BIOSIMILAR DEVELOPMENT – Biosimilars: The Process & Quality System Approach to Clinical Applications


Biosimilars are medicines that are highly similar to their ap­proved reference biologics as they claim to have no clinical dif­ferences in purity, potency, and safety. For regulatory approval for a biosimilar in the US, a sponsor must demonstrate that its product is highly comparable to an FDA-approved biologic, and that any residual differences do not affect the biosimilar’s safety and effectiveness. The sponsor’s claim plays a pivotal role for use of biosimilars in specialty therapy categories, such as immunol­ogy, endocrinology, and oncology. The new discoveries of inno­vative biosimilar products continues to challenge the clinical treatments for patients suffering from chronic diseases (ie, carci­noma, sarcoma, lymphoma, etc). These new innovative treat­ments have placed immense economic burden on emerging market developments and healthcare systems delivery. According to the European Medicines Agency (EMA), there are assessment reports showing a decrease in costs and marketing of biosimilars, leading to ease of access for patients. The following addresses biosimilar developments and future innovations. Emphasis is placed on quality system approaches to the development and availability of new biosimilar products. For approvals of new biosimilars, the sponsors of premarket applications must present analytical and biological characterization to demonstrate that a proposed biosimilar is highly similar to a licensed reference prod­uct. The premarket application protocol requires a sponsor to de­scribe the biosimilar product’s PK/PD clinical data comparing its safety, efficacy, and immunogenicity to that of the reference prod­uct. Emphasis is placed on design of studies, extrapolations, in­terchangeability, and c-GMP risk-based monitoring criteria. A brief description is presented on risk-benefit analysis that guides the clinical use of the new biosimilar drug product by providing patients’ organized data and appropriate labeling information in conformance with the new biosimilar drug’s intended clinical use.1,2


Biosimilar medicines have a profound impact on patients suffering from many debilitating and life-threatening diseases, such as rheumatoid arthritis, cardiac myopathies, leukemias, lym­phomas, multiple sclerosis, and various oncogenic cancers. Biosimilars are copies of biological medicines and require strin­gent comparison against their licensed reference products (design controls, CMC, GMP, nonclinical, and clinical). Biosimilars share the same amino acid sequences as their comparative biologics, but may consist of proteins having post-translational changes due to manufacturing processes (ie, glycosylation, phosphorylation, etc) These types of modifications may impact immunogenicity. The impact of post-translational changes require similarity stud­ies, such as analytical/biological, nonclinical, and clinical in order to ensure the safety and efficacy profiles of the resulting new biosimilars. Thus, developing new biosimilars require robust strategies to achieve the goal of reduced development costs. From GMP perspectives, Chemistry, Manufacturing, and Controls (CMC) will require comprehensive comparison data requirements along with nonclinical and clinical studies. When the final data and information are available, then a global strategic roadmap can be constructed to pursue the ultimate goal of providing quality biosimilars for patients in need of treatments for debilitat­ing and life-threatening diseases. For clin­ical assessment, the comparative PK and/or PD data in addition to comparative immunogenicity, safety, and efficacy data become essential for evaluation purposes. However, the PD measures should be rel­evant to clinical outcomes after dosing to ascertain PD response in terms of sensitiv­ity and specificity to detect clinically mean­ingful differences. When all of the aforementioned essential elements are ad­dressed, a strategy can be developed with regard to manufacturing process develop­ment, biosimilarity testing, scale-up, non­clinical testing, clinical studies, marketing, and clinical utility outcomes.1-8


