Key Considerations in Biosimilars Development

Understanding opportunities and challenges across all major phases of development.
Oct 01, 2012
Volume 25, Issue 10

Biosimilars are one of the fastest-growing development opportunities in biopharmaceuticals. A Datamonitor study estimates 2009 sales of biosimilar products in the United States and five leading European markets at $150 million. In 2015, when 32 biologics enjoying annual sales of $51 billion will have lost patent protection, biosimilar sales are expected to reach $3.7 billion (1). Unlike with generic small-molecule drugs, however, creating an exact copy of a therapeutic protein is impossible. Regulatory agencies, therefore, evaluate biosimilars based on their degree of chemical and therapeutic similarity to innovator biologics.

The depth and breadth of testing required to demonstrate similarity that meet regulators' expectations, some of which are still evolving, depends on the degree to which sponsors collect and validate comparability data during development. Those who create a compelling case will likely experience a lower regulatory burden.


The 2009 Biologics Price Competition and Innovation (BPCI) Act authorized the US FDA to devise an approval pathway for biosimilar products. FDA's February 2012 draft guidance document, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, defines biosimilars as molecules that are "highly similar" to a reference product, with "no clinically meaningful differences" (2).

The draft document warns of significant differences between approval mechanisms for small molecule and biologic follow-on products, specifically that a one-size-fits-all pathway would not be possible. FDA says it will instead "consider the totality of the evidence" when assessing follow-on products (2).

Specifically, FDA will consider the product's complexity, formulation, stability, and analytics, and then apply a risk-based approach relying heavily on pharmacovigilance. The draft FDA guidance is modeled on the European Medicines Agency (EMA) 2004 biosimilars guidance document, which is currently undergoing an update (3). In general, FDA and EMA biosimilars guidance documents are considered to be consistent with each other. The main difference between the two agencies' perspectives on biosimilars is tied to the issue of "interchangability." FDA has the authority to designate interchangability while EMA leaves this designation to national regulators. There are additional minor differences in the guidance documents. However, because the FDA guidance document is still in draft form and the EMA document is undergoing a revision, it is safe to say that both regions' regulations are evolving in this area.

Economic and market differences between biosimilars and generic drugs will be striking in the years ahead, according to a Federal Trade Commission assessment, as follows:

  • Competition between innovator drugs and biosimilars will more closely resemble brand-to-brand competition than brand-to-generic competition
  • Discounts for biosimilars will be modest, in the 10%–30% range, versus up to 90% for small-molecule generic drugs
  • FDA approvals will involve significant investments: eight to 10 years of development time and between $100 and $200 million, compared with three to five years and $1 million to $5 million for generic drugs
  • Biosimilars will be dominated by larger companies and large-market (above $250 million) indications
  • Biosimlars will experience slower uptake and lower market share than generic drugs due to the lack of automatic substitution (4).


Nonclinical considerations

Figure 1: Analysis of characterization of biosimilars versus new biologic entities (NBEs). There is a need for more extensive characterization for biosimilars than for innovator drugs. The trend in the industry is that analytical technology advances will continue at the same pace and will allow for more accurate physico–chemical and biological characterization, which may provide more guidance to nonclinical, pharmacokinetic/pharmacodynamic, and clinical studies.
Nonclinical data typically encompass comparative in vitro pharmacology and in vivo studies of efficacy, pharmacokinetics, and possibly toxicology, including toxicokinetics, antidrug antibody, and local tolerance. Biological characterization, usually part of the Chemistry, Manufacturing, and Controls (CMC) or drug quality package, also needs to be included in the nonclinical safety data package. In vitro and cell-based characterization will be the most critical assays from a nonclinical comparability perspective.

Critical nonclinical considerations during development planning should include all available regulatory guidances (e.g., EMA's molecular class-specific guidances), nonclinical innovator data from conferences, the European Public Assessment Reports (EPARs) and published literature.

One caveat to using existing data that has been generated in studies on older biological drugs is that the data may not be sufficiently detailed or comparable for validating study endpoints. Keep in mind that toxicokinetic and antidrug antibody data may be sparse or nonexistent and animal models used in older studies may no longer be available or relevant. Moreover, analytical methods have improved significantly, as has the ability to utilize biomarkers.

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