Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_101_библиотеки_им_акад_М_И_Перельмана

The methods dened in ICH Q6B are used to appropriately characterize the reference product. Some of these characterizations involve determining the physicochemical qualities, biological activity, immunochemical properties (if any), purity, impurities, contaminants, and quantity. Developers are encouraged to adopt newer technologies as available. As the quality attributes of the reference product vary from batch to batch, it is essential to establish the range of these variations to allow similar variability in the biosimilar candidate. The variations are either process- related (the expres­sion system) or product- related (the manufacturing system). Generally, any variation in the product­related attributes cannot be resolved, requiring the developer to create a different expression system; the same can be the case for process- related attributes, but these are readily xed. In both cases, safety studies cannot be submitted to justify a signicant difference.

For some analytical techniques, direct or side- by- side analysis of a proposed biosimilar and ref­erence product may not be feasible or may provide limited information (e.g., because of the low concentration of the active substance and the presence of interfering excipients such as albumin). Thus, samples could be prepared from the nished product (e.g., extraction, concentration, and other suitable techniques). In such cases, the methods used to prepare the samples should be outlined. Their effect on the samples should be appropriately documented and discussed (e.g., comparing active substances before and after formulation/ reformulation preparation).

Regulatory agencies are particularly sensitive to compliance with 21 CFR Part 11, a consider­ation where many companies frequently fail. Noteworthy, the agencies do not necessarily require that any IT basis is created; often, a manual record will also qualify, but the developer should always be able to prove that the original data remain intact and that it could not be manipulated.

A proposed biosimilar comparability exercise should include assessing the biological proper­ties of both the proposed biosimilar and the reference product as an essential step in establishing a complete characterization prole. Biological activity is the specic ability of the product to achieve a dened biological effect. Biological assays that use different and complementary approaches to measure the biological activity of the product should be considered, as appropriate. Depending on the

product’s biological properties, different types of assays can be used (e.g., ligand or receptor binding assays, enzymatic assays, cell- based assays, and functional assays), considering their limitations.

Next, complementary or orthogonal approaches should be performed to address any limitations in the validation characteristics of single bioassays. If relevant, separate assays should be performed to evaluate the binding and activation of receptors. Where appropriate, cross- reference to nonclinical and clinical section(s) of the dossier may be made. Biological assays are sensitive, specic, and suf­ciently discriminatory. The results of relevant biological assay(s) should be provided and expressed in units of activity calibrated against an international or national reference standard, when avail­able and appropriate. These assays should comply with appropriate requirements of the European Pharmacopoeia for biological assays, if applicable.

The purity and impurity proles of a proposed biosimilar and the reference product should be compared qualitatively and quantitatively by combining different analytical procedures. Appropriate orthogonal and state- of- the- art methods should be used to identify and compare product- related substances and impurities. This comparison should consider specic degradation pathways (e.g., oxidation, deamidation, and aggregation) of the proposed biosimilar product and the potential PTMs of the proteins. The age/ shelf- life of the reference product at the time of testing should be mentioned, and its potential effect on the quality prole should be discussed, where appropriate. A comparison of the relevant quantitative attributes tested at selected time points and storage conditions (e.g., accelerated or stress conditions) could be used to further support the similarity of the degradation pathways between the reference product and the biosimilar.

CQAs should be identied using analytical and in vitro functional tests. Functional experiments should be pertinent to the potential MOA in all therapeutic indications, including those that deter­mine apoptosis, complement- dependent cytotoxicity, antibody- dependent cellular phagocytosis, and antibody- dependent cellular cytotoxicity. Unless there is compelling evidence to the contrary, a biological occurrence should be considered when determining whether it applies to the MOA. Functional tests (ADCC, ADCP, and CDC) are not necessary for a reference product that primarily targets a soluble antigen.

Generally, eight batches will be tested, one of which should be the clinical batch. Therefore, the nal third- party analytical assessment will include at least three Pharmaceutical Process Qualication (PPQ) lots. More details are found later in the discussion of analytical assessment statistics.

In case relevant quality differences are conrmed (for which the absence of a clinically rele­vant effect will be difcult to justify), it may be challenging to claim similarity to the reference product, and thus, a complete application for marketing authorization may be more appropriate. Alternatively, the applicant could consider adequate revision of the manufacturing process to min­imize or avoid these differences.

It is not expected that all quality attributes of a proposed biosimilar product should be iden­tical to those of the reference product. However, where qualitative and quantitative differences are detected, such differences should be justied and, where relevant, demonstrated to have no effect on the product’s clinical performance. This may include additional non- clinical and clinical data, as outlined in the guidelines on similar biopharmaceutical products containing biotechnology- derived proteins as active substances: nonclinical and clinical issues. Particular attention should be given to quality attributes that might affect immunogenicity or potency or have not been identied in the reference product.

