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Clinical Immunogenicity Assessment
and loss of efcacy. Potential immunological adverse effects should be addressed in the risk management plan.
7.7.13.1 Management of Immunogenicity Testing
A harmful immune reaction to a therapeutic protein cannot always be avoided despite the developers’
efforts to select compounds with a low immunogenic potential. In such cases, the developers should,
if feasible, explore possibilities to reduce the adverse effect of immunogenicity observed during
clinical development. In some cases, immunosuppressive or anti- inammatory co- medication may
signicantly prevent or reduce adverse immunological effects. In some cases, as observed with
coagulation factors, it may be possible to re- establish the immunological tolerance with tolerization
regimens, for example, by administering larger doses of a therapeutic protein. Clinical studies
should document such therapeutic regimens.
7.7.14 exaMPle studies
Appendix 3 provides the details of a few study protocols used to secure biosimilar approval from
the EMA and FDA.
7.7.14.1 Infliximab
While the primary efcacy analysis demonstrated equivalent ACR20 response rates at week 30 with
the proposed biosimilar (Flixabi) and the reference product, the ADA rate measured in a highly
sensitive assay was approximately 5%– 12% higher in a proposed biosimilar cohort at the individual time points of determination (with nearly 50% of patients in the proposed biosimilar cohort
being ADA positive at any time in the trial). However, no meaningful effect on any of the efcacy
parameters analyzed was observed, as the primary endpoints were within the predened comparability margins.
7.7.14.2 Etanercept
While the product (Benepali) met all biosimilarity tests, a signicant difference in overall ADA formation was observed at week 24. The clinical effect of the difference in ADA seemed negligible, and
the difference largely vanished after 8 weeks of treatment.
The notion that PK studies are generally more sensitive in detecting potential product- related
differences than clinical trials may explain why a nding of similar efcacy could not overrule the
differences in PK. This may be perceived as overly strict. Yet, the outcome of efcacy trials depends
not only on drug exposure but also on the effective pharmacological action of the biological substance in vivo. Therefore, the objectives of both types of studies differ.
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of the Proposed Biosimilar
8.1 RESIDUAL UNCERTAINTY
A comparative clinical study will be necessary to support biosimilarity through scientic evidence
if there is residual uncertainty regarding clinically meaningful differences between a proposed
biosimilar product and the reference product based on structural and functional characterization,
animal testing, human pharmacokinetics (PK) and pharmacodynamics (PD) data, and clinical
immunogenicity assessment. The developers should provide scientic justication if they believe
that a comparative clinical study is not necessary.
A proposed biosimilar product undergoes testing in a stepwise manner for the detection and
removal of residual uncertainty at each step before moving to another testing. The steps involved
in the testing are as follows (in the same order): analytical, functional, in vitro, in vivo, clinical
pharmacology, and immunogenicity. While the developers of most of the biosimilars routinely conduct clinical efcacy testing as listed in Appendix 3, agencies consider unnecessary patient exposure
as being inappropriate and encourage them to meet up with agencies to understand what the agencies
consider as the remaining residual uncertainty.
In most cases, at this stage of development, a failed PK/ PD/ immunogenicity testing will reject a
proposed biosimilar product for a proposed biosimilar status. The developer may choose to rele the
applications as a new biological drug. The residual uncertainties persisting at this stage are identied
through structural, functional, or nonclinical testing, where the variation may not be evaluated fully
for its effect on the safety and efcacy of the product.
8.2 WAIVERS
When appropriate PD endpoints are achieved and when the mechanism of action is clearly understood, a PK/ PD study may be an adequate clinical workup for marketing authorization. However,
for complex, multifunctional biologicals, comparative efcacy and safety clinical trials conducted
in patients are still considered necessary components in the development of a proposed biosimilar
product. The need for testing in patients is driven by the often- unresolvable complexity of interactions
resulting from the molecule size, diverse moieties with different functions (e.g., Fab/ Fc- parts), multiple mechanisms of action, the effect of glycosylation pattern, and potential for immunogenicity
and life- threatening adverse effects.