Biosimilar medicines have been es­sential in the treatment of diseases ranging from autoimmune diseases to various types of cancers. The US biosimilar ap­proval process requires a thorough char­acterization of the molecular structure of the proposed biosimilar product with clin­ically meaningful outcome. In other words, the proposed biosimilar is expected to pro­duce clinical outcomes that are not signif­icantly different from those expected with licensed reference biologic drug approved by the FDA. This publication is intended to present guidances in reference to FDA’s regulatory framework for organizing spon­sor’s data in biosimilar 351(k) application. An example is the anti-CD 20 monoclonal antibody, rituximab, which has revolution­ized the treatment of patients suffering from non-Hodgkin’s lymphoma (NHL). In 2014, the National Cancer Institute (NCI) stated that since 1997, deaths due to NHL decreased each year and continue to fall. Recent information in regard to immune-oncology therapies have provided new treatment examples for patients with ad­vanced cancers, such as lung cancer and melanoma. Other biologic medicines, such as epoetins, infliximab, and filgras­tims have played important roles in the treatment of patients with serious life-threatening situations. These types of bio­logic medicines were developed based on data presented in comparison to approved reference products. These developmental paradigms have the potential to improve the affordability and accessibility and cost of biosimilar medicines (ie, TNFa inhibitors known as Humira, Enbrel, and Remicade). These studies have provided opportunities for developers and providers to make it available to patients and payers potentially significant cost savings. Neverthless, these kinds of advancements and opportunities make it possible for patients with clinical outcomes that are meaningful in comparison to original biologic-innovator drug products.9,11


The developmental perspectives con­sist of characterization of basic structures, such as protein backbone (physicochemi­cal) properties of the biosimilar product and biological activities associated with it. It may not be limited to primary, second­ary, tertiary, or quaternary protein struc­tures, but post-translational modifications may occur due to manufacturing processes, which may influence the func­tionality of the protein. For instance, effec­tor mechanisms associated with monoclonal antibodies may require as­sessing the biological activity of the biosimilar product in terms of receptor binding and pharmacodynamic effect. Fi­nally, other properties of the biosimilar poduct, such as formation of residual ag­gregates may require testing and accept­ability.8

Sponsors of innovative new biosimilar drugs follow the appropriate ICH guid­ance in regard to preclinical characteriza­tion of safety and effectiveness.4,6,9 These studies involve testing in a relevant animal species, which represent appropriate re­ceptor binding studies. The developmental paradigm for a new biosimilar drug em­phasizes clinical evidence to demonstrate that safety and efficacy of each indication for use is similar to the reference product’s clinical safety and efficacy information. While development of innovative biosimi­lars usually focuses heavily on clinical studies, the FDA’s guidances describe sim­ilarity studies at the physicochemical and biological level using a variety of analytical techniques (ie, cellular bioassays are con­sidered to be useful in comparing receptor binding kinetics and bioactivity).8


The sponsors of biosimilar 351(k) ap­plications have shown that clinical studies usually include side-by-side comparisons of pharmacokinetics, pharmacodynamics, immunogenicity, safety, and efficacy as de­scribed below:

Pharmacokinetic Studies: The pharmaco­ kinetic (PK) profiles of biosimilar biologic drugs are dependent on many factors, in­cluding product-specific characteristics, such as small differences in the quality at­tributes of a candidate biosimilar in com­parison to a reference product, which may potentially lead to differences in drug ab­sorption, distribution, metabolism, or ex­cretion.11 These types of clinical studies (ie, human PK/PD studies) play a central role in the biosimilar developmental process. Furthermore, these studies provide sensi­tive tools to assess potentially clinically rel­evant differences between candidate biosimilar and reference biologic. Human PK studies are generally conducted in a well-defined healthy-sensitive population who are not prescribed other medicines that could interfere with baseline human PK studies.8,12

Clinical immunogenicity studies in a healthy-sensitive population also provides information in regard to duration studies (antibody titers) after extended exposure to biosimilar product.8,9 Confirmatory safety and efficacy studies are helpful in assess­ing clinically relevant differences between the candidate biosimilar and reference product. These types of studies depend on whether PK studies are designed and con­ducted in settings to detect sensitivity to change. The type of study performed de­pends on whether that study is designed for parallel or cross-over groups. Gener­ally cross-over studies are not feasible due to the long half-lives associated with many biologic products, particularly monoclonal antibodies. For biosimilars with relatively short half-lives, such as filgrastims, insulin, or certain fusion proteins, cross-over stud­ies are preferred. Additionally, host factors, such as receptor affinity and patient status, may affect the disposition and clearance of biosimilar. Furthermore, concomitant medications (ie, immunosuppressants) may affect the PK of the biosimilar prod­ucts and could mask differences between the candidate biosimilar and the reference product. For those situations, particularly where monoclonal antibodies are used for cancer treatment, patients receiving first-line therapy with minimum heterogene­ity/prior therapies may show minimum impact on the clinical PK profile of candi­date biosimilar and reference product.8,11

