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Key Elements of the FDA\'s Draft Biosimilars Guidance

Peter Gaskin, BSc (Hons), Ph.D, Principal Aptuit Consulting

On 9th February the FDA announced publication of it\'s eagerly awaited draft guidance documents for biosimilars. For the Asian biosimilar industry this represents the first step towards access to a potentially lucrative new market. We review the key elements of the guidelines and compare and contrast with European biosimilar guidelines.

On 9th February, 2012 The US FDA announced the first three of the eagerly-awaited draft guidance documents for biosimilars (follow-on biologics):

Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product.

FDA defines a biosimilar as “a biological product that is highly similar to an already approved biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biosimilar and the approved biological product in terms of the safety, purity, and potency.”

Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

This guideline has been prepared based on Sponsor questions received during the development of the draft guidelines and covers a number of aspects addressed in the other two guidance documents in more detail.

Below are the key aspects of the two main draft ‘Scientific’ and ‘Quality’ guidance documents and have incorporated aspects also addressed in the ‘Questions and Answers’ document.

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

The key phrase in the draft guidance is ‘totality-of-the-evidence’ which describes a risk-based approach that the FDA will use to evaluate the data package supporting a biosimilar application.  In common with the long-standing European guidance and in line with expectations set by previous communications the FDA draft guidance states the importance of comparison against a reference product. However, unlike the European guidance the FDA, in the ‘Questions and Answers’ draft guidance indicates that the reference product used in animal and clinical studies does not always need to be licensed in the USA, and Rachel Sherman, Associate Director for medical policy at CDER has stated, “We want very badly to share clinical data that exist with non-licensed reference products”. In order to use data with a reference product not licensed in the USA bridging studies are required comprising comparative analytical studies and at least one clinical pharmacokinetic study (and if appropriate at least one pharmacodynamic study) conducted with the US licensed reference product.  In such cases the reference product would need to be manufactured in, and would also need to be licensed in, an ICH country.  Such an approach would not support a claim of ‘interchangeability’, but does seek to try to address the industry’s concerns about duplication of studies to support US and European claims of biosimilarity, although the hurdles required for using such an approach are set quite high.


FDA suggests a step-wise approach to compare the biosimilar with the reference product starting with structure and function and then moving on to pre-clinical toxicology. They recommend holding a pre-IND meeting when a proposed plan for the biosimilar development program is available and when information on the manufacturing process and preliminary analytical data are available. We recommend requesting a pre-IND meeting as it provides an opportunity to verify that the product is likely to be considered a biosimilar by FDA and to determine whether animal toxicity studies are likely to be considered useful.

As with European Medicines Agency guidelines nonclinical safety pharmacology, reproductive and developmental toxicity, and carcinogenicity studies are not likely to be required by FDA for biosimilars, and in some cases no animal toxicity studies may be required (for example if there is no animal species in which the biologic activity mirrors the response in man). Unlike the European guidelines however, FDA also suggests that non-comparative toxicology studies may be acceptable in some cases where animal toxicology studies are needed. Having a pre-IND meeting relatively early allows such issues to be discussed with FDA before pre-clinical toxicology studies are initiated, although Sponsors looking to also market their product in Europe will be aware that differences in toxicology requirements may occur between FDA and EMA. It may be possible to combine animal PK and PD end-points into toxicology studies where they are conducted, thereby reducing animal usage. Finally, the pre-IND meeting also provides a forum to discuss plans for human pharmacokinetic and pharmacodynamic (if there is a clinically relevant pharmacodynamic marker) studies and the requirements for assessment of clinical immunogenicity, safety and efficacy.

Unlike generic small molecules, biosimilars must show clinical “equivalence”. A clinical pharmacokinetic study should demonstrate similar exposure with the proposed biosimilar product and the reference product, with a pharmacodynamic study showing a similar effect on clinically relevant pharmacodynamic endpoints adding weight to the claim for biosimilarity. Comparative clinical pharmacokinetic and, where relevant endpoints exist, clinical pharmacodynamic studies are therefore key parts of a biosimilar submission package.  The clinical studies should use dose levels and dosing regimes expected to be used clinically, be conducted in appropriate patient populations, have clinically relevant PK and PD endpoints, and be designed to be sufficiently sensitive to identify potential differences between the reference and biosimilar products.

It is likely that the clinical assessment of immunogenicity for any biosimilar product will include some pre-marketing assessment, but the extent of pre- and post-marketing assessment required is likely to vary from product to product, based on the extent of similarity between the reference and biosimilar products and the extent of immunogenicity seen with the reference product in clinical use. Importantly, similar biological products with a better immunogenicity profile than the reference product may still be considered as biosimilars.

The draft guidance refers to the ICHQ5E guidance on “Comparability of Biotechnological / Biological Products Subject to Changes in Their Manufacturing Process” suggesting that the principles also apply to the development of biosimilars, but indicates that more information will be required for a biosimilar product as it will likely have a different manufacturing process to the reference product. The FDA has also published a draft guidance document which deals in more detail with issues of quality for biosimilars and which is discussed below.

Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product

Whilst the legal and regulatory framework for biosimilar guidance in the USA has only been recently put in place, regulators within FDA have been considering how one can ensure similarity of biological products for some time. Indeed, some of the central tenets of the guidance on the ‘Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product’ have been developed from those in the 1996 FDA ‘Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology Products.’ The guidance also specifically refers to the “Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody Product for In Vivo Use” also issued by FDA in 1996.

As with previous FDA guidance for biologicals the draft biosimilar quality guidance emphasises the importance of extensive analytical, physicochemical and biological characterisation. In the case of the biosimilar guidance this is a comparative exercise examining the similarities and differences between the biosimilar and a suitable reference product. As mentioned earlier, FDA does indicate that in some cases it may be possible to use a reference product which is not licensed in the USA for certain studies. Like the European quality guidance the FDA draft guidance document allows for minor differences in clinically inactive components of the biosimilar, with the emphasis for characterisation being primarily on the components of the biological product responsible for efficacy and safety.

The importance of the quality package for a biosimilar product cannot be over-emphasised as the assessment of quality of the biosimilar defines the extent of similarity to the reference product and is, therefore, pivotal to the design of the whole development programme.  Hence, the outcome of the quality assessment will determine the non-clinical and clinical study requirements.  We strongly recommend that sponsors conduct a comprehensive, comparative physicochemical and functional assessment of their biosimilar in comparison to a suitable reference molecule.  A good package will enable the Sponsor to propose a targeted and selective approach to non-clinical and clinical development with FDA with more likelihood of an agreement on a quicker and less expensive development program.

Author Bio

Peter Gaskin, BSc (Hons), Ph.D

Peter Gaskin is a Principal at Aptuit Consulting where he provides strategic technical and regulatory expertise to clients for drug development programs. He has over 18 years of drug development experience in a variety of senior roles in the pharmaceutical and contract research industry.

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