JOURNAL OF MARKET ACCESS & HEALTH POLICY

2023, VOL. 11, 2147286

[Link]

Proposal of International Council for Harmonization (ICH) Guideline for the

Approval of Biosimilars
a
Sarfaraz K. Niazi , Waleed Mohammed Al-Shaqhab and Zafar Mirzac
a
College of Pharmacy, University of Illinois, Chicago, IL, USA; bPharmacology Department, College of Medicine, Imam Muhammad Ibn Saud
Islamic University, Riyadh, Kingdom of Saudi Arabia; cSchool of Universal Health Coverage, Shifa Tameer-i-Millat University, Islamabad,
Pakistan

ABSTRACT ARTICLE HISTORY

Objectives: Since the initial release of biosimilars 18 years ago, regulations for their licensing Received 2 August 2022
have changed considerably; however, there is no global consensus on these regulations. Revised 7 November 2022
Accepted 9 November 2022
Establishing harmonized regulatory guidelines for the approval of biosimilars with support
from the ICH, an independent, non-profit association under Swiss law, will significantly enhance KEYWORDS
the affordability of biological drugs. Biosimilars; International
Methods: Regulatory guidelines from the Food and Drug Administration (FDA), European Council for Harmonization;
Medicines Agency (EMA), Medicines and Healthcare products Regulatory Agency (MHRA), and Food and Drug
World Health Organization (WHO) were analyzed for historical changes and elements critical to Administration; European
the safety and efficacy of biosimilars. Medicines Agency; global
approval; regulatory
Results: Analysis of all EMA and FDA filings show that none of the animal testing and clinical
guidance
efficacy testing failed because animals do not have the required receptors to initiate pharmaco­
logic responses, and efficacy studies cannot be statistically powered to conclude any results. New
analytical technologies will enable good biosimilarity determination, avoiding both tests.
Conclusion: Scientifically based ICH guidelines that remove redundant studies will reduce
development costs, improve safety, and allow global drug distribution based on single compli­
ance. These guidelines are particularly necessary for emerging countries lacking the expertise and
resources to evaluate biosimilar filings.

Background
be rationalized and harmonized because of concerns
The International Council for Harmonization (ICH), formerly related to the rising cost of healthcare, escalating costs of
the International Conference on Harmonization (also known research and development, and the requirement to rapidly
as ICH), held inaugural assembly meetings on make safe and effective new treatments available to
23 October 2015, to establish the ICH as an international patients. The founding members of the ICH are the EU,
association and legal entity under Swiss law [1]. This foun­ the US, Japan, and the UK (added post-Brexit on
dation has a 25-year track record of successfully delivering 16 June 2022) [2]). The founding industry members were
harmonized guidelines for global pharmaceutical develop­ the European Federation of Pharmaceutical Industries
ment and regulation, and it has long recognized the need (EFPI) and Japanese Pharmaceutical Manufacturer’s
to harmonize various guidelines. In the 1960s and 70s, the Association (JPMA), and the Pharmaceutical Research and
laws, rules, and standards for reporting and analyzing data Manufacturers of America (PhRMA). The standing regula­
on the safety, quality, and efficacy of new pharmaceutical tory members are Health Canada and Swissmedic, and 20
goods in most countries were greatly expanded, regardless regional legislative authorities are also members.
of whether the countries had previously implemented pro­ The ICH guidelines provide extensive details on the
duct registration procedures. In addition, the industry has quality of biological drugs. For instance, the ICHQ5E guide­
been expanding internationally, and new global markets lines ensure the maintenance of product quality upon
are being developed. However, because of differences in transfer of a biological process. This can establish
the technical standards between nations, many time- a foundation for a new guideline, where the emphasis is
consuming and costly test procedures must be duplicated shifted from the pre-approval cycle. We propose a new
to market new products internationally. Regulations must overarching guideline proposed by ICH that encompasses

CONTACT Sarfaraz K. Niazi niazi@[Link] College of Pharmacy, University of Illinois, Chicago, IL, USA
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ([Link] which
permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
2 S. K. NIAZI ET AL.