It is important to consider the design of study for biosimilar’s route of adminis­tration and absorption kinetics for com­parative PK profiles. Bioequivalent testing protocols are very helpful to assess PK sim­ilarities. Many biologics biosimilars are usually administered via intravenous injec­tion or infusion, making bioavailability ap­proximately 100% possible. However, for a candidate biosimilar intended to be ad­ministered subcutaneously, simply com­paring Cmax and AUC methods may not be suitable to assess the PK similarity of the candidate biosimilar and its reference. In those situations where there are differ­ences in absorption and distribution modes, analysis and comparison of addi­tional PK parameters (ie,T1/2, Ke, and Cl) distribution and clearance of biologics biosimilars may be useful. From a clinical perspective, methods used to determine serum concentrations in test results from volunteers/patients need to be validated with the guidelines and standards based on (National Committee for Clinical Lab­oratory Standards-NCCLS). Notably, NCCLS recognized ligand-binding assays are used for the detection of patient sam­ple analytes for US FDA premarket ap­provals.1-14

Pharmacodynamic Studies: Human phar­macodynamic (PD) profiles play a central role in detecting any clinically relevant dif­ferences that may exist relating to the as­sessment of biosimilarity between a biosimilar and reference biologic.13 PD testing is aimed at determining a safe dose range in which a biosimilar drug can be administered and the methods of absorption and distribution in the body are de­termined. A primary consideration in these studies is limiting risk to the subjects and determining safety or toxicity limits. These studies usually include PK and PD testing to help establish the relationship between biosimilar drug dose and plasma concen­tration levels, as well as therapeutic or toxic effects.8,12,13

Clinical Safety & Efficacy Studies: Clini­cal safety assessment for biosimilar prod­ucts consist of a comparison of the overall adverse event profile inclusive of specific types of adverse drug reactions occurring after the initiation of treatment. It is useful to compare the types of hazards and severity levels of adverse reactions in those events that have been observed through­out the reference product’s life-cycle in order to determine whether the candidate biosimilar product has shown new safety concerns. This type of study helps selecting a patient population that determines likelihood of detecting a difference in critical control points in the assessment of clinical differences. This may become an issue for the assessment of safety profile parame­ters for testing the biosimilar product’s side-by-side comparison for monotherapy versus concomitant therapies. This type of testing in a relatively homogeneous popu­lation may increase the ability to detect dif­ferences in safety parameters by reducing perplexity that may occur due to the use of concomitant medications and/or presence of concomitant conditions. This type of testing is helpful in detecting meaningful differences between safety profiles of biosimilar assessment. For this perspective, appropriate risk management study de­sign and post-marketing surveillance for new biosimilars are crucial for the strengthening of the safety database. Therefore, this type of approach, for the proposed labeling of the biosimilar prod­uct indicates the same risks to patients as the reference product’s labeling.

Clinical efficacy assessment for a biosimilar product is a key component of the FDA’s approval process. When design­ing the clinical efficacy studies, it is impor­tant to consider the relevant mechanism(s) of action considering all the indications for use sought for approval. It is known that some biologics can function through mul­tiple mechanisms of action, and the mech­anisms involved in the treatment of one disease may not be the same as mechanisms involved in the treatment of other diseases. The ability to detect a difference is of utmost importance for the candidate biosimilar’s development. In order to max­imize the sensitivity of a clinical efficacy study, sponsors should perform a thor­ough review of the available clinical data for the reference product in order to deter­mine the population-endpoint associated with the study database. By performing a thorough systematic review of data avail­able for the reference product, the biosim­ilar product’s sponsor can identify critical control points of the new biosimilar prod­uct in terms of magnitude of effect and the timing of response that are necessary to guide study design in establishing clinically meaningful similarity margins. The pri­mary endpoints should provide adequate sensitivity margins to detect differences in efficacy of the candidate biosimilar in comparison to the reference product. The clinical sensitivity protocol (ie, ability to de­tect the endpoint differences) is important for the candidate biosimilars. In order to achieve the maximum clinical efficacy sen­sitivity, the protocol should include both se­lection of well-defined populations and endpoints that in combination will be sen­sitive to detect differences that may provide clinical efficacy profile of candidate biosimilar in comparison to the licensed reference product. This type of data com­parison provides assessment of candidate biosimilar’s population endpoints that may be associated with a large effect size and a robust historical reference product’s available dataset. These studies performed in comparison to reference product, the sponsor of candidate biosimilar 351(k) application can identify manufacturing critical control points inclusive of the mag­nitude of effect and the timing of response that are necessary to establish clinically meaningful similarity margins. The pri­mary goal for determining endpoint(s) should be to provide acceptable sensitivity to detect differences/similarities in clinical efficacies of the comparative data. For in­stance, there are several endpoints com­monly used to assess the efficacy of biosimilar products.15,16

