This article reviews FDA’s recent efforts to streamline the biosimilar approval process and address quality concerns with the publication of new guidelines that suggest resources to aid in the biosimilar development and characterization process.
By Feliza Mirasol
Recent guidelines released by FDA emphasize the agency’s efforts to ease the path toward regulatory approval for biosimilars and marks significant action taken by the agency to help promote competition in the biologic market. In May 2019, the agency published the draft guidance Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations (1) and the guidance Considerations in Demonstrating Interchangeability with a Reference Product Guidance for Industry (2).
Congress created an approval pathway in the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-approved biological brand, or reference product. The pathway is intended to benefit patients by making more treatment options available through biosimilar and interchangeable products, increasing access to life-saving medications, and potentially lowering healthcare costs through competition. Because of patient need, well-functioning biosimilar and interchangeable pathways are critical to the agency’s broader efforts to improve competition. That’s why FDA has developed and is working to implement a Biosimilars Action Plan that includes a suite of ongoing efforts to encourage innovation and competition among biologics and the development of biosimilars (3).
Establishing Comparative Analytical Assessments
The new draft guidance, which was issued to replace earlier guidance that had been withdrawn by FDA on the back of industry concerns and objections (4), outlines the agency’s recommendations for the design and evaluation of comparative analytics studies needed to demonstrate biosimilarity between a proposed biosimilar and the reference product. The document also provides recommendations to sponsors on what scientific and technical information to include for the chemistry, manufacturing, and controls (CMC) section of a marketing application for a proposed biosimilar.
The document also gives guidance on the factors that sponsors should consider when performing comparative analytical assessment for a proposed product. Factors to consider include the expression system, the manufacturing process, physicochemical properties, functional activities, target binding, impurities, the reference product and reference standards, the finished drug product, and stability. The document gives details on how comparative analytical assessments should cover these key factors.
The draft guidance also emphasizes the need for sponsors to have a thorough understanding of the reference product, which is critical for a successful biosimilar development program. Understanding the physicochemical and biological characteristics of the reference product, doing a full characterization, and familiarizing oneself with publicly available information on the reference product are recommended approaches for forming the basis of understanding for that product. Because protein products are, by their nature, complex molecules that are manufactured in living cells and later on purified through a variety of technologies, they will naturally have inherent lot-to-lot variability in their quality characteristics. Thus, it is important to sufficiently characterize the lot-to-lot variability of the reference product and the proposed biosimilar through comparative analytical assessment.
Important to the comparative analytical assessment process is the use of adequate lots from both the reference product and the proposed biosimilar.
The draft guidance suggests that for the reference product, sponsors should acquire multiple lots of reference product throughout the development program of their proposed biosimilar, and that they should be in sufficient quantity to conduct multiple physiochemical and functional assays. This will help ensure an accurate picture of the full range of product variability. For the proposed biosimilar, a sponsor should include at least 6–10 lots (including investigational-scale and commercial-scale material) of biosimilar product in the comparative analytical assessment. Including these lots will help ensure that characterization of the proposed biosimilar is adequate and that manufacturing variability is well understood. It will also ensure that the sponsor has an adequate comparison to the reference product.
The final interchangeability guidance is informed by FDA’s cumulative experience providing development-stage advice to sponsors of proposed interchangeable products. The agency also considered numerous comments on the draft interchangeability guidance and made changes to provide increased clarity to stakeholders. In this final guidance, FDA gives an overview of the important scientific considerations that sponsors should focus on when setting out to demonstrate interchangeability between their proposed therapeutic product (i.e., proposed interchangeable biosimilar or proposed interchangeable product) with a reference product.
Several factors impact the type and amount of data and information that would be needed to support a demonstration of interchangeability. The product-dependent factors that should be taken into consideration are the proposed interchangeable product’s complexity and the extent of characterization—both comparative and functional—and product-specific immunogenicity risk (of the reference product). FDA encourages sponsors to consider these two factors together to inform the type of data they should collect and the information they will need to support a demonstration of interchangeability within a particular context. Sponsors will also need to determine the data and information necessary to support interchangeability on a
To demonstrate interchangeability, a sponsor typically sets up switching studies to show that the risk of safety of diminished efficacy from switching between the proposed interchangeable product and the reference product is not greater than using the reference product only. FDA’s guidance suggests that switching studies evaluate changes in treatment that result in two or more alternating exposures, or switch intervals between the interchangeable product and the reference product.
