The Biosimilar Guidance Documents; Industry Responds

Regulatory Summary
In an effort to incentivize the market place to introduce competitively priced biologics, the Biologics Price Competition and Innovation Act, passed by the Senate in 2009, was signed into Federal Law as part of the Patient Protection and Affordable Health Care Act by President Obama in 2010.  Among other components the BPCI Act:
  •             Establishes an abbreviated pathway for approval of biologic drugs that are similar to a currently marketed biologic drug (351k)
  •            An amended definition of biological products to include proteins[1]


  •            Confers 12 years of patent protection to the biologic innovators of the original products
  •            Confers 1 year of patent protection for the first biopharmaceutical that is approved as comparable to the established biologic product
Essentially, this act paved the way for the entrance of generic biopharmaceutical products to the market place.
The Act will allow manufactures of biopharmaceuticals to abbreviate the application process by demonstrating that their product is similar to an existing biologic, reducing (but not eliminating) the requirement to support claims of the safety, purity and efficacy of the biologic with extensive clinical evidence. This Act will do for the biologics market place what the Waxman Hatch bill of 1984 did for traditional small molecule pharmaceuticals[2], (Abbreviated New Drug Application process (ANDA)), and what the 510(K) process did for the Medical Device market place; allowing a new and similar product to follow an abbreviated application process, relying on existing clinical data that generated during the innovative product’s approval process.
Whether or not the impact of those acts to their respective markets and to therapeutic innovation in general has been valuable or harmful continues to inspire heated debate.
While the impact of generic products on drug innovation and medical progress is highly debated, the industry continues to speak with one voice with regard to the need for clarification of the pathway to approval of biosimilars.  While the total cost to market for a generic is considerably less than the cost to market for an innovative product, the cost is still considerable and success far from certain.
Agency Guidance


If industry is to react to the obvious financial incentives offered by the generic market place, the pathway to approval must be clear, and industry must be confident that FDA has prepared its infrastructure to adapt to this change.  The first step has been taken in the form of the recently issued draft FDA Guidance Documents on Biosimilars.

The FDA has drafted and released three (3) documents, providing:
  •           Guidance on the scientific challenges of demonstrating biosimilarity
  •           Guidance on the quality considerations when dealing with therapeutic protein products when demonstrating biosimilarity
  •           The provision of answers to questions submitted by industry
Critical Terminology
Prior to going further down this road, it is useful to provide precise definitions of the terms used within The Act:
  •           Comparability is a term that pre-dates this legislation, and has been used in the past by FDA to describe the state of an approved biologic before and after a change has been made to a controlled manufacturing process by the same manufacturer.
  •           Theraputic equivalent is a term used within the 1984 Waxman Hatch act that refers to the demonstration of the equivalence of synthetic drugs made by two different manufacturers (this term has been commonly replaced by the public with “generic.”)
  •           Follow-on biologic products[3] are those that have characteristics that are generally similar to a previously approved product.
  •           Follow-on biologics that are proven to be highly similar to a reference product and meet the relevant regulatory requirements for safety, purity, and potency can approved by FDA as biosimilar to the reference product.   Biosimilarity differs from comparability as this process involves two different manufacturers.
  •           A reference product is a previously approved biologic that a biosimilar candidate is claiming comparability to within an abbreviated application process (Follow-on biologic products that receive approval via a standard biologics licensing application (BLA) cannot be referred to as biosimilars, as their approval process did not seek to establish comparability to another product.  They can however, be potential reference products).
  •           If the manufacturer of a biosimilar product can prove that switching between the reference product and the biosimilar maintains efficacy without increasing risk, the biosimilar product may be deemed interchangeable by FDA.
  •           If the manufacturer of a biosimilar can be prove that their version is superior to the reference product, then FDA may determine the generic candidate is actually a biobetter.
  •           A protein is classified as any alpha amino acid polymer with a specifically defined sequence that is greater than 40 amino acids in size.
  •           A chemically synthesized polypeptide is any chemically synthesized polymer composed of 100 or fewer amino acids.


Engineering generic versions of biopharmaceutical products presents industry a greater challenge than did the development of therapeutically equivalent small molecule synthetics.  Biological products are created from living and unique organisms and are typically large and extremely complex molecules, which are impossible to routinely duplicate precisely.  The same is not true of small molecule generics, which are composed of simple synthetic ingredients that can be precisely manufactured.
The biosimilar approval process recognizes this reality (as did the comparability process before it) and, as such, the abbreviated approval process does not seek to confirm that the biologic therapies are identical; it instead seeks to confirm that any difference between the generic and the original is clinically insignificant.
Within the scientific guidance document, FDA encourages manufacturers to follow a stepwise approach to demonstrating the comparability of the biosimilar candidate and the reference product.  The Agency points out that when dealing with biologics, lots can vary from each other widely, even when produced by a single manufacturer.  With this level of variation possible even when using controlled manufacturing processes, FDA acknowledges that they will be making many decisions on a case by case basis, relying heavily on the robustness of the body of data provided.
Data Required
Data submitted with abbreviated biologic license applications should be comparable to the data set submitted with the reference product during the original American[4]approval process, and should include (by indication for use):
  •           structure and function descriptions
  •           animal toxicity data
  •           human pharmacokinetics (PK) and pharmacodynamics (PD) data
  •           human immunogenicity data
  •           clinical safety and effectiveness data
Scope of Clinical Testing Required
The more robust the data set, the less likely it becomes that the Agency will require complex studies in animals or humans.  However, the process allows FDA to render decisions with regard to the level of human clinical trials required, after the initial data set is reviewed.
The response from industry seems to be that the scientific guidance document does not offer much guidance, and that this lack of specificity results in significant risk for rejection of initial applications for biosimilars.
Multiple Indications
If an initial application is rejected and extended clinical trial requirements are requested, the financial incentive for engineering a biosimilar is greatly diminished.  FDA seems to have predicted that response and has included in the guidance an additional, albeit potential, incentive for biosimilar applicants. The guidance states that if a reference product is licensed for multiple indications, and a biosimilar demonstrates efficacy for one of those indications[5], the FDA may determine that the original data set could be used to support approving the candidate for the other indications of the reference product.
Industry feedback has also included some level of disappointment that the guidance doe not clarify the Agency’s stance with regard to the issue of interchangeability.  While industry had expressed a need for clear guidance on this topic, the Agency has responded by noting that the issue is still being considered, noting that interchangeability presents significant issues with regard to long-term use.  Once a biosimilar is deemed interchangeable, there is the potential for decision making at the pharmacy level of the supply chain to result in repetitive substitution for single patients[6].  However, the guidance does present at least one limit of the potential of interchangeability approvals; it is unlikely that data sets clinically comparing biosimilar candidates with a non-U.S. licensed product would ever be considered an adequate candidate for an interchangeability approval.