Generally, overall survival is consid­ered a quality indicator for the demonstra­tion of clinical efficacy for innovative new biosimilars for oncology treatments. Com­paring endpoints for early applications, such as response rates or progression-free survival may be more appropriate in some oncology settings. The important factors being the overall affect of study population endpoints and the timing of therapeutic ef­fects in regard to duration of treatment and follow-up. The comparative studies to demonstrate clinical efficacy of new biosimilars should be designed and pow­ered to test a hypothesis of equivalence, and this should include randomization and double-blinded factors. The selection of equivalence margins should be part of predesigned protocols based on statistical applications and historical data available for the reference product. Predefined equivalency margins include differential criteria for efficacy determination consid­ered clinically meaningful.17

Immunogenicity: Immunogenic studies have an impact on PK/PD, safety, and ef­ficacy of biosimilars. Structural and man­ufacturing changes in a biosimilar can have different immunogenic responses. For instance, formulation changes in a product containing epoetin alfa have been reported to show a significant rise in the number of cases of red cell aplasia in chronic kidney disease patients due to generation of neutralizing antibodies that cross-reacted with endogenous proteins.18 The formation of anti-drug antibodies (ADA) has been reported with severe acute infusion reactions affecting immunogenic­ity responses in patients.19 Furthermore, anti-drug antibodies (ADAs) have been shown to interfere with the clinical efficacy of biologic drugs, such as the anti-TNF an­tibodies that are useful in the treatment of a number of autoimmune diseases.20 The modified complexity of biosimilar struc­tures has been reported that differences in post-translational modifications, such as folding and conformational changes, could lead to differences in the elicit re­sponse to immunogenicity.21,22 Therefore, it is essential that sponsors of new biosim­ilar applicants assess the formation of ADAs in comparative clinical studies in order to determine whether processed mo­lecular differences might lead to differ­ences in the immune responses, which subsequently could affect safety/efficacy of the new biosimilar product.

In designing immunogenicity studies, patient-specific factors play a key role in the interpretation of data (ie, genetic fac­tors, age, concomitant medications, dura­tion, and route of administration, previous exposure to similar products – any or all of these factors may contribute to patient’s risk of developing ADA against the candi­date biosimilar). Also the underlying dis­eases of study participants may influence the rate of ADA against a particular biosimilar product. It has been reported that infliximab had shown rate changes from 7% to 61% in patients with psoriasis, ankylosing spondylitis, Crohn’s disease, and rheumatoid arthritis.14,23 All of these factors should be considered in design and interpretation of the immunogenicity studies for the new biosimilar product.24

Extrapolation: The concept for extrapola­tion is based on the principle that biosim­ilar product has demonstrated that intended clinical use and its outcome will not differ meaningfully whether a patient receives the candidate biosimilar or its ref­erence product. Extrapolation must be supported by scientific evidence of the can­didate biosimilar’s human PK/PD, safety, and efficacy data in a well-defined patient population based on a similar safety and efficacy profile as reference biologic. It is essential that both the candidate biosimilar and licensed reference product share the same mechanism of action.10 The biosim­ilar sponsor need not conduct clinical stud­ies in every indication for use described in the reference product’s labeling. Instead, the FDA guidance advises the biosimilar applicant to conduct clinical evaluations in one or two indications, then provide scien­tific justification for extrapolating clinical data to support a determination of biosim­ilarity for each condition of use for which licensure is sought. The underlying ration­ale under the concept of extrapolation is the scientific principle that biosimilar pro­tein structure determines the molecular (output) function, clinical PK/PD data, safety, and efficacy outcome of the pro­posed biosimilar product.