As more proposed biosimilar products are approved globally and safety and efcacy data are
becoming available to regulatory agencies, there is a trend of questioning the relevance of any comparative efcacy testing. When clinical efcacy testing does not show a meaningful comparison,
exposes patients to avoidable risks, and does not establish relevance to multiple indications approved
DOI: 10.1201/9781003392026-8
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Clinical Efficacy Assessment
for the reference product, then agencies will expect the developers to adduce arguments supporting
the avoidance of such clinical efcacy testing.
In most cases, a comparative clinical study is essential to rule out clinically meaningful differences
in efcacy and safety between a proposed biosimilar product and the reference product. A clinical
efcacy trial may not always be necessary, for instance, when a clinically relevant PD endpoint is
available. In such cases, scientic justication is needed to conduct an efcacy study, yet safety and
comparative immunogenicity data are still required.
8.3 TYPES OF STUDY DESIGN
Comparative safety and efcacy testing is conducted using three types of study design.
Generally, an equivalence design should be used. A noninferiority design may be acceptable
if justied based on a strong scientic rationale and considering the characteristics of the reference product, for example, safety prole/ tolerability, dose range, and dose- response relationship.
A noninferiority trial may be accepted only where the possibility of a signicant and clinically relevant increase in efcacy can be excluded based on scientic and mechanistic evidence. However, as
in equivalence trials, assay sensitivity has to be considered in a noninferiority trial.
The correlation between the “hard” clinical endpoints recommended by the guidelines for new
active substances and other clinical/ pharmacodynamic endpoints that are more sensitive in detecting
clinically meaningful differences may have been demonstrated in previous clinical studies assessing
the reference product. In this case, it is unnecessary to use the same primary efcacy endpoints
as those used in the reference product’s registration application. However, it is recommended to
include some common endpoints (as secondary endpoints) to facilitate comparison with the clinical
studies assessing the reference product.
The developers are advised to consult the European Medicines Agence (EMA) European Public
Agency Reports (EPARs) and the FDA Biological Licensing Application (BLA) review documents
relating to the proposed biosimilar product to choose the testing model for establishing clinical
safety and efcacy; in the absence of such data, the developers should suggest a testing model to
the agencies for marketing authorization by agencies before study initiation. However, neither the
agencies nor the developers are bound or required to use any testing model that is published or submitted/ accepted by any regulatory agency.
8.3.1 study designs foR coMPaRative safety and efficacy testing
8.3.1.1 Traditional Comparative (Two- Sided) Study
In a traditional comparative study, the null hypothesis states that the proposed biosimilar and the reference product do not have any difference. The burden of proof rests on the research hypothesis of
the difference between the two products in terms of efcacy. If the evidence is not strong enough in
favor of a difference, then equality cannot be ruled out. This model is not suitable for the assessment
of biosimilars.
8.3.1.2 Equivalence Testing
In an equivalence testing, the null hypothesis states that the proposed biosimilar is not equivalent to
the reference product in terms of equivalency, and the burden of proof rests in the research hypothesis. If the evidence in favor of equivalence is not strong enough, then nonequivalence cannot be ruled
out. The null and research hypotheses in an equivalence testing are simply the converse of those of a
traditional comparative study. This is the most common model used in testing except that the margin
of difference, M2, is based on the clinical judgment that can be questioned. The term “equivalent”
means that the efcacy of the two therapies is close enough to not be considered superior or inferior
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to the other. This concept is formalized in dening a constant, called the “equivalence margin,”
dening a range of values for which the efcacies are “close enough” to be considered equivalent.
Practically, the margin is the maximum clinically acceptable difference that one is willing to accept
in return for the secondary benets of the new therapy.
An inherent disadvantage in using the equivalence model lies in the choice of difference (M2)
considered acceptable; this difference is established mainly based on clinical judgment, as objective
studies will not be available for reference. The total response (M1) is deduced from the reference
product data.
The choice of equivalence margins in comparative efcacy studies is more complicated.
