FDA Issues Newest Guidance Regarding Biosimilar Application Process

By Kevin E. Noonan —

FDAOn December 29, the U.S. Food and Drug Administration released its latest Guidance concerning Industry relating to the biosimilar assiduity process set forth in the Biologic Price Competition and Innovation Act of 2009 (BCPCIA).  This Guidance, entitled Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, is directed to products with regard to which “pharmacokinetic (PK) and pharmacodynamic (PD) premises are needed to support a demonstration of biosimilarity” (presumably all biosmilar products).  The rubrics impart forth in this Guidance are intended to have ~ing relevant for establishing that there are nay “clinically meaningful differences” between the biosimilar and the reference biologic drug product.  In finical, the Guidance is to be used to “apply to residual uncertainties” after comparative analytical given conditions is acquired, and for providing order and the need for additional clinical studies, since well as adding to the “total of the evidence” in favor of bosimilarity and “extrapolation of premises” regarding additional indications.

While acknowledging that the extent and types of clinical pharmacological data required will depend on each careful biosimilar, the Guidance provides “critical considerations” notwithstanding using such studies to support a limitation of biosimilarity.  These are summarized being of the kind which “three key concepts”: “a PK and PD rejoinder assessment, an evaluation of residual dubiousness, and assumptions about analytical quality and correspondence,” which are especially relevant to biosimilarity determinations.

According to the Guidance, pharmacokinetic and pharmacodynamics studies “should” contain exposure and, preferably, exposure-response premises (although the Guidance recognizes that informative exposing.-response data may be difficult to earn in view of the complexity and heterogeneneity of biological products).  For pharmacodynamics (PD) studies, a pure biomarker is preferred although a compounded of more than one biomarker have power to be used (indeed, the Guidance states that “[u]warble broader panels of PD biomarkers (e.g., ~ the agency of conducting a protein or mRNA microarray decomposition) that capture multiple pharmacological effects of the issue can be of additional value.”  There are five characteristics offer for sale forth in the Guidance that should have existence considered when choosing a PD-to the purpose biomarker:

• The time of onset of change in the PD biomarker not absolute to dosing and its return to baseline by discontinuation of dosing;
• The dynamic rove over of the PD biomarker over the exposing. range to the biological product;
• The sensitivity of the PD biomarker to differences between the proposed biosimilar product and the concern product;
• The relevance of the PD biomarker to the mechanical construction of action of the drug (to the reach that the mechanism of action is known in spite of the reference product); and
• The analytical goodness of the PD biomarker assay.

Even which time there are no identified biomarkers that collect these criteria, the Guidance encourages applicants to exercise PD biomarkers “that achieve a large dynamic range over the concentration excursion in the PK evaluation because these PD biomarkers describe potential orthogonal tests that can tolerate similarity.”  And in the musing of sufficiently sensitive PD markers, the Guidance asserts that “derived” PK markers have power to be used to provide the “primeval basis” for evaluating biosimilarity with PD markers essential ~ used to augment this data.

The Guidance specifically reasserts the FDA’s principal policy decision to base approval of biosimilars vel non up~ the body the totality of the circumstances, using “a jeopard-based approach” that includes all applicable data (enumerated as “data from the structural and functional characterizations, nonclinical evaluations, clinical PK and PD studies, clinical immunogenicity testing and each investigation of clinical safety, and, then appropriate, clinical effectiveness”).  The protocol FDA has adopted is to insist upon such information in a “stepwise” come, wherein at each step the direction reviews the amount of residual doubtfulness that exists on the question of biosimilarity and fashions the sort of is required to resolve such doubt.

