4.14 Interchangeability

Understanding biosimilarity

A rapid immunogenicity assay using immunochromatographic test strips is a newly developed IM assay method that requires no sample dilution and wash steps, thus, capable of detecting both high- and low-af nity ADAs. It is very tolerant of acid dissociated samples. ANP’s nano intelligent detection system (NIDS)® rapid IM assay can be utilized for not only patient sample testing during clinical trials but, more importantly near-patient monitoring of immunogenic reactions, particularly after the biologic drug/biosimilar is approved (related publication). ANP offers various rapid IM assay products and services using both a handheld reader and a high throughput screening reader. There are several challenges in detecting ADAs; for example, ADAs in an immune patient may already be bound to the biotherapeutic drug in circulating immune complexes, especially in the presence of the excess drug. Unless dissociated from these complexes, the ADA will not be detectable in any IM assay of any format. The typical approach to this challenge is to perform an acid dissociation pretreatment of the sample to liberate the ADA from the immune complexes, and then after neutralization, immediately run the IM assay. The IM assay is run immediately after neutralization to prevent the immune complexes from reforming. Endogenous protein interferences can cause erroneous results in immunogenicity tests in whatever format. For mAbs and similar biotherapeutics that function by binding and blocking disease-associated active proteins, the drug’s target molecule can create a bridging or a sandwich complex with the drug conjugate reagents in the IM assay. This leads to a false positive result in IM assays in the absence of ADA. Acid dissociation by itself will not resolve this problem. Other approaches that may work involve using a different blocking antibody that will bind interfering target proteins prior to running an immunogenicity assay. Once blocked, the target molecules can no longer form bridging complexes with the drug conjugate reagents. However, these blocking antibodies are dissociated from the target molecules upon acid dissociation, thus, removing their therapeutic effect. If added immediately after the neutralization step in the acid dissociation process, the blocker will not have enough time to bind the target proteins since the IM assay are run immediately. For drugs where the historical data suggest a low ADA production, the studies are short, allowing a risk-based approach that the FDA allows.

A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness of the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products. 193

Biosimilarity: The FDA Perspective

194 An interchangeable biological product is biosimilar to an FDA-approved reference product and meets additional standards for interchangeability. An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the healthcare provider who prescribed the reference product. The FDA requires licensed biosimilar and interchangeable biological products to meet the Agency’s rigorous standards of safety and ef cacy. That means patients and healthcare professionals will be able to rely on the safety and the effectiveness of the biosimilar or interchangeable product, just as they would the reference product. Subsection (b)(3) of the PHSA 351(k)(3) describes the term interchangeable or interchangeability in reference to a biological product that is shown to meet the standards described in Subsection (k)(4), meaning that the biological product may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. This is a major commercial event for a biosimilar product. However, to achieve interchangeability, several de nitions and concepts should be followed. A biological product is considered interchangeable with the reference product if • The biological product is biosimilar to the reference product, and • It can be expected to produce the same clinical result for any given patient. In addition, for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished ef cacy of alternating or switching between use of the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch. An interchangeable product should be able to be substituted or alternated by a pharmacist, without intervention or even necessary noti cation of the prescribing doctor, whereas a biosimilar product may yield a comparable outcome as the reference, but may require transitioning or input by a healthcare provider, in order to be switched or alternated with the reference (or not be able to at all,) due to other factors such as excipients. Thus, biosimilarity does not imply interchangeability. Interchangeability is expected to produce the same clinical result in any given patient, which can be interpreted as that the same clinical result can be expected in every single patient. While physicians and hospitals may adopt interchangeability on their own, there remain legal challenges to be resolved in treating a biosimilar product as an interchangeable biosimilar product. The demonstration of biosimilarity is a stepwise exercise based rst on the analytical and functional similarity and then supported with preclinical and clinical data and, if additionally necessary, patient data. The demonstration of interchangeability remains debated in the United States, and the FDA is currently conducting surveys to seek insight into the types of protocols that will allow the statutory evaluation of “no

Understanding biosimilarity

reduced effectiveness” and “no higher side effects” upon switching and alternating. It will take a few years for details of what is considered appropriate to be established, but in the future, it is more likely that these products will be readily substituted, very much the small molecule generic products. Figure 4.14 shows a broader view of interchangeability. However, taking into consideration the current statutory requirements embedded in the guidance limits what is required to establish interchangeability. Besides the two requirements stated earlier, the statute further states “in a clinical setting,” which is construed as testing in patients. These three requirements can be enabled by clinical effectiveness studies (as opposed to clinical ef cacy trials) that must be conducted to demonstrate that “switching and alternating” is acceptable. The concept of switchability used for small molecules does not apply to biosimilars. From the FDA’s perspectives, interchangeability includes the notion of switching and alternating between a reference licensed product (R) and biosimilar test product (T). The concept of switching is referred to like the switch from not only R to T or T to R (narrow sense of switchability) but also T to T and R to R (broader sense of switchability). As a result, in order to assess switching, biosimilarity for R to T, T to R, T to T, and R to R needs to be assessed based on some biosimilarity criteria under a

Substitution and interchangeability at a glance

U.S. − FDA

e FDA can designate a biosimilar as an interchangeable biologic when the following criteria are met:

1. e biologic product is biosimilar to the reference biologic product; and

2. It can be expected to produce the same clinical results as the reference product in any given patient; and

3. For a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.

Europe − EMA

Decisions on substitution are made at national level. In many EU countries, automatic substitution of biologics is officially prohibited or not recommended.

WHO

e WHO does not define standards on interchangeability for biologic medicines. It recognizes that a number of issues associated with the use of biologics should be defined by the national authorities.

Figure 4.14 Interchangeability. (Courtesy of Amgen, Thousand Oaks, California, http://www.amgen.com/img/misc/biosimilars_06_large.jpg.) 195