Prespecied margins include the largest differences that would not be clinically relevant. The
margins need not be symmetric if dose- related toxicities occur or if the dose used is closer to the
plateau of the dose- response curve. There is a small likelihood of dose- related effects. In most
studies, a margin of 15% is suggested, such as in the testing of Remsima for American College
of Rheumatology 20 at 30 weeks and Samsung Bioepis’ iniximab biosimilar. However, the
adalimumab “similar biologic,” approved in India (Exemptia) (www.ncbi.nlm.nih.gov/ pmc/ artic les/
PMC 5215 647/ ), is used at an equivalence margin of 28.5%, allowing for a much smaller sample size
and a margin of 23% for an iniximab biosimilar biologic in India. The choice of margin becomes
more complicated, for instance, when comparing anticancer drugs, where the outcome is binomial
and often difcult to predict.
8.3.1.3 Noninferiority Testing
In a noninferiority testing, the null hypothesis states that the proposed biosimilar product is inferior
to the reference product. The research hypothesis is that the new therapy is either equivalent or
superior to the current therapy. Only one margin (the lower or upper limit, depending on what is
appropriate for the specic study or endpoint) is used in a noninferiority model. The noninferiority
testing requires a smaller sample size than that required in an equivalence model. The condence
interval expresses the degree of uncertainty associated with a statistical parameter, such as the
difference between two treatment effects (e.g., risk difference) or the ratio. For example, if the
objective response rate is the primary endpoint, then the risk ratio would serve as a primary efcacy parameter. The condence interval is different from the point estimate for a population parameter. For example, the sample mean, objective response rate, and median survival duration are
some examples of point estimates of unknown population parameters. Noninferiority trials do not
rule out the possibility of increased activity of a proposed biosimilar product associated with more
adverse events.
Comparability margins in applying statistical modeling are established based on the effect size
of the reference product and clinical judgment. They should represent the largest difference in efcacy that would be negligible in clinical practice; treatment differences within this range would then
be acceptable because they have no clinical relevance. The acceptable equivalence margins depend
on the patient population, endpoints, backbone therapy, and estimated treatment effect, and slight
differences may occur depending on the selection of publicly available reference studies.
Relying on noninferiority studies to establish biosimilarity is remarkably criticized for the very
nature of the need for such studies that includes the overall rationality of these studies.
When noninferiority testing is conducted, a response (M1) and an acceptable difference that can
only be arbitrary should be established, given the observed high variability of biological responses.
Agencies are open to suggestions on in silico PK studies and other modeling studies, possibly
obviating the need for comparative efcacy studies; the developers are encouraged to minimize
testing in patients to secure faster and low- cost marketing authorization of biosimilars. In our
opinion, such studies will be limited only to a few highly complex drugs with mixed mechanisms of
action and where other assessments cannot be matched well.
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8.3.2 justification of extRaPolation
Clinical Efficacy Assessment
All indications approved for the reference product as of the marketing authorization date are
extrapolated for the proposed biosimilar product. However, suppose a proposed biosimilar product
is tested in a comparative efcacy trial, in a single study in one of the many available indications
where the mechanisms of action can differ among the indications, a question arises regarding the
suitability of a single comparative efcacy testing to allow such extrapolation.
8.3.3 ethics and PRacticality
In most cases, recruiting a suitable patient population is very difcult, such as in the case of anticancer
drug testing, where the patients have inevitably been exposed to many drugs, and it is unethical to
expose patients to treatment regimens of monotherapy that are not in the best interest of the patient.
In several instances, the patients may not survive until study completion, which creates a dilemma
for both the developer and the patients.
8.4 SELECTION OF STUDY PROTOCOLS
A comparative clinical study should be adequately sensitive to rule out clinically meaningful
differences within predened comparability margins. The developers should consider the following
factors when designing an adequately sensitive clinical study:
• Characteristics of the study population(s) (e.g., underlying disease, immune competence).
• Clinical studies’ characteristics, such as study duration, route of administration, dosage
regimen, clinical endpoint(s), and assessment duration.
• Risk and effects of immunogenicity.
• Effects of concomitant therapies (e.g., monotherapy vs. combination therapy).
• Use of appropriate comparability margins.
• In some instances, the evaluation of more than one sensitive population may be necessary.