If a sponsor believes that these types of data are not necessary, FDA will expect the sponsor to provide a justification for their decision to not include switch study data as part of their demonstration of interchangeability. An instance where a switching study may not be necessary is one where biological products (interchangeable and reference) are not to be administered to a patient more than once. For products that are intended to be administered multiple times, FDA encourages sponsors to meet with the agency to discuss their development approach, including at this time any proposed justification as to why switching studies
are not needed.
Another important consideration in setting up a switching study is to define the primary endpoint for the study. According to the guidance, the primary endpoint should assess the impact of switching, or alternating, between a proposed interchangeable product and the reference product. The impact should be assessed on a pharmacokinetic (PK) and pharmacodynamic (PD) level, if available. PK and PD endpoints, which are distinguished from clinical efficacy points, are typically more sensitive to detecting changes in exposure and/or activity that can arise from alternating or switching products.
US Product vs. Non-US Product
The interchangeability guidance also sets forth recommendations for sponsors wishing to use data derived from a switching study or studies in which the comparator product is a non-US-licensed product. In this case, the sponsor should provide adequate data and information to effectively form a “bridge” between the non-US-licensed comparator and its counterpart, the US-licensed reference product. This would allow the sponsor to justify the relevance of the data obtained using the non-US-licensed comparator. FDA notes in the guidance that a US-licensed reference product and the non-US-licenses comparator product often have subtle differences in specific structural features (e.g., acidic variants, deamidations), process-related impurities, or formulation.
These differences may be subtle and may not preclude use of the non-US-licensed comparator in certain studies to support a demonstration of biosimilarity because the comparator in those cases is being used as a control in an evaluation that does not involve switching back and forth. It becomes an issue, however, when the evaluation does involve switching between products (interchangeable and comparator) because multiple exposure to each product has the potential to prime the immune system to recognize the subtle differences between products, which can intensify the overall immune response.
In light of the complexity of using a non-US-licensed comparator product, FDA cautions that the type and extent of data needed to justify the use of a non-US-licensed comparator in a switching study may be different or more extensive than is needed in other contexts or other studies in which the non-US-licensed comparator is used. The agency believes, however, that with adequate data and information, it may still be reasonable to use a non-US-licensed comparator in a switching study.
Effective Analytical Methods
High-resolution mass spectrometry (HR–MS) is the go-to method for primary structural analysis and characterization of complex protein molecules, particularly following post-translational modifications. For higher-order structural analysis, various biophysical techniques are mainly employed, according to a paper published by M. DiPaola and I. Javeri (5).
Mass spectrometry has been known as a key technology for characterizing an originator’s biological product (i.e., the reference product) and for performing comparability studies between proposed biosimilar molecules and the reference product. A new generation of mass spectrometers introduced over the past five years (e.g., time-of-flight [ToF] instruments quadrupole (Q)–ToF, ion trap–ToF, or ToF–ToF, and orbital ion trap mass spectrometers) now offer improved high-mass resolution and mass accuracy for characterizing primary structures (5).
For higher-order structures, however, including secondary and tertiary structures, commonly used methods resulted in low resolution and failed to provide structural details to illuminate distinctions in the subtle differences among higher-order structures. Until recently, higher-order structures were characterized using a combination of biophysical techniques, including intrinsic tryptophan fluorescence, extrinsic fluorescence, far- and near-ultraviolet circular dichroism, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. Meanwhile, though it is possible to use methods such as multidimensional nuclear magnetic resonance or X-ray crystallography to obtain more detailed analysis of higher-order structures, these methods are far too time consuming and costly to run, according to M. DiPaola and I. Javeri, who conclude that mass spectrometry may be the answer. Mass spectrometry has been found to be useful in providing detailed analysis of higher-order structures and in a timely manner.
1. FDA, Draft Guidance for Industry: Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations (Rockville, MD, May 2019).
2. FDA, Guidance for Industry: Considerations in Demonstrating Interchangeability with a Reference Product (Rockville, MD, May 2019).
3. FDA, “Statement from Acting FDA Commissioner Ned Sharpless, MD, on Policy Advancements to Help Bring Interchangeable Biosimilars to Market,” Press Release,” May 10, 2019.
4. J. Wechsler, BioPharm International 32 (7) 6–7 (2019).
5. M. DiPaola and I. Javeri, BioPharm International 32 (9) 34–38 (2019).