulations (eg, the Drug Registration Rules). As technical guidance, it cannot address several fundamental issues for the administration of biosimilars in the absence of clear legislative authorisation (eg, interchangeability with the reference product, naming rules and labelling requirements). These issues will need to be addressed by law or regulations. Further, the CDE has not substantiated the guideline with detailed guidance specific to the stages of biosimilar development or product categories.

In comparison, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) both regulate biosimilars with a combination of legislation, regulations and technical guidance. The technical guidance documents address each of the major product categories and each stage of the biosimilar development process. The US Biologics Price Competition and Innovation Act 2009 creates an abbreviated licensure pathway for biosimilars in the United States. From 2012 to 2015 the US FDA published seven guidance documents (both final and draft) to implement the law, covering the scientific and quality considerations in demonstrating comparability as well as several procedural issues (eg, exclusivity).

Approval pathway

Other than creating a set of technical review principles which differ from those applicable to innovative biologics, the guideline does not create a separate pathway for biosimilars, due to the absence of legislative authorisation. Biosimilars are essentially subject to the same approval pathway as that used for innovative biologics, albeit with a different set of data requirements. Companies must mark in their investigational new drug applications and new drug applications that submissions are intended to be reviewed as biosimilars.

In the European Union and the United States, biosimilars are entitled to an abbreviated approval pathway. For example, the US Biologics Price Competition and Innovation Act creates an abbreviated licensure pathway for biosimilars under Section 351(k) of the Public Health Service Act. A biosimilar may rely on, among other things:

"publicly available information regarding the U.S. FDA's previous findings and determination that the reference product is safe, pure and potent and may not be required to provide full product-specific non-clinical and clinical data."

The actual approval timeline under the biosimilars pathway is also notably faster than novel biologics. For example, Novartis AG filed a Section 351(k) application for Zarxio in July 2014 and – based on review of evidence that demonstrated Zarxio to be comparable to Amgen's Neupogen – in March 2015 the US FDA approved Zarxio as the first biosimilar for use in the United States (ie, within nine months of receiving Novartis's application).

Choice of reference product

In China, a reference product used in analytical and pre-clinical studies can be approved in China or elsewhere. However, the same reference product must be approved in China at the time that comparative clinical studies are initiated. The reference product should usually – but not always – be the originator's product. Approved biosimilars themselves cannot act as reference products.

Under the US and EU regimes, as long as an acceptable bridge can be established between the reference product and the EU or US-approved products, products approved outside the European Union or the United States can also be the reference products. Further, in Europe a foreign licensed reference product must be approved in a country or region with similar scientific and regulatory standards as those of the EMA.

Requirements for safety and efficacy studies

The new CDE guideline provides for reduced pre-clinical and clinical data requirements, on the condition that no significant differences are identified in pharmacology or analytical comparisons. This can be demonstrated by establishing comparability in production processes, physical and chemical properties, potency, purity and so forth. However, the guideline is unclear on whether large-scale confirmatory clinical studies can be waived, even if comparative pharmacokinetic/pharmacodynamic (PK/PD) studies and immunogenicity studies are performed on patients and have demonstrated high comparability.

The EMA's guidelines, on the contrary, offer a risk-based approach, under which the scope of studies will depend on product complexity, the inherent ability to be characterised by quality parameters and the mode of actions across indications. The EMA's updated overarching guideline for biosimilars, effective as of April 30 2015, specifically provides for the possibility of biosimilar approval based on PK comparative studies and supportive PD data, without comparative efficacy studies.

Regulatory exclusivity

As with small molecule generics in China, there is no exclusivity protection for first-to-market biosimilars. The first approved biosimilar will have no additional competitive advantages in market access.

In contrast, in the United States a one-year exclusivity period is granted to the first biosimilars determined to be interchangeable with the reference product for any condition of use. During this period, no other biosimilars may be deemed interchangeable with that reference product.

Separately, China has a relatively shorter exclusivity period for first-approved pioneer drugs. There is only a new drug monitoring period of up to five years to fence off follow-on applications, and the protection applies only to locally manufactured new drugs. Market entry of biosimilars in China is mainly restricted by patent exclusivity. In the United States and Europe, biosimilars cannot be approved until at least 10 years after approval of the reference product. This regulatory exclusivity can balance the interests between innovative biologics manufacturers and biosimilar manufacturers.

Interchangeability

'Interchangeability' generally refers to the fact that a biosimilar can produce the same clinical results as the reference product in any given patient and that there is no greater risk in safety or diminished efficacy in switching between the biosimilar and its reference product.

The new CDE guideline does not mention the concept of interchangeability, while the EMA leaves it to the discretion of national competent authorities of each EU member state. In the United States, if a biosimilar is deemed interchangeable, pharmacists may substitute the reference product with the biosimilar, without specific instructions from the healthcare providers who prescribe the reference product. If the biosimilar is not interchangeable, the healthcare providers will refer to the specific name of the biosimilar in the prescription note in order for pharmacists to dispense the biosimilar.

Comment

The publication of the new Chinese guideline represents significant progress in the development of biosimilars. Patients are expected to have access to more affordable biologics in China. At this early formative stage of biosimilar regulation in China, the guideline presents a good starting point for biopharmaceutical companies to weigh advantages against disadvantages when choosing between China's new biosimilar pathway and the pathways in other foreign jurisdictions.

For further information on this topic please contact Katherine Wang at Ropes & Gray LLP by telephone (+86 21 6157 5200) or email (katherine.wang@ropesgray.com). The Ropes & Gray LLP website can be accessed at www.ropesgray.com.

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