The essential biosimilar parameters of extrapolation are listed below:

  • The uncertainty margin or acceptable analytical/functional differences be­tween the candidate biosimilar and the licensed reference product
  • The mechanism of action (MOA) of each indication for use and the justifi­cation that the residual differences will not contribute to any meaningful differ­ences in the clinical safety and efficacy of the biosimilar’s intended use sought by extrapolation
  • High similarity in PK/PD comparisons of the candidate biosimilar and the refer­ence product’s established indications for use and the justification that any residual differences will not contribute to misinterpretation of data (extrapola­tion justification that residual differences will not lead to any meaningful differ­ences in safety, effectiveness, and im­munogenicity sought by extrapolation)
  • Clinical safety and immunogenicity pro­files of the new biosimilar and licensed reference product are compared for in­dications for use, and the justifications are provided that residual differences will not contribute to safety and effec­tiveness bias under extrapolation studies

The FDA’s guidance for extrapolation states that data derived from clinical stud­ies should be sufficient to demonstrate pu­rity, potency, safety, and the intended use of the proposed biosimilar product in com­parison to licensed biologics.10 The spon­sor of biosimilar 351(k) application may apply for licensure for one or more indi­cations for use based on MOAs for which the reference product is licensed. MOAs for safety and efficacy for different indica­tions present a major challenge for extrap­olation.25 For instance, MOAs for hormonal protein drugs may be different from antibody drugs. Hormonal protein drugs, such as human growth hormone (hGH) somatropin, generally have similar structure and function as the corresponding endogenous hormones, and their MOAs are considered to be identical with the same binding receptor with identical biological effects. Whereas MOAs for an­tibody drugs may be different due to com­plexity of antibody structure, especially the complexity of post-translational modifica­tions, such as glycosylation causing differ­ent structural variations of the same antibody whose residual mixture could be different from batch to batch technically making it difficult an exact copy of anti­body drug. Structural residual uncertainties in the antibody structure could be detected during the physico-chemical characteriza­tion step in the manufacturing process.10 Glycosyation may have potential impacts on the PK/PD of the biosimilar drug anti­body.25,26 Remicade (infliximab) biosimilar was approved for inflammatory diseases, such as ankylosing spondylitis (AS), inflam­matory bowel diseases (IBD), psoriatic arthritis (PsA), plaque psoriasis (PsO), and rheumatoid arthritis (RA). Clinical studies for the proposed biosimilar Inflectra/Rem­sima (CT-P13) were conducted for AS and RA and extrapolation to IBD. In these stud­ies, the structural uncertainties reached to lower levels of glycans, which caused to lower antibody-dependent cell-mediated cytotoxicity (ADCC) responses.

Adalimumab biosimilar ABP501, biosimilar of Humira, was approved for rheumatoid arthritis (RA), Juvenile idio­pathic arthritis (JIA) in patients approxi­mately 4 years or older, AS, PsA, UC, adult CD, and PsO, while the clinical studies for the proposed biosimilar ABP501 was con­ducted in PSO and RA. The physico-chem­ical characterization (with no major residual uncertainties reported) provided justification for extrapolation in compari­son to CT-P13.27 The clinical studies sup­porting the similarity of ABP501 included single-dose PK similarity study in healthy subjects, which was conducted to assess PK parameters simply because these sub­jects were not under concomitant medica­tions treatments and did not have medical conditions that could potentially affect PK. The study showed PK equivalence assessed by AUCinf and Cmax between ABP501 and US approved licensed product.28 Ad­ditional study in subjects with moderate to severely active rheumatoid arthritis and plaque psoriasis demonstrated clinical similarity (safety, efficacy, and immuno­genicity) for ABP501and the reference product.28 Additionally, the study results in­dicated that there was no increased risk to safety, efficacy, and immunogenicity switching from reference product to ABP501.28

Scientific justification for the biosimilar candidate’s extrapolation is based on the totality of evidence presented to demon­strate the analytical characterization of high similarity coupled with high similarity in functional testing for a solid extrapola­tion justification.9,10 The justification goal for extrapolation of safety is dependent on reducing the residual uncertainty. It is crit­ical that residual uncertainty will not con­tribute to any significant difference in clinical safety and efficacy in indications sought by extrapolation.