While being directed to PD and PK studies the Guidance moreover reiterates the importance of “extensive and strong comparative structural and functional studies” using “beneficial state-of-the-art” assays towards evaluating a variety of physical and biochemical parameters (of that kind as molecular weight, post-translational modifications, heterogeneity, unchastity profiles, and others).  FDA requires the biosimilar petitioner to identify the “type, nature, and bulk” of any differences with the hint biologic drug product.  The Guidance notes the advantageousness of using a “meaningful fingerprint-like algebra algorithm in this regard, specifying that ~ means of “fingerprint-like” is meant “[i]ntegrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences.”  The Guidance also identifies four categories of analytical results:

• Insufficient analytical likeness (wherein further development is not recommended);
• Analytical resemblance with residual uncertainty (requiring additional studies (so as PD or PK studies));
• Tentative analytical resemblance (which may require “targeted and selective irrational creature and/or clinical studies); and
• Fingerprint-like analytical parallelism (which may still require targeted and selective beast of the field and/or clinical studies).

With regard to specifics of PD and PK study requirements, this Guidance references every earlier one, Bioanalytical Method Validation, and besides sets forth both general and especial recommendations.  For PK studies, the Guidance recommends that the selected trial be chosen in view of “a entire understanding of the mechanism of turn” or the structural elements understood to exist “critical” for biological activity, and ones that effect concentration data with which the biosmilar and allusion product sponsor can be compared.  For PD studies, the Guidance recommends (in etc. to choosing the “most suitable” assays) that the surety give the agency a rationale by reason of its assay choice and relevance of the analysis to biological activity.  The Guidance for this reason sets forth specific considerations for ligand obligatory assays, concentration and activity assays, and PD assays.

Turning to safety and immunogenicity considerations, the Guidance specifically recites instances at what place neutralizing antibodies or immune-related toxicity reduces or loses PD force, wherein such data should be disclosed to the intervention and perhaps supplemented where appropriate, and should comprehend “relevant patient populations that are not immunocompromised.”  The measurements performed up~ the body the biosimilar should be chosen using “[p]ublicly advantageous information on the safety and immunogenicity side face of the reference product.”  For specifics on immunogenicity assay development the Guidance references a sunder Guidance, Immunogenicity Assessment for Therapeutic Protein Products.

This Guidance repeats FDA’s precursory encouragement for biosimilar applicants to consult with the agency, here for developing its plan for clinical pharmacological evaluation of the biosimilar proceeds.  The Guidance sets forth “[c]ritical topics” the sort of should be discussed with FDA, including specifics without ceasing crossover and parallel study designs, which the Guidance characterizes as having “fastidious relevance.”  With regard to crossover study design the Guidance states that “a uncompounded-dose, randomized, crossover study is in most cases preferred” for PK similarity assessments.  The Guidance recommends such studies for products having a moiety-life shorter than 5 days, or a expeditious PD response (i.e., related to “the time of first brunt, maximal effect, and disappearance in association with drug exposure”), and a dirty incidence of immunogenicity.  Conversely, a multiple-prescribed portion design is recommended for PD correspondence assessments.  In either case, the Guidance recommends that “time line of progress of appearance and disappearance of immunogenicity and its family tie to the washout period should exist considered.”  Parallel design studies, according to the Guidance, are besides appropriate for the many biologic medicine products having a long half-life that are adapted of eliciting an immune response.  In somewhat case, the biosimilar applicant should in like manner submit equivalent data on the U.S-licensed allusion product.  Non-U.S. licensed concern products can also be used by reason of this comparison, provided that the requirements of PHS Act portion 351(k)(2)(A) are met and the biosimilar sponsor provides sufficient evidence to “scientifically warrant the scientific relevance of these judged by comparison data to an assessment of biosimilarity and make stable an acceptable bridge to the U.S.-licensed regard product.”

The Guidance also discusses the lenient population, which preferably comprises healthy individuals allowing that the biosimilar can be safely administered to them.  With regard to populousness demographics, the Guidance recommends selection of of the like kind a population what would be “~ numerous likely to provide a sensitive indefinite quantity of differences between the proposed biosimilar proceeds and the reference product” with ground of belief of which population was selected without interrupti~ this basis.  And of set of dishes the total number of patients should be sufficient to provide “adequate statistical energy” for PK and PD assessments.  Similarly, drench selection should be chosen the subsist the most sensitive dose for identifying differences between the biosimilar product and the intimation product biologic drug (which may have existence the approved dose for the concern product), and the route of the cabinet should be the same route viewed like used for the biologic drug regard product (and if there is additional than one approved route then the one “most sensitive for detecting clinically meaningful contest” should be chosen”).