all other applicable guidelines and a step-by-step develop­ discounting and monopolizing the market by blocking
ment program that does not include animal and efficacy the supply of other products to distributors [18].
testing. The ICH guideline will align better with recent Regarding the ‘patent dance,’ wherein a biosimilar
changes proposed by EMA and MHRA, but as an indepen­ developer must present its dossier to a reference pro­
dent organization, it will not be bound to any jurisdiction. duct company to determine how to litigate, a new law
Compliance with this new overarching guideline will be [19] now requires the reference product company to list
a global requirement, including with World Health patents with the FDA where litigation is imminent. This
Organization (WHO) guidelines, which should be merged has dramatically reduced the risk of patent litigation. As
with this guideline. a result, only a few litigations are pending, most
The WHO has provided advice to 194 countries [3], recently against aflibercept, trastuzumab, and natalizu­
including regulatory approval of biosimilars, but this mab [20].
advice remains incomplete and questioned for its scien­ Biosimilarity can be determined based on
tific validity [4,5]. Various regional guidelines have also a combination of analytical testing, biological assays,
been developed [6], such as in India [7], where exten­ and clinical pharmacology comparisons but not on ani­
sive animal toxicology and token efficacy testing are mal pharmacology, toxicology, or efficacy testing in
mandated. The ICH guidelines will fulfill these advising patients. Therefore, unnecessary testing is tantamount
roles more effectively than the WHO guidelines. to subject abuse and must be prohibited rather than
Therapeutic proteins are produced using recombi­ merely discouraged [21].
nant engineered biological agents, bacteria, and mam­
malian cells and are named biological drugs. A new
Animal testing
biological drug is approved based on characterization,
safety, and efficacy testing results. In addition, Animals have been frequently used in biomedical
a biosimilar candidate is approved based on its similar­ research. The early Greek physician-scientists Aristotle
ity to a reference product to ensure that there is ‘no (384–322 BC) and Erasistratus (304–258 BC) conducted
clinically meaningful difference’ [8]. experiments on living animals. Galen (129–199/217 AD),
The first biosimilar guideline was introduced and who was influential in the history of medicine and
approved by EMA in 2006 [9]. The FDA proposed the Greek physician and practiced in Rome, also performed
biosimilar approval guidelines in 2009 [10]. Last year, as animal experiments to evaluate their anatomy, physiol­
the Brexit transition period ended, the MHRA published its ogy, pathology, and pharmacology. Ibn Zuhr
first comprehensive guideline on 14 May 2022 [11] that (Avenzoar), an Arab physician practicing in Moorish,
differs from all other guidelines by providing clear recom­ Spain, in the 12th century, began using animals in
mendations on the requirements for animal and clinical experiments to test surgical techniques before applying
efficacy studies. these methods to human patients [22]. Recently, the
The regulatory agencies have 18 years of experience in testing of drugs in animals has been criticized, as these
approving and using biosimilars and have published hun­ studies now appear to offer low value, most notably for
dreds of reports summarizing the safety and efficacy of biological drugs. Unlike the reactive chemical groups in
these agents. A strong consensus has emerged [12,13] chemical drugs, which can interact with numerous tis­
stating that significant amendments to the approval guide­ sues to induce a harmful response, biological drugs’
lines for biosimilars are needed not only to reduce the pharmacological response and toxicity depend on
current cost of USD 100–300 million [14] but also to their receptor-binding properties. Therefore, biological
enhance the safety of these products, which may be jeo­ drugs are not likely to elicit pharmacological or toxico­
pardized when using studies to justify non-compliance with logical responses [23]. Hence, the FDA recommends
more sensitive studies like analytical assessment and clinical that animal testing be waived, even for new biological
pharmacology profiling. Furthermore, reducing develop­ drugs [24].
ment costs is essential to widening access to biosimilars The method used for testing also contributed to the
[15,16], which comprise only nine more than 150 biosimilar lack of relevance of toxicological findings in animals to
candidates in the US and 14 in the EU. Once the testing those in humans. For instance, animal testing methods
requirements are harmonized, many smaller companies typically require administration of a large dose to elicit
can enter the market to fulfill the need for biosimilars. a toxic response. However, within these dose ranges,
In early years, reference product companies the responses are not linear; thus, any difference attrib­
attempted to block the entry of biosimilars into the uted to the lack of demonstrable pharmacology by
market; however, these efforts were unsuccessful [17], biological drugs in animals cannot be observed.
and they have instead used a strategy of heavily However, considerable futile animal testing is still
 JOURNAL OF MARKET ACCESS & HEALTH POLICY 3