Interchangeability: The FDA requires switching studies (at least three switches) with primary endpoints measuring PK/PD providing assessments for sensitive changes in immunogenicity and efficacy.8 The FDA guidance (FDA 2017b) addresses the use of post-marketing data for a biosimilar product with real-time evidence providing sensitive PK/PD information as a part of post-marketing surveillance process.5,6,8 Current biosimilars include Humira, Enbrel, Rituxan, Remicade, Avastin, Herceptin, and Lantus in their re­spective lists of top drugs that are widely available through the FDA’s approval process.29 A biosimilar applicant can apply for interchangeability status (1 year inter­changeability exclusivity is allowed). To achieve interchangeability approval, the biosimilar applicant is required to show substantial switching studies between the candidate biosimilar and RP. However, the 1-year exclusivity applies only to inter­changeability status. Biosimilar candidate product is expected to produce the same clinical result as the RP in any given patient and also not to pose excessive risks to patients if they switch between the RP and in­terchangeable product without the intervention of the biosimilar product’s pre­scriber – the interchangeable product may be given in place of the RP at the pharmacy level (Interchangeability Guidance, US FDA 2017a). The FDA expects minimum im­munogenicity risk-related outcomes by switching candidate biosimilar and RP products. The PD/PK endpoints become es­sential sensitivity indicators in the switching studies. The important point of the FDA’s stepwise approach is to consider the out­come supporting biosimilarity assertions in its totality of evidence (ie, filgrastim and be­vacizumab interchangeability studies)13,16,22,30


Biosimilars have recently emerged as a new class of biologic drug that has the potential to have access to many critical medicines through the reduction of costs. Furthermore, there is need to ensure that new biosimilars are as safe and effective as their innovative counterparts. To date, there are approved biosimilar drugs, span­ning a variety of indications for use-from autoimmune disease to growth deficiency, that have fulfilled the needs for the treat­ment of diseases/abnormalities. It is ex­pected that future biosimilar developments will provide robust pipeline for biosimilars intended to be used in oncology and other severe diseases. At the same time, the manufacturers of biosimilars will have to stay abreast of these biosimilar drugs development and the new technologies, such as the interpretation of data from switching and interchangeability studies. The FDA’s guidance on demonstration of inter­changeability emphasizes that alternating use of a proposed biosimilar in compari­son to the reference product would not incur more risk than the use of the refer­ence product alone. This article is primarily focused on considerations for the quality system approach to design of studies for clinical applications for designated patient populations and selection of conditions of use.


The views and opinions expressed in this article are those of the author and do not represent official views of the US FDA.


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Dr. Kaiser J Aziz completed a 30-year career with the FDA as a clinical regulatory scientist and manager of drug and device evaluations, approvals, reengineering, standards, good manufacturing and quality system applications. He worked with individual and industry organizations in design and total product life cycle (TPLC) approaches to premarket applications for medical devices, pharmaceuticals, and combination products (510ks, NDAs, and PMAs). Prior to joining the FDA, he developed and implemented quality assurance standard operating procedures and protocols for medical diagnostic systems in hospitals, physicians’ offices, and clinical reference laboratories. During his tenure at FDA, he served as an adjunct faculty in the Department of Medicine and Physiology, NIH Graduate School, where he developed and taught courses in Clinical Pharmacology, Toxicology, Therapeutic Drug Monitoring, and Clinical Laboratory Medicine. Currently, he serves as an adjunct faculty at Virginia Tech’s Medical HACCP Alliance Program, where he teaches Quality Risk Management courses and workshops using HACCP principles for the pharmaceutical industry. He was an invited guest editor on Nanotechnology and Clinical Trials in the journal of Clinical Ligand Assay. He is the author of book chapters, textbooks, and over 70 publications in professional and trade journals. His expertise includes Quality System Approach to Medical Device and Pharmaceutical Premarket Applications.