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Biosimilars Law Blog

Posted in News & Events

FDA’s Long-Awaited Biosimilars Guidances—The Prologue to Biosimilars in the U.S. has been published

The U.S. Food and Drug Administration released three draft Guidances on implementation of the Biologics Price Competition and Innovation Act of 2009. The Q&A, Scientific Considerations, and Quality Guidances cover the overall framework for biosimilar application requirements as envisioned by FDA. Notably, FDA has deferred guidance on how to establish interchangeability.

FDA emphasizes a “step-wise” approach for sponsors in their development plans for biosimilars and the Agency’s “totality of the evidence” approach to review of biosimilar applications. While there is little that is unexpected or unanticipated for those that have been following the public discourse, there are a number of things to note:

  • Potential flexibility on the choice of clinical endpoints to support a proposed biosimilar, including endpoints different from those used to support approval of the reference product.
  • Potential flexibility on use of data from non-U.S.-licensed products as part of the demonstration of biosimilarity.
  •  Important discussions on delivery devices that accompany biological products, on establishing the biosimilar has the same “strength” as the reference product, and on the possibility of post-market studies for biosimilars.
  • How biosimilars may be labeled to identify the corresponding reference product, indication(s), route of administration, and interchangeability (or lack thereof).
  • A discussion of what constitutes “publicly available” information regarding prior determinations that the reference product is safe, pure and potent, including how the FDA’s  “action package” for a Biologics License Application (BLA) product may be used.
  • Definitions of “protein” and “chemically synthesized polypeptide” that affect whether products are regulated under the Public Health Service Act or Food Drug and Cosmetic Act.

The draft Guidances will be open for comment and the process and deadlines for submitting comments – including the scheduling of any public meetings on the Guidances – will be published in the Federal Register. We note that FDA took roughly five years to finalize the regulations governing the 1984 Hatch-Waxman Act on generic drug products. How the agency will process the volumes of comments that are likely to follow the publication of these landmark draft guidance documents will be interesting and worthy of close attention.

Posted in Global Comparisons

EMA regulatory approval changes for biosimilars on the horizon in the E.U.?

As mentioned in a previous post, the EMA set the standard for regulatory approval of biosimilars* with the adoption of their overarching general guideline in 2005 (CHMP/437/04 — PDF), followed shortly thereafter by guidelines on quality issues (EMEA/CHMP/BWP/49348/2005 — PDF) and on non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005 — PDF). The pathway for biosimilar approval was further delineated by the issuance of a number of product-class specific guidances, e.g., for epoetins and somatropins.

After more than five years of experience reviewing, approving and regulating biosimilars, the EMA has recently issued concept papers that articulate contemplated changes in the general biosimilars guidelines. While some may view these as a loosening of standards, others may view these contemplated changes as a refinement of the pathway. Either way, Europe’s experience with biosimilars is likely to color the U.S. Food and Drug Administration’s (FDA) implementation of the U.S. biosimilar pathway enacted in the Biologics Price Competition and Innovation Act of 2009 (PDF). FDA expects to issue initial guidance soon.

The comment period for the EMA concept paper on the revision of guidelines for biosimilars’ non-clinical and clinical issues (PDF) was open until December 31, 2011; the comment period for the concept paper on the revision of the general guidelines (PDF) is open until February 29, 2012. Draft revised guidelines are expected to be issued by the EMA in the first half of 2012.


*Called “similar biological medicinal products” under E.U. law (Directive 2001/83/EC)

Posted in Biosimilar Definitions

Biosimilars, biosimilarity—what does ‘highly similar’ mean?

It is largely up to the FDA.

In the U.S., what constitutes “highly similar” in the context of biosimilars is ultimately up to how the U.S. Food and Drug Admininstration applies the statutory language under the Biologics Price Competition and Innovation Act of 2009 (PDF). Demonstration that a biological product is “highly similar” to its reference product is a central tenet for biosimilarity under what is known as the 351(k) pathway, which establishes the abbreviated approval pathway for a biosimilar in the U.S. The statute reads, in part, as the initial step in demonstrating biosimilarity:

An application submitted under this subsection shall include information demonstrating that the biological product is biosimilar to a reference product based upon data derived from analytical studies that demonstrate that the biological product is highly similar to the reference product nothwithstanding minor differences in clinically inactive components.