being conducted for biosimilars, as demonstrated by also questioned this concept and stated that clinical
the most recent FDA and EMA filings [25]. efficacy testing is ‘broken’ [32] and that real-world evi­
Organoids, organs-on-chips, and in silico modeling dence should be promoted, as outlined in the 21st
can be used rather than animal testing models to Century Cure Act [33].
develop more precise and dependable scientific techni­ The clinical efficacy testing to support establishing bio­
ques when necessary. Non-clinical in vivo testing has similarity is the least sensitive when testing products with
also been replaced by in vitro assays over the past ten highly similar analytical and clinical pharmacology profiles.
years to accommodate the changes in animal protec­ The reasons for these outcomes include a low study power,
tion legislation. These actions can reduce animal use. requirement for a larger number of subjects than that used
Additionally, these strategies align with the Regulatory to approve the reference product, arbitrarily accepting
Science Strategy of the EMA for 2025, which aims to a clinical difference, inability to evaluate the clinical
develop a more flexible regulatory environment that response, nonlinearity of responses, and patient population
supports human and veterinary health [26]. variation. In addition, the logic of evaluating biosimilar
The results of animal toxicology studies may be mislead­ candidates in only one efficacy study when the biosimilar
ing if used to justify differences in impurities, post- product may have several indications with different
translational modifications, or antibody reactions. To date, mechanisms reduces such testing to merely ‘checking
all biosimilar applications have included animal data [27]; in a box’ [34], as stated by Dr. Woodcock.
many instances, the FDA has ignored these data in the Clinical efficacy studies have never demonstrated clini­
review process, mainly if these data were used to justify cally significant differences between a biosimilar and its
any variability in the analytical assessment [25]. reference product or resulted in the withdrawal or recall
The EMA and FDA have approved over 130 biosimilars of the reference of its biosimilar product from the market.
[28,29]. The regulatory filings showed that none of these These data are available in 96 European Public Assessment
products were toxic in animals, confirming that animal Report files and 39 approval documents obtained from the
testing is of little value in supporting the claim of biosi­ EMA [35] and FDA [36]. None of the 141 studies reported on
milarity [30]. These observations and conclusions typically [Link] failed to demonstrate the difference
have strong scientific reasoning, but the sponsors are between the reference product and its proposed biosimilar
concerned that the study findings will eventually be dis­ product [37]. In some instances, the data were reanalyzed
proven, resulting in a costly delay in market access. to declare equivalence, and immunogenicity was reported
There is remarkable awareness of the utility of ani­ in one case [38,39]. Additionally, from 2002 to 2022, 435
mal testing for biosimilars. However, this may soon be randomized controlled clinical trials were listed in the
a moot point, as the US Senate is considering a bill to PubMed database, revealing no clinically significant differ­
prohibit the testing of biosimilars in animals. In the ence between biosimilar candidates and their reference
Biologics Price Competition and Innovation Act product and its reference product [37].
(BPCIA), section (bb) was amended from “(bb) animal The Bayesian hypothesis provides a more straightfor­
studies (including the ‘assessment of toxicity’ to ‘an ward argument for how the aforementioned observations
assessment of toxicity (which may rely on, or comprise, determine the sensitivity of clinical efficacy testing [40],
a study or studies described in item (aa) or (cc)); (aa) is wherein the posterior probability determines the probabil­
an analytical assessment and (cc) in clinical testing.’ In ity of the correctness of an observed outcome. With almost
addition, Senator Lujan of New Mexico proposed a bill 100% posterior probability demonstrating equivalence,
in the senate to remove all references to animal testing either the tested products are biosimilar or the study design
[31]. Other such bills are imminent and will lead to large is inadequate to determine the difference. In both
amendments to the BPCIA. instances, these tests are redundant.
In October 2022, the FDA established a pharmaceutical
research program in which switching testing of biosimi­
Clinical efficacy
lars could be waived to allow the interchangeable status
Clinical efficacy testing of new drugs is essential; how­ of biosimilars, and real-world evidence could replace the
ever, regulatory authorities have criticized the adoption clinical testing of biosimilars. These are important steps
of testing protocols. For example, Dr. Janet Woodcock, announced by one of the most conservative regulatory
the previous acting commissioner of the FDA and one agencies and provide insight into the future of biosimilar
of the longest-serving leaders of the Communicable testing [41].
Disease Emergency Response CDER) Program of the The main reason for removing clinical efficacy testing is
FDA has stated: ‘Why should we put patients through not to reduce the cost of development but to reduce ethical
all these different trials just to check a box.’ The FDA and safety concerns. Ethical concerns arise from the
4 S. K. NIAZI ET AL.

Figure 1. Current step-by-step approach for establishing biosimilarity (left) and the proposed plan (right). Source: Food and Drug
Administration.