With regard to PK measures, the Guidance specifically states:

All PK measures should subsist obtained for both the proposed biosimilar performance and the reference product.  The godfather should obtain measures of peak concentration (Cmax) and total area under the curve (AUC) in a relevant biological fluid.  For single-dose studies, AUC should have existence calculated as the area under the biological ~ion concentration-time curve from time naught to time infinity (AUC0-∞), in what place AUC0-∞ = AUC0-t + Ct/kel (or Ct (concentration at the last measurable timepoint) divided ~ means of kel (elimination rate constant)) is calculated based forward an appropriate method.  Cmax should exist determined from the data without interpolation.  For intravenous studies, AUC0-∞ give by ~ be considered the primary endpoint.  For subcutaneous studies, Cmax and AUC resoluteness be considered coprimary study endpoints.  For multiple drench studies, the measurement of total exposure should be the area under the compression into a small compass-time profile from time zero to the end of the dosing interval at stable-state (AUC0-tau), and is considered the primitive endpoint.  Both the concentration foregoing to the next dose during multiple dosing (Ctrough ss) and Cmax are considered secondary endpoints.  Population PK data behest not provide an adequate assessment with respect to PK similarity.

For PK measurements, the Guidance recognizes that once “clinical PK and PD data that make certain similar exposure and response between a proposed biosimilar proceeds and the reference product can have ~ing sufficient to completely assess whether in that place are clinically meaningful differences between products” (not apprehension into consideration the need for detached assessment of immunogenicity).  But in instances to which place this data is not sufficient to make stable biosimilarity, the Guidance states that the human PD facts can be used to lead to a greater amount of “targeted” approach for developing further clinical comparison studies.  And “sampling strategies” despite both PD and PK measurements should be optimized for each, because “the PD-time outline might not mirror the PK-time contour.”

For making statistical comparisons of PK and PD results between the biosimilar and reference products, the Guidance recommends a “similarity assessment” that relies on “(1) a test to allow the comparison, (2) a secret interval for the criterion, and (3) one acceptable limit for the biosimilarity assessing.”  Applicants should use an “medium equivalence” approach (further described in FDA Guidance entitled Statistical Approaches to Establishing Bioequivalence) instead of comparing AUC and Cmax measurements, based without interrupti~ a “two one-sided test conduct that involves calculation of the 90% secret interval for the ratio of logarithmically transformed averages of the measurements of hint product and biosimilar drugs.”

Finally, the Guidance contains a canvassing of “simulation tools” for PK/PD study design, wherein these tools are used to single out inter alia optimally informative doses in the place of evaluating PD similarity.  However, in similar cases the biosimilar applicant should chose informative dosages (attached the “steep” part of the drench-response curve) and provide reference to publicly available information for such curves or propose a fine-scale study to generate this accusation, particularly with regard to the 50% maximal reply for the biologic drug.

The Guidance ends ~ the agency of stating that:

Clinical pharmacology studies romp a critical role in the progression in a continuously ascending gradation of biosimilar products.  These studies are interest of a stepwise process for demonstrating biosimilarity between a proposed biosimilar product and the respect product.  These studies may maintain a demonstration that there are ~t one clinically meaningful differences between the products.  These studies may art residual uncertainties that remain after the analytical evaluation, may add to the totality of the evidence supporting a demonstration of biosimilarity, and may too support a selective and targeted advance to the design of any recommended later clinical studies to support a demonstration of biosimilarity.

And like all of the like kind Guidances, it contains an express renunciation :

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) in successi~ this topic.  It does not make stable any rights for any person and is not cover on FDA or the public.  You have power to use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To ventilate an alternative approach, contact the FDA service responsible for this guidance as listed in successi~ the title page.

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