How the FDA interprets “highly similar” has far-reaching implications that may include:

  • Products that are similar enough to use the abbreviated 351(k) pathway but different enough to avoid IP protections of the reference biologic;
  • 12-year exclusivity for second generation biologic products;
  • “Improved” versions of a previously approved product.

In crafting the biosimilars legislation, Congress ceded a lot of scientific discretion to the FDA. To their credit, the FDA has convened a number of opportunities for stakeholder input both leading up to and after passage of the BPCIA.

In this approach, FDA has followed in the footsteps of their European counterparts. Europe has been ahead of the U.S. in both the legal authorization and regulatory guidance for biosimilars. As part of their ongoing dialogue with stakeholders in the E.U., the European Medicines Agency convened a stakeholder meeting in July 2009 to discuss guidelines for biosimilar monoclonal antibodies because the next wave of biosimilar applications is likely to include these products. As indicated in an unofficial meeting summary, innovator and biosimilar stakeholders generally agreed that amino acid differences should not be allowed. While noting that the U.S. and E.U. biosimilar schemes are not the same, the principle invoked here for biosimilarity is that the products should be as structurally similar as possible. Many aspects of structure, such as glysosylation, may not be completely controlled by the developer and manufacturer, but amino acid sequence can be controlled. And where such control is possible, it should be applied. Thus from a scientific perspective, there is no reason to tolerate differences in amino acid sequence between the reference and biosimilar product. Identical amino acid sequences may not be sufficient to demonstrate the products are “highly similar” but they are likely necessary.

As FDA develops its biosimilar guidances, it will be interesting to see whether such principles are embraced and articulated. The result will have a large impact on biosimilar applications and the ever-evolving definition of “highly similar.”

Posted in Biosimilars vs. Generics

Why are generic drugs the ‘same’ and biosimilars only ‘similar’ to their corresponding reference products?

It’s the law and science.

The regulatory world of biological drugs is more complex and perhaps less clear than for the world of small molecule drugs. This is particularly true in the U.S. where, for historical reasons, biologics and small molecule drugs are regulated under separate statutes, the Public Health Services Act (PHSA) 351 and the Food Drug and Cosmetic Act (FDCA) 505, respectively.* The underlying science for biologics is also in some ways more complex than for small molecule drugs. It is the intersection of the legal framework and the science that makes generic drugs the “same” as their reference products and biosimilars “similar” to theirs.

At the time that the Hatch-Waxman amendments were passed in 1984, the concept of therapeutic equivalence was already well developed and generally understood by pharmaceutical chemists, industry, and regulators. Therapeutic equivalence is defined as pharmaceutical equivalence and bioequivalence. Stated more simply, the active substance in the drugs is the same and they are distributed throughout the body to the same extent and within the same amount of time. Thus, when creating an abbreviated approval pathway for generic drugs in the Hatch-Waxman legislation, the scientific basis for the abbreviated pathway was not at issue. The same cannot be said for the creation of an abbreviated approval for biosimilars.

Biologics regulated under the PHSA were not included in the Hatch-Waxman generic pathway, in part, because at the time the science for these products was not sufficiently advanced for different, unrelated manufacturers to make reliable copy versions. Over the next couple of decades, science advanced, biotechnology became more commercialized and the number of biotechnology-derived biologic medicines continued to grow.

Scientists, forever the optimists, began to see the feasibility of making copies of existing biotechnology products. At the same time, biotech entrepreneurs realized that the patents on some of the earlier biotech products would be expiring. Thus the concept of a biosimilar was born.

However, unlike the regulatory pathway for generic drugs, there has not been consensus on the scientific criteria for biosimilars. Therefore, creating a pathway—in the U.S. and elsewhere—has tried to work out the science at the same time as the legal and regulatory standards.

The differences between small molecule drugs and biologics are the basis for the differences in the regulatory standards for their respective abbreviated pathways.