universal belief that healthy subjects should not be unne­ Proteins, polypeptides, and products and deriva­
cessarily exposed to testing, as codified in the US 21 CFR tives that contain them, such as conjugates, drug-
320.25(a)(13), which states that ‘No unnecessary human antibody conjugates, fixed-combination products, or
testing should be performed’ [42]. In addition, risks can be any other product that was first approved in a full
attributed to using human subjects for studies that will not Biologics License Applications (BLA). Proteins and
add any value to the evaluation of biosimilar products polypeptides can be purified and characterized
[41,42]. using analytical methods and developed using
recombinant or non-recombinant cell culture expres­
sion systems. An example of a non-recombinant cell
Proposed guideline structure culture expression system is the production of
Botox.
Several ICH guidelines provide scientific support for the Alpha-amino acid polymers comprising 40 or fewer
development of biological products and should be amino acids are considered peptides rather than pro­
included in the proposed overarching ICH guidelines teins. Glucagon, liraglutide, nesiritide, teriparatide, and
adopted by regional agencies. In addition, ICH offers teduglutide are peptides. A peptide is regulated as
a long list of guidelines for monitoring the quality of biolo­ a chemical drug and copied as a generic drug.
gical products, which will become part of the overarching It does not apply to other product categories, such
guidelines of the ICH [43] to enable global harmoniza­ as proteins and polypeptides that have been removed
tion [6]. from tissues and bodily fluids.
The structure of the overarching ICH guidelines is as Vaccines are considered biological products and are
follows. Figure 1 illustrates the changes in the approval approved by the FDA under its CBER division, whereas
process. CBER handles therapeutic proteins, and the concept of
Scope. These guidelines are expected to serve as biosimilars applies only to CDER products. Newer
global compliance documents. Regional agencies must mRNA vaccines are chemical products, and no consen­
draft ICH guidelines. Full compliance is also expected. sus has been established regarding whether they can
be chemical drugs [44]. Theoretically, mRNA vaccines
Definition. A biosimilar product has the same safety, can be considered chemical drugs, and the ICH should
efficacy, mode of action, dose, frequency, route, and not be concerned with how these products are classi­
concentration (strength) as the reference product. The fied by the FDA but should follow the EU classifica­
following products are considered. tion [45].
 JOURNAL OF MARKET ACCESS & HEALTH POLICY 5

● Reference Product. This biological product is first upstream and downstream steps, not justified by
approved using a complete dossier in one of the any nonclinical or clinical testing.
four ICH original member countries (the US, EU, ○ Impurity Profile. A biosimilar may have fewer
UK, and Japan). If the reference product has been impurities in terms of type and amount but no
registered in multiple member countries using the unmatched impurity in any amount because the
same dossier, the product should be secured from impurity differences cannot be justified in safety
any of these countries. Only one reference source studies unless prior reported scientific data are
is used in the study. The supply of the reference available to support the safety of unmatched
product must be adequately documented, along impurities. Unmatched or higher impurities can
with the shipping details, to ensure that the pro­ be removed or reduced during the downstream
duct is delivered without adverse exposure. The process, but these steps may affect the yield.
lowest-strength products should be selected for ○ Expression System. The expression system
testing when several products with various determines the product-related critical quality
strengths are available. Multiple batches of refer­ attributes (CQAs), including primary and sec­
ence products should be directly sourced from ondary structures, tertiary structures, conforma­
appropriate markets with different companies. tional stabilities, oligosaccharide patterns,
This requirement enables biosimilar developers glycopeptide mapping, monosaccharide/sialic
to identify reference product variability, reflecting acid content, size variants, charge variants,
manufacturing variability. These steps are costly, linked proteins, and product-associated var­
and reference product companies have attempted iants, which are further subdivided from the
to block access to their products. ICH guidelines primary structure (HCD). The expression system
cannot be applied because of a lack of jurisdic­ should be in the same class as that used to
tional authority. The reference product batches express the reference product, although this is
should be tested within their permitted shelf not required by the FDA or EMA. The develo­
lives and maintained under the recommended pers are also advised to select steady expression
(label) storage conditions. Testing batches that systems; typically, high-yielding cell lines pro­
have been stored for a long time (e.g., frozen at- duce more variability in the properties of the
80°C) or beyond their designated shelf life may product. Therefore, the cell lines should be qua­
occasionally be possible if reliable data are avail­ lified according to ICH Q5D.
able showing that the storage conditions do not ○ Primary Amino Acid Sequences. The primary
affect the relevant quality attributes, as demon­ amino acid sequence should be identical to the
strated in sample analysis. The age of the refer­ sequence found in the reference product in
ence product batches (relative to their expiry a side-by-testing and not from any public data­
dates) at the testing time must be documented base or pharmacopeial listing. Some differences
during the analysis. in the amino acid sequence are acceptable such
● Characterization. The reference product is charac­ as terminal lysine group differences. The N- and
terized using the techniques described in ICH Q6B. C-terminal amino acid sequences, free SH
However, newer technologies are routinely intro­ groups, and disulfide bridges should be com­
duced, and developers should select the most ana­ pared appropriately. Any modifications or trun­
lytically sensitive methods. These characterizations cations should be quantified, and any intrinsic
include the determination of physicochemical or expression system-related variability should
properties, biological activity, immunochemical be described. Any detected differences between
properties (if any), purity, impurities, contaminants, the biosimilar and the reference medicinal pro­
and quantity. As the quality attributes of a reference duct should be justified concerning the micro-
product vary between batches, it is essential to heterogeneous pattern of the reference medic­
establish the ranges of these variations to allow inal product (e.g., C-terminal lysine variability).
for similar variability in biosimilar candidates. ○ Post-translational Modifications (PTMs). The
These variations are either process-related (manu­ presence and extent of post-translational mod­
facturing system) or product-related (expression ifications (e.g., glycosylation, oxidation, deami­
system). Generally, variations in product-related dation, truncation) should be appropriately
attributes are not resolved, leading to the require­ characterized. If present, carbohydrate struc­
ment for different expression systems. Process- tures should be thoroughly compared, includ­
related attributes should be modified by adjusting ing the overall glycan profile, site-specific
6 S. K. NIAZI ET AL.