Quality Systems

FDA continues to communicate with industry with regard to the critical requirements for process control and Quality Systems. The guidance document on Quality Systems reiterates that the Agency expectation that all manufacturers demonstrate that they have a comprehensive understanding of the manufacturing processes, and that the origin of the understanding should be identifiable output of the product development process.
The Agency expectations regarding Quality Systems include, but are not limited to:
  •           Manufacturers of biosimilars must use quality-by-design and quality risk management tools
  •           Manufacturers of biosimilars must have and demonstrate knowledge and control over the manufacturing processes
Theraputic Proteins
The guidance document and the Department of HHS congressional statements remind us that while the biosimilar legislation may be applied to various types of biologic products, the agency considers follow-on proteins the most challenging.  As such, the quality guidance document focuses on the complexity of issues surrounding demonstrating biosimilarity with protein based reference products.
The guidance provided to manufacturers on these topics includes, but is not limited to, the following:
  •           The need to ensure that the binding activities performed for the candidate biosimilar are performed in a fashion equivalent to that used for the reference drug.
  •           If the reference product exists in any type of formulation, it will need to be extracted for characterization.  FDA reinforces the need to choose an extraction method that does not alter the original functional characteristics of the reference molecule.
  •           Sponsors must conduct significant validation studies to ensure that the in-house reference standard postextraction is behaving similarly to the reference product in its original form.
  •           Compare the strength of the biosimilar and the reference product; expressing the total content of drug substance in the same measure as the reference product. The guidance document tells us that the Agency expects the biosimilar candidate to have the same total content of drug substance and the same concentration of drug substance as the originator medicine.
The third in the series of guidance documents issued on Biosimilars provides answers to frequently asked questions.  The document categorizes questions in three (3) general buckets:
  •           Biosimilarity or Interchangeability
  •           BLA Requirements
  •           Exclusivity
We will not be reviewing this document within this blog, but urge readers to consult it in the event that any of the questions and answers contained within may be helpful.
In Summary
Upon review, it is clear that industry feels that the clarification offered by the guidance documents fell short of providing answers to all of the critical questions that surround the Agency’s internal process of reviewing and approving abbreviated biologic licenses.
While the Agency points out that the guidance documents and the path to approval offer flexibility, response from the market place indicates that industry perceives this flexibility as a lack of specificity.  Where there is lack of specificity, there is uncertainty, increased risk, and an inability to predict development costs and time lines, which may deter manufacturers from entering the biosimilar market.
Private sector reactions to the guidelines have included public statements from corporate executives rescinding plans to enter the biosimilar market in America, choosing instead to apply for European licenses.  A process for the approval of biosimilars has been in effect in the EU since 2004, and the biosimilar guidelines issued by the European Medicines Agency (EMA) are much more specific and contain detailed requirements for specific classes of biological drugs.
In response, FDA has committed to providing at least one more guidance document focusing on interchangeability standards.
Clear Take Aways
  •           The abbreviated application pathway for biosimilars may be an iterative process that increases risk to pipeline predictability.
  •           The Agency will be making case by case decisions and recommends early interaction with the Agency in order to prevent initial application rejections, unplanned clinical studies and unexpected delays.
  •           Biosimilar approval will require some level of clinical trial, by indication.
  •           Industry and the consumer should note that the guidance suggests that the Agency may permit slight differences between biosimilars and reference products.
  •           Protein based biosimilar candidates have detailed and specific requirements that must be included in the application data set.
  •           The risks posed by interchangeability are significant enough for the Agency to refuse to commit to an approval pathway at this time.  FDA has committed to issuing a guidance document on that topic after the Agency and the industry have been through the process and has a greater body of data to consult.
  •           Approved biosimilars will be subject to stringent post-licensure pharmacovigilance requirements.
© Coda Corp USA 2012.  All rights reserved.
Gina Guido-Redden and Corrine R. Knight

[1] Except any chemically synthesized polypeptide
[2] While this legislation does the pave the way for birth of the generic biopharmaceutical, it is worth noting that the approval process for a biologic under the terms of this act is significantly stringent, when compared to the approval process for generic small molecule pharmaceuticals or medical devices.
[3]A biologic follow-on, is not always a biosimilar.
[4]The guidance does allow candidate biosimilars to be compared to licensed European reference products.  However, these situations would require additional bridging studies.  Bridging studies would allow a manufacturer to attempt to demonstrate that the European reference product is comparable to the reference version approved in the United States.
[5] Including a very strong data set
[6]Consistent switching over the long term, between a reference and an interchangeable biosimliar.
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