4.6 Fingerprint similarity

Understanding biosimilarity

the product is similar to ngerprint-like comparisons, no further studies may be required if the similarity data removes residual uncertainty. It is important, therefore, to understand what constitutes residual uncertainty. As discussed earlier, any uncertain or unexpected observation about the product creates a residual or remaining uncertainty. Note that it is not the uncertainty or the unexpected observations but that these remain uncertain is the focus of description. For example, if the biosimilar candidate shows extra chromatography peaks that are fully identi ed and are established to not impact the structure of the protein at any level, then these do not remain residually uncertain.

The regulatory guidance provided by the FDA has always been evolutionary and in some instances revolutionary—in the case of biosimilars, it is the latter; the concept of biosimilarity is based on the scienti c rationale that has evolved, yet still questioned by many. A good example of how the FDA, unlike any other regulatory agency in the world, takes a bold step is exempli ed by the example of the approval of low–molecular weight heparin (LMWH). The product was approved without any phase 3 clinical trials, despite the hue and cry by the originator of the product (meaning several citizens’ petitions, extensive press coverage to clinicians to confuse the science, and commercial efforts to protect a multibillion dollar franchise). The FDA stated that

the EMA has set guidelines for LMWH products such as enoxaparin that only require the products to contain a similar (as opposed to the same) active ingredient to that contained in another already marketed LMWH product. Because the proposed LMWH product in Europe will contain an active ingredient that is similar to (as opposed to the same as) the brand name product, there might be uncertainties as to whether the two products are the same with regard to safety and effectiveness. Thus, sponsors of a similar enoxaparin product under the EMA framework are expected to provide clinical studies showing comparable effectiveness to the proposed similar LMWH product as well as clinical data showing comparable safety (including with respect to Heparin Induced Thrombocytopenia).

In contrast, the FDA requires a generic enoxaparin product to contain the same active ingredient as Lovenox. Based on the FDA’s scienti c experience and expertise, and relevant scienti c information, the FDA has concluded that the ve criteria (see response to Q#8) are suf cient to ensure that the generic enoxaparin product has the same active ingredient as Lovenox. The FDA also evaluates impurities in the generic enoxaparin product, particularly with respect to their effect on immunogenicity. With the FDA approach, there is no scienti c need to perform additional clinical studies to demonstrate equivalence of clinical effectiveness and 163

Biosimilarity: The FDA Perspective

safety of generic enoxaparin to Lovenox. Although the EMA Guideline requires clinical studies to demonstrate comparable effectiveness to a similar LMWH, the FDA notes that its approach (i.e., the ve criteria) is more sensitive to differences between two enoxaparin products than the clinical studies recommended in the EMA guideline.

Thus, sponsors of a similar enoxaparin product under the EMA framework are expected to provide clinical studies showing comparable effectiveness to the proposed similar LMWH product as well as clinical data showing comparable safety (including with respect to Heparin Induced Thrombocytopenia).

Figure 4.6 shows the ve criteria used in the approval of enoxaparin to show its ngerprint-like similarity. The reason why I provided the example of enoxaparin, which is not a protein, is because this product is at least as equally complex as proteins, perhaps more, when we look at the simple proteins as lgrastim and growth hormone. No other regulatory agency in the world allows two levels of approval of biosimilars—biosimilars and interchangeable biosimilars. A signi cant market advantage can be gained if a product is approved as interchangeable. In most cases, the sponsor reaching this level of similarity will be able to request a waiver of any further clinical trials in patients and in most cases in healthy subjects. This has long been the goal of many regulatory agencies and, in its true expression, holds the promise to reduce

FDA developed five criteria for fingerprinting evaluation of enoxaparin

Equivalence of physiochemical properties

Equivalence of heparin source material and mode of depolymerization

Equivalence in diasaccharide building blocks, fragment mapping, and sequence of oligosaccharide species

Equivalence in biological and biochemical assays

Equivalence of in vivo PD profile FDA: “ e five criteria ensure that generic enoxaparin will have the same active ingredient components as those of Lovenox’s enoxaparin (within the context of its variability) even though the contribution of each component has not been fully elucidated. erefore, pharmacological activity of the active ingredient of the generic enoxaparin and that of Lovenox can be expected to be the same.”

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Figure 4.6 Fingerprinting and enoxaparin: The FDA perspective. (From FDA—Biosimilars: An Update—Focused on Quality Considerations, http://www.fda.gov/downloads/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs/AdvisoryCommitteefor PharmaceuticalScienceandClinicalPharmacology/UCM315764.pdf.)