glycosylation patterns, and site occupancy. The ○ Charge variations are proteo-forms that origi­
presence of glycosylation structures or variants nate in various colloidal matrices (such as
not observed in the reference product would culture media, in-process buffers, or formula­
require appropriate justification, with particular tions) during different manufacturing process
attention to non-human structures (non-human phases and show changing charges. Cation
linkages, sequences, or sugars). The PTMs exchange chromatography is best suited for
increase the functional diversity of the pro­ adjusting charge variants.
teome via the covalent addition of functional ● Stability. Accelerated and stress-stability investiga­
groups or proteins, proteolytic cleavage of reg­ tions are required to determine the degradation pro­
ulatory subunits, or degradation of total pro­ files and enable direct assessment of the structural
teins. These modifications include similarity of the biosimilar candidate with its reference
phosphorylation, glycosylation, ubiquitination, product. These studies support analytical similarity
nitrosylation, methylation, acetylation, lipida­ assessment since the nature of molecular breakdown
tion, and proteolysis and influence most aspects depends on the structure. The ICH Q5C and Q1A(R)
of normal cell biology and pathogenesis. should be considered. The long-term degradation
Therefore, identifying and understanding PTMs profiles should be comparable to similar profiles of
is critical for optimizing the downstream and the reference product. The appearance of unmatched
upstream manufacturing processes to match impurities between the biosimilar products and its
the PTM profile with the reference product. reference product during the lifecycle of the biosimilar
However, matching the PTM profile is labor- product indicates differences that should be moni­
intensive and requires state-of-the-art analytical tored for adverse events.
tools. ● Process Qualification. Upstream and downstream
○ Non-enzymatic PTMs. Non-enzymatic PTMs processes must be validated before evaluating the
include oxidation, phosphorylation, sulfation, analytical similarity of the biosimilar candidate
acetylation, methylation, and hydroxylation pro­ with its reference product. Bridging studies are
ducts obtained during manufacturing. Liquid required to validate changes in the production
chromatography is preferred for characterizing size; once clinical pharmacology studies are com­
PTMs and quantifying the related molecular pleted, no batch size change is allowed. The devel­
variants and impurities. oper may conduct the bridging studies under
○ Other Variabilities. Examples of heterogene­ ICHQ5E, but only after the biosimilar product has
ities introduced during the production, admin­ been licensed or approved. Process-related varia­
istration, and storage of biological products tions or residuals include cell substrates, host cell
include size-based heterogeneities (aggregates, proteins, host cell DNA, cell cultures, and down­
fragments, and subvisible/visible particles), stream processing residuals. The preferred meth­
charge-based heterogeneities (acidic and basic ods for HCP and HCD detection and quantitation
variants), and other product modifications (such are enzyme-linked immunosorbent assays and
as reduced, oxidized, glycated, and misfolded real-time or quantitative polymerase chain reac­
proteins). tions. However, because the variants are compo­
○ During the production process of biosimilars, nents of the release specification, they are not
protein hydrophobic patches unfold because examined during the drug-substance qualification
of environmental changes, resulting in aggre­ phase.
gation or fragmentation that might alter the ● Release Specification. Tests for sterility, endotox­
immunogenic property of the product. As ins, microbiological limits, container volume, uni­
a result, protein loss because of interactions formity of dosage units, and acceptable particulate
in the stationary phase and salt-induced matter are covered in the general monographs of
aggregation or dissociation is common dur­ the pharmacopeia, and these standards can be
ing size-exclusion chromatography analysis. used to demonstrate compliance. Additionally,
To evaluate the size distribution quantita­ particulate matter may require comparative test­
tively, sedimentation velocity-analytical ultra­ ing because it can be responsible for inducing
centrifugation, a matrix-free substitute for immunogenic responses and are evaluated in
size-exclusion chromatography, can be used. release specification tests.
 JOURNAL OF MARKET ACCESS & HEALTH POLICY 7