The following are examples of factors that may inuence the type and extent of the comparative
clinical study data needed:
• The nature and complexity of the reference product; extensiveness of structural and functional
characterization; and ndings and limitations of comparative structural, functional, and nonclinical testing, including the extent of the observed differences.
• The extent to which differences in structure, function, and nonclinical pharmacology
and toxicology predict differences in clinical outcomes, in conjunction with the degree of
understanding of the mechanism of action of the reference product and disease pathology.
• The extent to which PK or PD in humans is known to predict clinical outcomes (e.g., PD
measures known to be relevant to effectiveness or safety).
• The extent of clinical experience with the reference product and its therapeutic class, including
the product’s safety and risk- benet prole (e.g., whether there is a low potential for off- target
adverse events), and appropriate endpoints and biomarkers for safety and effectiveness (e.g.,
availability of established and sensitive clinical endpoints).
• The extent of any other clinical experience with a proposed biosimilar product.
The developers should provide scientic justication for how they intend to use these factors
to determine the clinical study type(s) that is needed and whether any necessary study design was
needed. For example, suppose a comparative clinical study is needed, then the developers should
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explain how these factors were considered in determining a study design, including the endpoint(s),
population, similarity margin, and statistical analyses.
Additionally, specic concerns related to safety or effectiveness regarding the reference product
and its class (including the history of manufacturing- or source- related adverse events) may yield
more comparative clinical data. Alternatively, suppose there is information regarding other biological products that could support a biosimilarity determination (with marketing histories that demonstrate no apparent differences in clinical safety and effectiveness proles), then such information
may serve as an additional factor for supporting a selective and targeted approach to the clinical
program.
In the absence of surrogate markers for efcacy, it is usually necessary to demonstrate comparable clinical efcacy between a proposed biosimilar product and the reference product in an
adequately powered, randomized, parallel- group comparative clinical study(s), preferably with a
double- blind design, using efcacy endpoints. Generally, the study population should represent
approved therapeutic indication(s) of the reference product and be sensitive in detecting potential
differences between a proposed biosimilar product and the reference product. Occasionally, changes
in clinical practice may require a deviation from the approved therapeutic indication, for instance,
a concomitant medication used in combination treatment, line of therapy, or severity of the disease.
Deviations need to be justied and discussed with regulatory authorities.
8.5 STUDY DESIGN
Careful consideration should be given to the study design, including the choice of primary efcacy
endpoints and comparative clinical margins. Each of these aspects is important and should be justied on based on clinical evidence. The study should be conducted using a clinically relevant and
sensitive endpoint to show the absence of a clinically meaningful difference between the proposed
biosimilar product and the reference product. The chosen endpoint could be different from that set
in the original study for the reference product (e.g., a well- established surrogate or a more sensitive endpoint). An acceptable comparability margin should be dened in all cases, considering the
smallest effect size that the reference product would reliably be expected to have based on publicly
available historical data. If multiple endpoints are used, then the principles described above should
be applied.
In line with the principle of similarity, equivalence trials are generally preferred. If noninferiority
trials are considered, then they should be justied, and the developer is advised to consult with regulatory agencies before study initiation. The developers should be aware that such trials’ results could
suggest the statistical superiority of a proposed biosimilar product relative to the reference product.
In such instances, the superiority observed should be assessed for clinical relevance, including its
effect on safety. If the superiority observed is considered clinically meaningful and is associated
with increased adverse drug reactions over those seen with the reference product, the product would
no longer be considered a biosimilar. Moreover, demonstration of noninferiority of a proposed
biosimilar product to the reference product might not provide strong supporting evidence for the
authorization of other indications, particularly if the other indications include different dosages than
those tested in the clinical study.
8.5.1 efficacy endPoints
Using a comparative clinical study, the developers should set endpoints to assess clinically meaningful differences between a proposed biosimilar product and the reference product. The endpoints
may differ from those used as primary endpoints in clinical studies of the reference product if they
are scientically supported. Certain endpoints (such as PD measures) are more sensitive than clinical
endpoints and, therefore, may enable more precise comparisons of the relevant therapeutic effects.