Due to the greater size (10 to 1000 times, typically) and complexity of biologics and the heterogeneity of biological processes, current science does not allow one to make “identical” copies of a biologic or even to analyze them to the level of precision that is possible for small molecule generic drugs that are the “same” as their reference listed drug. In fact, as analytical techniques improve, more and more differences at the molecular level are seen between similar biologics produced by different manufacturers. So for the forseeable future, biosimilars will remain “similar”, and not the “same”, as their reference products, and authorizing law, regulation and guidance should reflect this. Thus in the U.S., generic drugs are approved under the FDCA 505(j) and biosimilars will be approved under the PHSA 351(k), reflecting the statutory and scientific distinctions between a generic drug and a biosimilar.


*Without digressing too much, some products that would scientifically be considered biologics are regulated as “drugs” under the FDCA instead of as biologics under the PHSA due to largely historical reasons.

Posted in Global Comparisons

Global Dis-Harmonization of Biosimilar Naming and Labeling

The Food and Drug Law Institute held a recent “Dialogue” on the naming and labeling of biosimilars in the U.S. as the Food and Drug Administration (FDA) implements the abbreviated pathway for biosimilars authorized under the Biologics Price Competition and Innovation Act. While the representatives from FDA participated on both panels—naming and labeling, the remainder of the panelists were different on each panel, allowing a range of views from the World Health Organization (WHO), industry consultants and attorneys in the field on 16 November 2011.

As individual regulatory authorities around the world adopt abbreviated regulatory approval schemes for biosimilars, no harmonized approach to naming and labeling has emerged. The European Medicines Agency (EMA) has been the pioneer in establishing a framework for biosimilars and has approved the first wave of biosimilar products for the European market. However, the EMA has been relatively agnostic about the naming of related, similar biologics because while the authority to approve biologics, including biosimilars, resides with the EMA, authority for naming and labeling resides with the regulators of individual member states.

Other regulatory systems with biosimilar approval pathways have adopted different approaches (including Health Canada, Japan’s Ministry of Health Labor and Welfare, and Australia’s Therapeutic Goods Administration), and the WHO policy for assigning international non-proprietary names (INN) to biologics has not necessarily helped with harmonization. Briefly, the WHO INN policy is that biologics with identical amino acid sequences and no post-translational modifications should have the same INN; biologics with different amino acid sequences (even one difference) should have different, related INNs; and biologics with the same amino acid sequences that differ in their post-translational modifications should have different, related INNs. However, application for an INN is voluntary and not every developer of a biologic applies for an INN.

This has led to several incongruous situations. For example, in Europe, there are multiple biosimilars to the innovator version of epoetin-alpha. Epoetin-alpha is a glycosylated protein and thus these post-translational modifications tend to differ between manufacturers because of the cells used and the processing steps. Although all of the biosimilars approved using epoetin-alpha as a reference product have differences in glycosylation from the reference product, they do not all have different INNs. Some of these use the INN, epoetin-alpha, while at least one of them uses its unique INN, epoetin-zeta.

According to the WHO representative, Australia’s TGA would not let a sponsor of a biosimilar to epoetin-alpha use that INN as a non-proprietary name in Australia because according to their assessment, as well as maintaining consistency with WHO INN policy, the post-translational modifications differed between the biosimilar and the reference products, and thus they should have different non-proprietary names. However, apparently the sponsor did not want to apply for an INN for their own product, and thus TGA assigned them a non-proprietary name that is used, for now, in Australia only.

The United States Adopted Name (USAN) Council is responsible for assigning non-proprietary names in the U.S. and works closely with the WHO to achieve consistency, where possible, in naming.

The FDA has said that while they seek global regulatory harmonization where possible, the U.S. will have to adopt a policy that is consistent with the authorizing statute and that works with U.S. medicines and health care systems. Perhaps the anticipated draft guidance(s) on biosimilars, likely to be issued by the end of 2011, will provide direction on how the U.S. will handle naming of biologics in an environment where multiple, similar products are on the market simultaneously and no international harmonization exists.