● CQAs. The characteristics of the reference product avoid the necessary studies to defend the differences.
that can significantly impact safety and efficacy are All excipients should be free of animal products.
established and can be based on expression systems.
Reference product characterization allows for the
establishment of CQA for release and analytical
Analytical assessment
assessment in the comparator mode. Specifications
are set before analytical assessment. The reference ● Test Methods. Critical products and process-
product is characterized using appropriate testing related variants are compared with the reference
techniques to identify its physicochemical character­ product to enable suitably but not necessarily
istics, biological activity, immunochemical character­ validated methods, as some test methods cannot
istics, purity, and contaminants. The lots used during be fully validated. Analytical methods must be
the development phase can be used as test lots. sensitive, qualified, and sufficiently discriminatory
However, initial clinical trials testing many pharmaco­ to detect possible differences. The methods used
kinetic (PK)/pharmacodynamic (PD) studies must to assess the quality attributes for the batch
include at least one. In addition, all test methods release can also be used for analytical assessment,
must be validated or verified if drawn from pharma­ as detailed in the ICH guidelines (ICH Q2A, Q2B,
copeia. Injectable products are allowed to vary based Q5C, and Q6B), where appropriate. In addition,
on inevitable variabilities, such as ±3% protein con­ robust data requires the application of suitable
tent, no more than 3% impurity, no single impurity of orthogonal methods.
more than 1%, or ±15% for potency testing. ● Number of Batches. Based on the anticipated
Pharmacopeial specifications for qualification of the variability, three batches of the reference product
dosage form, such as sterility, fill volume, delivered are adequate to confirm a higher-order structure.
volume, and physical properties, are not tested for Development lots can be used for analytical
comparison purposes. assessments, but at least one at-scale Current
● Formulation. The formulations of biosimilars can dif­ Good Manufacturing Practice (cGMP)P is required.
fer from those of reference products; however, these This lot is used for clinical testing, and regulatory
differences can only involve their inactive compo­ filing will require a bridging study with at least
nents. Despite variations in the constituent composi­ three process performance qualification lots. There
tion, a formulation with the same or fewer inactive is discord among the agencies regarding statistical
ingredients is recommended unless intellectual prop­ modeling; but if it is used then to assure a power
erty constraints exist. No novel excipients should be of 0.18 in a t-test of the 3Sigma approach (μref-
present in formulations with no history of use as 3σref and μref + 3σref), at least ten batches are
reference products. Because the delivery form may required.
have a different configuration or components, ● Data Evaluation. Non-quantitative data out­
human factor studies are conducted without assump­ puts, such as spectroscopy charts, can be com­
tions regarding the reference product. This precaution pared visually. The ICH guideline Q5E and FDA
is necessary to avoid unexpected outcomes that are guidelines provide more details, and statistical
not worth the risk, as many formulation options are testing is gaining acceptance by the EU
compatible with every biosimilar. The suitability of the and WHO.
formulation should be demonstrated in terms of the ● Reference Standards. To avoid confusion with
integrity, activity, and potency of the active ingredient the reference product, developers created
as well as its stability, compatibility (i.e., how it inter­ a reference standard for conducting analytical
acts with excipients, diluents, and packaging materi­ assessments. For biological assays and physico­
als), and compatibility. For example, suppose the chemical testing of succeeding lots, an in-house
primary packaging in contact with the product is primary reference material is a suitably described
different in its chemical properties, such as glass ver­ sample created by the manufacturer from
sus plastic. In that case, additional safety studies are a representative lot or lots against which an in-
required to ensure the absence of unexpected leach­ house working reference material is calibrated. It is
ing of the packaging components into the product. the only reference material used as the reference
The FDA has recently raised this issue, and detailed and working reference materials. Publicly available
compatibility studies are required. Developers are reference standards (e.g., Ph.D.) cannot be used as
advised to choose a primary packaging material that reference products to demonstrate biosimilarity.
is identical in composition to the reference product to However, these standards can be used to qualify
8 S. K. NIAZI ET AL.