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TABLE 8.1
Clinical Efficacy Assessment
Clinical Endpoints in Testing of the Proposed Biosimilar
Absolute neutrophil count for granulocyte– colony- stimulating factor
Blood glucose concentrations in clamp studies for detecting insulin
Complete pathological response in breast cancer
Disease Activity Score- 28 versus American College of Rheumatology- 20 in rheumatoid arthritis disease
Objective response rate in solid tumors and lymphoma
Factor X and anti- factor II activity, magnetic resonance imaging– related endpoints for interferon- β,
Use of serum calcium levels for teriparatide
Bone mineral density together with serum C- terminal crosslinks, a bone resorption marker, as co- primary efcacy
endpoints for denosumab to treat and prevent osteoporosis
α4- integrin receptor saturation for natalizumab as the binding is directly linked to clinical outcomes
Serum lactate dehydrogenase levels and for eculizumab
In some situations, assessing many PD measures using a comparative clinical study will enhance
the sensitivity of the study. The adequacy of the endpoints depends on the extent to which PD
measures correlate with the clinical outcome, the extent of structural and functional data supporting
biosimilarity, the extent of understanding of the mechanism of action, and the nature or severity of
the outcome affected.
While the “hard” clinical outcome remains the most desirable endpoint, other clinical endpoints
that require shorter study durations have been widely used (Table 8.1).
The developers should justify that the chosen model is relevant and sensitive to detect potential differences in efcacy and safety. Differences detected between the efcacy of a proposed
biosimilar product and that of the reference product should always be discussed as to whether they
are clinically relevant. Generally, clinical data help in addressing slight differences observed in the
previous steps and conrm the comparable clinical performance of the proposed biosimilar product
and the reference product. Clinical data cannot be used to justify substantial differences in quality
attributes.
Comparative margins should be prespecied and justied based on both statistical and clinical
evidence by using the reference product’s data as well as all comparative clinical study designs and
assay sensitivity (see ICH topic E9 Statistical principles for clinical studies and CHMP guideline
CPMP/ EWP/ 2158/ 99 on the choice of the noninferiority margin).
8.6 CLINICAL SAFETY
Clinical safety is important throughout the clinical development program and is assessed during the
initial PK and PD evaluations and in any comparative clinical efcacy study. Comparative safety
data should generally be collected during pre- authorization, depending on the type and severity of
safety issues known for the reference product. The duration of safety follow- up pre- authorization
should be justied. More attention should be paid to comparing the type, severity, and frequency of
the adverse reactions between a proposed biosimilar product and the reference product, as reported
in literature. The developers should evaluate the specic risks anticipated for a proposed biosimilar
product in the application dossier. This includes, in particular, a description of possible safety
concerns that may result from a manufacturing process different from that of the reference product,
especially those related to infusion- related reactions and immunogenicity.
Immunogenicity testing of a proposed biosimilar product and the reference product should be
conducted during comparative efcacy testing of a proposed biosimilar product in the same assay
format and sampling schedule as those for the reference product, which must meet all current
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standards. Analytical assays should be performed in parallel with the reference product and the
proposed biosimilar product (in a blinded manner) to measure the immune response against the
product received by each patient. The analytical assays should preferably detect antibodies against
both the proposed biosimilar product and the reference product. Yet, they should, at minimum,
detect all antibodies developed against a proposed biosimilar product. Generally, 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 efcacy and safety parameters.
The duration of immunogenicity studies should be justied on a case- by- case basis depending
on the duration of the treatment course, the disappearance of the product from the circulation (to
avoid antigen interference in the assays), and the time for the emergence of the humoral immune
response (at least 4 weeks when an immunosuppressive agent is used). Follow- up duration should
be justied based on the time course and characteristics of unwanted immune responses described
for the reference product, for instance, a low risk of clinically signicant immunogenicity or no
signicant trend for increased immunogenicity over time. For long- term administration, 1- year
follow- up data will usually be required pre- authorization. Shorter follow- up data pre- authorization
(e.g., 6 months) might be justied based on the reference product’s immunogenicity prole. If
needed, immunogenicity data for an additional period, that is, for up to 1 year, could then be
submitted post- authorization. For the individual, refer to product- specic proposed biosimilar
guidelines.