PK/ PD studies are pivotal to establishing analytical similarity; immunogenicity similarity, in some instances; and bioavailability, where applicable. Generally, studies conducted in healthy subjects will be more meaningful for two reasons: rst, to recruit subjects with a narrow demographic vari­ation to reduce the inter- and intra- subject variability, and second, to reduce the impact of disease and related treatments on the disposition prole. However, in some instances where the likelihood of the production of antidrug antibodies is very high, more particularly for an endogenous product, it may be unethical to recruit healthy subjects owing to unnecessary drug exposure, requiring the use of a patient population. Regardless of the choice of the population, the goal should be to reduce the number of subjects in the study; in this regard, the developers can conduct a two- arm (two- dose), parallel, two- phase (dose 1 and dose 2) study with a follow- up duration suitable for immunogen­icity evaluation; there may be situations where PD determination may restrict the use of this model. The developers may also conduct a post hoc analysis, especially when a study fails to meet the predetermined acceptance criteria, to facilitate the discussion of whether the pre- determined criteria could have been made broader. A post hoc analysis does not aim to change the acceptance criteria retrospectively but rather to determine whether the failed study constitutes a signicant residual uncertainty. The post hoc analysis may not include additional characterization of the results that are closer to the midpoint of the acceptance range as erroneously suggested in some guidelines established by other agencies.

The US FDA has recently issued guidelines to remove the requirement to test clinical immuno­genicity of insulin if it meets analytical similarity testing; the factors responsible for this waiver are a smaller molecule with less complexity. More waivers of this type can be expected in the future.

PK and pharmacodynamic (PD) studies, which are an extension of analytical evaluation, reect how the body perceives the chemical and vice versa. For a product used as intravenous adminis­tration, PK studies are necessary to evaluate the degree and strength of receptor binding that may alter PK characteristics such as the drug distribution volume and clearance, even if a biosimilar is not administered parenterally, such as a biosimilar injected into the eye. PK/ PD studies aim to com­pare the proles of the reference product and the biosimilar candidate, not to characterize them; therefore, such studies can be performed on a homogeneous population to decrease inter- and intra­subject variability and reduce study sample size. A robust design should accommodate a crossover or parallel design. A crossover approach can easily reveal changes but might not be appropriate for reference products that are robust inducers of immune responses or long half- lives. Modeling and simulation should be performed to optimize the study design, including selecting the most sensitive dose(s), study population, and sample size PK differences, if relevant population PK or PK- PD models for the reference product are available in the literature. Both linear (nonspecic) clearance and nonlinear (target- mediated) clearance should be considered through dosage choice and assessment of partial areas under the curve (AUCs). The statistical approach should specify any modications for body weight or additional variables (such as sex/ gender) to be used in the statistical analysis of a parallel- group experiment. The equivalence margins must be pre- specied, and the appropriate range is often 80.00%– 125.00%. The key PK parameters, typically AUC C

Although the comparison of target- mediated clearance is of signicance in the biosimilarity exer­cise, it may not be feasible in patients because of major variability in target expression, including variability over time. However, because in vitro studies are expected to show comparable inter­action between a proposed biosimilar and its target(s) (including FcRn for a monoclonal antibody), the absence of a pivotal PK study in the target population is acceptable if additional PK data are collected during efcacy, safety, and PD studies to allow evaluation of the clinical impact of variable PK and possible changes in PK over time. These correlations can be made by determining the PK prole in a subset of patients or in a population.

If the reference product can be administered both intravenously and subcutaneously, then the evaluation of subcutaneous administration will usually be sufcient to cover both absorption and elimination. It is possible to waive the intravenous administration assessment if the proposed biosimilar comparability in both absorption and elimination has been demonstrated for the subcuta­neous route. The PK study of intravenous administration needs to be conducted when the molecule has an absorption constant much slower than the elimination constant (ip- op kinetics).

In a single- dose PK study, the primary parameters are AUC and AUC

In any PK study, antidrug antibodies should be measured parallel to the PK parameters using appropriate sampling time points.

Immunogenicity testing of a proposed biosimilar and the reference product should be conducted within a proposed biosimilar comparability exercise using the same assay format and sampling schedule, which must meet all current standards. Analytical assays should be performed with both the reference product and the proposed biosimilar molecule in parallel (in a blinded manner) to measure the immune response against the product that was received by each patient. The analyt­ical assays should preferably detect antibodies against both the proposed biosimilar and the refer­ence product. Yet, they should at least detect all antibodies developed against a proposed biosimilar molecule. Usually, the incidence and nature (e.g., cross- reactivity, target epitopes, and neutral­izing activity) of antibodies and antibody titers should be measured and presented. They should be assessed and interpreted about their potential effect on clinical efcacy and safety parameters.