and standardize methods. No specification in any nonlinear (target-mediated) clearance should be

monograph for drug substances or products can considered through dosage selection and evalua­
be used to establish the specification of tion of partial areas under the curve. Body weight
a reference product or biosimilar candidate. adjustments or other factors (such as subject sex)
However, these test methods can be used for to be employed in the statistical analysis of paral­
verification. lel-group experiments should be predefined in the
● Functional Assays. Analytical and in vitro func­ statistical analysis strategy. The equivalence mar­
tional assays should be performed to identify gins must be pre-specified; an interval of 80.00–
CQA. Functional experiments should be pertinent 125.00% is generally acceptable. PK trials should
to the potential mode of action for all therapeutic demonstrate the equivalence of the primary PK
indications, including those examining apoptosis, parameters, typically the AUC0-∞ and Cmax. If
complement-dependent cytotoxicity, antibody- the extrapolated portion of the AUC0-∞ comprises
dependent cellular phagocytosis, and cytotoxicity. >20% of the total AUC0-∞ in >20% of the obser­
A biological property should be considered applic­ vations, the study’s validity should be re-
able to the mode of action unless sufficient evi­ evaluated. Root-cause analysis is necessary if a PK
dence is presented. Functional tests (antibody- study is unsuccessful (i.e., 90% confidence inter­
dependent cell-mediated cytotoxicity, cellular pha­ vals for the main PK parameters do not fall entirely
gocytosis, and complement-dependent cytotoxi­ within the prespecified acceptance limits) to mod­
city) are not required for reference products that ify the planning and execution of a new PK study.
primarily target soluble antigens. In most cases, the cause of study failure is subject
● Pharmacokinetic and Pharmacodynamic. These variability, which can be reduced by selecting nar­
studies are an extension of analytical assessments row criteria for qualification regarding sex and
that reflect how the body sees the molecule and age. A PK trial can be used to test PD parameters,
vice versa and are required even when a product and descriptive results should be provided to sup­
is administered intravenously. PK studies are port the findings of biosimilarity.
required to assess the extent and strength of ○ Immunogenicity. B cells and T-cells are activated
receptor binding, which may change the PK para­ to trigger immune responses. B cells are the lym­
meters, such as the distribution volume and clear­ phocyte population that transforms into plasma
ance. These studies are necessary for all cells that produce and release antibodies in large
biosimilars, even if they are not administered via quantities. These antibodies are immunogenic.
the parenteral route, such as biological drugs Differences in the antibodies will not be concerning
injected into the eye. PK/PD studies are conducted if the immunogenicity profile is different but does
to compare rather than characterize the reference not affect the disposition.
product profile and biosimilar candidate profile.
This comparison can be performed in a restricted Consequently, the FDA is waiting to test the immu­
population to reduce inter- and intra-subject varia­ nogenicity of insulin if the product meets other analy­
bility, thereby reducing the study size. All studies tical assessment qualifications [46]. Almost all biological
should conform to the standards associated with therapeutic proteins trigger an immunological
bioequivalence testing. Ideally, PK experiments response, developing anti-drug antibodies (ADA). Most
should be planned and powered to demonstrate ADAs against therapeutic monoclonal antibodies exert
equivalence to the reference product in healthy neutralizing effects by targeting the antigen-binding
volunteers. Crossover or parallel studies should be region of the therapeutic monoclonal antibody.
supported by strong designs. Although Nonetheless, fully human antibodies can be highly
a crossover strategy is superior in identifying immunogenic according to the nature of the ADA
changes, it may not be suitable for reference pro­ response. Technically, ADA detection is complex, and all
ducts that induce strong immune responses or tests have limitations, including a limited ability to detect
have long half-lives. If suitable population PK or ADA in the presence of medicine because of the creation
PK/PD models for the reference product are avail­ of immunological complexes (IC), which can lead to an
able in the literature, modeling and simulation underestimation of the incidence of ADAs. Enhanced
should be considered to optimize the study assays that can break apart drug-ADA ICs have increased
design, such as selecting the most sensitive dose­ the number of ADA patients. Because of the wide varia­
(s), study population, and sample size to analyze bility in ADA assays, the immunogenicity of various com­
PK differences. Linear (nonspecific) clearance and pounds determined in different studies cannot be
 JOURNAL OF MARKET ACCESS & HEALTH POLICY 9