Increased immunogenicity when compared with the reference product may become concerning
for the benet/ risk analysis and may question biosimilarity. However, lower immunogenicity for
a proposed biosimilar product is a possible scenario that would not preclude authorization as a
biosimilar. In case of defective development of neutralizing antibodies against the biosimilar, then
efcacy analysis of the entire population could erroneously suggest that the proposed biosimilar
product is more efcacious than the reference product. Therefore, it is recommended to pre- specify
an additional exploratory subgroup analysis of efcacy and safety in patients who did not mount an
antidrug antibody response during the clinical study. This subgroup analysis could help establish
that the efcacy of a proposed biosimilar product and the reference product is, in principle, similar
if not affected by an immune response.
8.6.1 study PoPulation
The choice of the study population should enable the assessment of clinically meaningful differences
between the proposed biosimilar product and the reference product. Often, the study population
used for testing a biosimilar will have characteristics consistent with those of the population studied
for the reference product’s marketing authorization for the same indication. However, there are
cases where a study population could be different from that used in clinical studies supporting the
reference product’s marketing authorization. For example, if a genetic predictor of response was
developed following the reference product’s marketing authorization, then it may be possible to use
patients with the response marker as the study population.
8.6.2 saMPle size and study duRation
The sample size for and duration of a comparative clinical study should be adequate in order to
detect clinically meaningful differences between a proposed biosimilar product and the reference
product. Certain endpoints, such as PD measures, may be more sensitive than clinical endpoints and
facilitate a smaller sample size in a study of limited duration. In cases where the sample size and
duration of the comparative clinical study may not be adequate for detecting relevant safety signals,
a separate assessment of safety and immunogenicity may be needed.
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8.6.2.1 Study Design and Analyses
Clinical Efficacy Assessment
A comparative clinical study for a proposed biosimilar development program should be designed to
investigate whether a proposed biosimilar product and the reference product exhibit clinically meaningful differences. The design should consider the nature and extent of residual uncertainty about
biosimilarity based on data generated from comparative structural and functional characterization,
animal testing, human PK and PD studies, and clinical immunogenicity assessment.
Generally, agencies expect a clinical study or studies designed to establish statistical evidence
that a proposed biosimilar product is neither inferior nor superior to the reference product by more
than a (possibly different) specied margin. Typically, an equivalence design with symmetric inferiority and superiority margins would be used. Symmetric margins would be reasonable when, for
example, there are dose- related toxicities.
In some cases, it would be appropriate to use an asymmetric interval with a larger upper bound
to rule out superiority than a lower bound to rule out inferiority. An asymmetric interval could be
reasonable; for example, in cases where the dose used in the clinical study is near the dose- response
curve plateau. There is a small likelihood of dose- related effects (e.g., toxicity). In most cases, the
use of an asymmetric interval would generally allow for a smaller sample size than would be needed
with symmetric margins. However, if there is a demonstration of clear superiority, then further consideration should be given as to whether a proposed biosimilar product can be considered a proposed
biosimilar to the reference product.
In some cases, depending on the study population and endpoint(s), ruling out only inferiority
may be adequate to establish that the proposed biosimilar product and the reference product have
no clinically meaningful difference. For example, if it is well established that doses of the reference product pharmacodynamically saturate the target at the clinical dose level, then it would be
unethical to use lower than clinically approved doses; in such cases, a noninferiority design may
be sufcient. The developers should provide adequate scientic justication for the choice of study
design, study population, study endpoint(s), estimated effect size for the reference product, and
margin(s) (how much difference to rule out). The developers should discuss their study proposal(s)
and the overall clinical development plan with regulatory agencies before initiating the comparative clinical study.