compared. If the ADA titer (i.e., concentration) is suffi­ more indications. The content and format of the
ciently high and long-lasting, the development of drug- label must comply with the FDA guidance [55].
ADA ICs can drastically modify the PK and directly ● Substitution. Biosimilars can be substituted or inter­
decrease the medication efficacy. Although a clinical non­ changed with reference products or other approved
response is likely to be observed in patients with high ADA biosimilars by using the same reference product. This
titers, free medication concentrations may still be high conclusion assumes that biosimilars have an immuno­
enough to exert effects in patients with low ADA titers. genicity profile that is highly similar to that of
ADA also increases the risk of adverse events, including a reference product. Although inter-patient differences
hypersensitivity reactions. ADA is present before are expected, if the specific product is known not to
a clinically apparent adverse reaction, demonstrating its affect its disposition kinetics as a function of immuno­
predictive significance. Algorithms are currently available genicity, concerns are reduced, even though safety
to guide therapeutic decisions in clinical practice and concerns that may alter the general response, such as
assist in developing safer and more cost-effective thera­ anaphylaxis, remain and require individual patient
peutic strategies. These algorithms integrate therapeutic monitoring.
drug monitoring and immunogenicity information into ● Pediatrics. No pediatric compliance studies are
the clinical evaluation of patients administered biologics required for biosimilars.
[47,48]. Patients may already show a low titer of antibodies ● Human Factor Studies. These are required to ensure
that cross-react with specific therapeutic antibodies and that the correct dose is administered to patients.
develop ADAs during therapy. These effects also depend However, if the administration device used is very
on the design of the therapeutic drugs for immunogeni­ similar to that used for the reference product, the
city [49–54]. Hence, although immunogenicity testing need for these studies is waived. If a device is covered
may be redundant in certain situations, patients should under a patent, a tactic often used by innovators,
be diagnostically monitored for the development of ADAs. other devices can be used. Of concern is the contact
During PK trials, data on immunogenicity and safety with the primary container, which is likely to be USP
should be collected. Evaluation of ADA production rate, Class 1. In addition, no such studies are required when
kinetics, and impact on PK (and PD) using a predetermined a healthcare professional administers a product.
group study of ADA-negative and ADA-positive partici­ ● Risk Management Plan. The risk management
pants are some of these options for predicting adverse plan for a biosimilar product is the same as that
events. Although they would not replace immunogenicity for the reference product. Furthermore, the brand
assessment in PK trials, in vitro immunogenicity assays name and batch number must ensure precise bio­
may enhance functional and analytical assessments. similar traceability. This is critical for ensuring
Short-term immunogenicity analyses may not reflect real- patient safety [56,57]. The adverse event database
world experiences with biologics, including those with in the EU and the FDA guides such instances.
biosimilars. Particularly, rare ADA-related adverse events
may not be detected in the premarketing phase because
of the limited size of the exposed population and greater
scrutiny of patient care in the clinical trial setting.
Regulatory procedures
Therefore, immunogenicity should be monitored in phar­
macovigilance and risk management plans that also moni­ Overarching guidelines for ICH are expected to be
tor other drug reactions. adopted globally, enabling developers to register their
products across many jurisdictions based on the same
● Naming. Biosimilars should have a unique data. However, several additional considerations are
brand name enabling post-market required to expedite the entry of biosimilars.
pharmacovigilance. Suppose a product is approved in one of the ICH
● Label. The label must state all risks associated with countries [58]. In that case, its approval should be auto­
the reference product, present the same indica­ matic and subject to submitting a copy of the dossier
tions, and be formatted and detailed without that resulted in the authorization. This applies to both
exception, as described in this guidance. Once new and biosimilar biologics. Prescription information
a biosimilar candidate is shown to be highly simi­ should conform to the label of the original license and
lar to the reference product, all indications not be modified in a local jurisdiction. The registration
granted to the reference product are allowed, pro­ of these products does not require proof of tolerance in
vided they are not protected by market exclusivity the local population. This is identical to the require­
or patents. A developer may not request fewer or ments for the country of origin. No efficacy testing is
10 S. K. NIAZI ET AL.

performed in the local population because these stu­ significantly impact healthcare globally. Therefore, it
dies can never fail and waste resources. would be desirable for leading countries, such as
For products approved in non-ICH countries, the Saudi Arabia, Brazil, and India, to take the lead in this
regional agency should adopt an EMA evaluation sys­ program.
tem using external rapporteurs. This is not an admission Now, the responsibility lies with the ICH; a formal
of the lack of qualification of an agency to perform request has been submitted to the ICH by the authors,
evaluation, but rather a means of harmonizing the and we hope this publication will draw the interest of
quality of the dossier and giving a fair chance to the stakeholders and agencies alike.
developers to assure safety and efficacy. The rapporteur
submits the report to the agency and sponsor to decide
whether to accept the submission. The EMA offers a list Disclosure statement
of rapporteurs who can include experienced reviewers. No potential conflict of interest was reported by the author(s).
The developer can rebut the evaluation and challenge
the findings to make them fair and transparent. The
ORCID
same is true for Current Good Manufacturing Practice
compliance, which must be demonstrated by third- Sarfaraz K. Niazi [Link]
party auditors.
Funding
Conclusion This work was supported by the Deanship of Scientific
Research at Imam Mohammad Ibn Saud Islamic University
Biosimilars are among the safest categories of biological (IMISU) through the Research Partnership Program under
products. However, as a new class of drugs, the regula­ Grant RP-21-11-02.
tory guidelines established to demonstrate their com­
parable safety and efficacy have resulted in complex
and costly pathways proposed by major regulatory References
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