8.6.3 clinical endPoints
One or more clinical studies are sufcient to demonstrate the safety, purity, and potency of a proposed
biosimilar product in one or more of the indications for which the reference product is licensed. This
typically includes assessing immunogenicity, PK, and, in some cases, PD, and it may also include
a comparative clinical efcacy study. The European Medicines Agency (EMA) guidelines state that
clinical data help in addressing any slight differences observed in analytical similarity, nonclinical
pharmacology, and PK and PD (where possible in healthy subjects) to conrm the comparable clinical performance between a proposed biosimilar and the reference product. However, clinical data
cannot be used to justify substantial differences in quality attributes. The developers may choose to
withdraw their proposed biosimilar application and le it as a new biologic, a strategy that worked
for Teva for its lgrastim product, which was ultimately approved as a new biologic (Granix); noteworthy, when exploiting this path, the developer is not required to provide any comparative data
with the reference product, but the literature data can be used to justify safety and efcacy claim to
some extent.
The outcome of efcacy trials depends not only on drug exposure (PK prole) but also on the
proper pharmacological action of the biological substance in vivo. Therefore, the objectives of both
types of studies differ. Efcacy trials are usually designed as equivalence trials (or noninferiority
trials) to ensure that the efcacy of a proposed biosimilar decreases or increases when compared
with that of the reference product. However, some residual uncertainty regarding the potentially
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TABLE 8.2
157
Suggested Comparative Clinical Study Endpoints
Pathological complete response in breast cancer
Disease Activity Score- 28 versus American College of Rheumatology- 20 in rheumatoid arthritis disease
Objective response rate in solid tumors and lymphoma
Absolute neutrophil count for granulocyte– colony- stimulating factor
Blood glucose concentrations in clamp studies for insulin detection
Low- molecular- weight heparin. Factor X and anti- factor II activity
Magnetic resonance imaging– related endpoints for interferon- β
Serum calcium levels for teriparatide
Anti- factor X and anti- factor II activity
Bone mineral density together with serum C- terminal crosslinks, a bone resorption marker, as co- primary efcacy
endpoints for denosumab, a monoclonal antibody used to treat and prevent osteoporosis
For natalizumab, α4- integrin receptor saturation as the binding is directly linked to clinical outcomes
For eculizumab, a potential pharmacodynamics marker to study biosimilarity is serum lactate dehydrogenase because of the
sustained reduction observed in intravascular hemolysis for the treatment period owing to the reduced need for red blood
cell transfusions and less fatigue
increased efcacy of a proposed biosimilar may be acceptable in exceptional cases. The data from
other evaluation exercises support the conclusion of biosimilarity and safety.
Clinical endpoints (Table 8.2) used in comparability studies of the proposed biosimilar should
enable the measurement of any unconfounded pharmacological effects and be sensitive in detecting
potential clinically relevant differences between the proposed biosimilar candidate and its reference
product. However, the clinical endpoints need not be the same as those approved in the development
of the reference product; if the endpoints are sensitive in demonstrating any clinically meaningful
difference, then these should be acceptable.
Clinical endpoints used in clinical efcacy comparability studies should ideally measure
unconfounded pharmacological effects and be sensitive in detecting potential clinically relevant
differences between the proposed biosimilar candidate and its reference product. In this regard,
hard clinical endpoints such as overall survival are relatively insensitive and are often inuenced by
disease- and patient- related factors. Regulatory agencies encourage the developers to suggest novel
validated clinical markers as a better choice than patients’ responses (Table 8.2).
8.6.4 extRaPolation of clinical data acRoss indications
Suppose a proposed biosimilar product meets the biosimilarity and other regulatory requirements
for marketing authorization as a proposed biosimilar product based on, among other things, data
derived from one or more clinical studies sufcient to demonstrate safety, purity, and potency in an
appropriate condition of use. In that case, the developers must seek marketing authorization of the
proposed biosimilar product for one or more additional conditions of use for which the reference
product is authorized.
However, the developers would need to provide sufcient scientic justication for extrapolating
clinical data to determine biosimilarity for each condition of use for which marketing authorization
is sought.
Such scientic justication for extrapolation should address, for example, the following issues
for the tested and extrapolated conditions of use:
• Mechanisms of action of the proposed biosimilar in each condition of use for which marketing
authorization is sought; this may include
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