Rationalizing FDA Guidance on

Biosimilars—Expediting Approvals and

Acceptance
KEYWORDS

Biosimilars, FDA, 351(k), Analytical Similarity, Statistical Tier Testing, Equivalence Interval,
Immunogenicity Testing, Biosimilarity, BPCIA, Interchangeable Biosimilars, Comparability
Protocol

AUTHOR

Sarfaraz K. Niazi, Ph.D., SI, FRSB, FPAMS, FACB

Adj. Professor of Biopharmaceutical Sciences, University of Illinois
Founder and Executive Chairman, Karyo Biologics, LLC
Hoffmann Estates, IL 60169

BACKGROUND
Since the passage of H.R. 3590 Sec. 7002 in 20091, commonly known as the BPCIA, the
FDA has licensed eleven products as of June 20182 comprising eight molecules: filgrastim,
pegfilgrastim, adalimumab, rituximab, bevacizumab, infliximab, epoetin, and etanercept. Other
approvals of drugs soon to become biosimilars3, insulins approved by FDA include Lusduna4 and
Basaglar.5 The FDA has issued several final and draft guidelines to help the industry better
understand the current thinking of the FDA on demonstrating biosimilarity6, the primary
determinant for licensing a product, either as a biosimilar or as an interchangeable biosimilar.
The slow entrance and acceptance of biosimilars into US market is a result of high cost and
a long time for development, $100-250 Million and 7-8 years,7 as well as a gross misunderstanding
about the safety of biosimilars, principally integrated into the minds of prescribes and the public
by the originator product companies. While the FDA has recently launched a campaign to educate
all stakeholders regarding the safety of biosimilars,8 there remain many unmet needs at the FDA

1
https://www.fda.gov/downloads/drugs/ucm216146.pdf
2

https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/t
herapeuticbiologicapplications/biosimilars/ucm580432.htm
3
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf
4
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=208722
5
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205692Orig1s000TOC.cfm
6

https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/General/ucm
444891.htm
7
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031732/
8
https://blogs.fda.gov/fdavoice/index.php/2017/10/fda-taking-new-steps-to-better-inform-physicians-about-

1
level to simplify and expedite licensing of biosimilars as pointed out by the author in a recent
Citizen Petition to FDA and several publications9,10,11.
The suggestions made in this article come from decades of on hands-on experience of the
author in developing dozens of biosimilars products globally, and also taking them through 351(k),
505(b)(2) filings.
THE BPCIA
This review focusses on what the FDA, the biosimilar developers, and other stakeholders
can do, staying within the boundaries of the statute, to make biosimilars more accessible. To
understand what the FDA can do, and how are the guidelines constructed, a review of the BPCIA
is necessary.
(k) Licensure of biological products as biosimilar or interchangeable

(1) In general

Any person may submit an application for licensure of a biological product under this subsection.

(2) Content

(A) In General
(i) Required Information

An application submitted under this subsection shall include information demonstrating that

(I) the biological product is biosimilar to a reference product based upon data derived from—
‘‘(aa) analytical studies that demonstrate that the biological product is highly similar to the
reference product notwithstanding minor differences in clinically inactive components;
‘‘(bb) animal studies (including the assessment of toxicity); and
‘‘(cc) a clinical study or studies (including the assessment of immunogenicity and
pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and
potency in 1 or more appropriate conditions of use for which the reference product is licensed and
intended to be used and for which licensure is sought for the biological product;
(II) the biological product and reference product utilize the same mechanism or mechanisms of action for the
condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to
the extent the mechanism or mechanisms of action are known for the reference product;
(III) the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for
the biological product have been previously approved for the reference product;
(IV) the route of administration, the dosage form, and the strength of the biological product are the same as
those of the reference product; and
(V) the facility in which the biological product is manufactured, processed, packed, or held meets standards
designed to assure that the biological product continues to be safe, pure, and potent.
(ii) DETERMINATION BY SECRETARY. —The Secretary may determine, in the Secretary’s discretion, that an
element described in clause (i)(I) is unnecessary in an application submitted under this subsection.

biosimilars-through-education-about-these-potentially-cost-saving-options/
9
https://www.europeanpharmaceuticalreview.com/article/70987/obstacles-success-biosimilars-us-market/
10
http://www.bioprocessintl.com/manufacturing/biosimilars/ebook-challenges-facing-biosimilar-products-us-
markets/
11
https://www.regulations.gov/document?D=FDA-2018-P-1876-0001

2
 (4) Safety standards for determining interchangeability

Upon review of an application submitted under this subsection or any supplement to such application, the Secretary
shall determine the biological product to be interchangeable with the reference product if the Secretary determines
that the information submitted in the application (or a supplement to such application) is sufficient to show that—

(A) the biological product—

(i) is biosimilar to the reference product; and

(ii) can be expected to produce the same clinical result as the reference product in any given patient; and

(B) for a biological product that is administered more than once to an individual, the risk in terms of safety or
diminished efficacy of alternating or switching between use of the biological product and the reference product is
not greater than the risk of using the reference product without such alternation or switch.

The statutory requirements provided above in section k.1.2.A.i.I form the entire basis of
the development of biosimilars, but remarkably all of these requirements are left to the discretion
of the FDA as shown in k.1.2.A.ii leaving only k.1.2.A.i.I-V the conditions that can not be changed
by FDA.12 The licensing of interchangeable is an add-on step as shown above in k.1.4.A-B. The
biosimilar product must demonstrate the same clinical results as the reference product, making it
necessary to test in patients. When a biosimilar product is repeatedly administered, a study using
a switching and alternating protocol must show no diminished efficacy and no greater risk
compared to reference product without alternation or switch.

The FDA yet approves its first interchangeable product, the discussion in this paper is
intended to address the issues related only to biosimilars since the pathway to interchangeable is
carved out in the statute, and the FDA is not at freedom to change it.
ACTIONS REQUESTED
To allow faster development and adoption of biosimilar products, the following changed
in the regulatory approval process are recommended:
 Modify the current default status of requiring bridging studies between a US-licensed
product and a non-US approved comparator, to establish biosimilarity, provided the
non-US product meets specific qualifications.
 Present clear and open scientific views to the public, more particularly, to the
prescribers that a biosimilar product has “no clinically meaningful difference” from the
originator product and thus it should be acceptable for naïve patients, without getting
involved with the legality of substitution.
 Encourage the development of in vitro immunogenicity testing methods to reduce
exposure of test subjects on ethical grounds, as well as to allow comparison of multiple
batches to improve the safety evaluation.
 Replace the current arbitrary comparisons of critical quality attributes with clinically
relevant limits and ranges in testing analytical similarity, animal toxicology, PK/PD,
immunogenicity and other safety and efficacy attributes.

12
https://www.gpo.gov/fdsys/pkg/USCODE-2010-title42/pdf/USCODE-2010-title42-chap6A-subchapII-partF-
subpart1-sec262.pdf

3
  Minimize clinical studies by combining studies and avoiding studies in patients where
possible.
 Clarify the policy on analytical methods validation.
 Change the requirement of the use of at-scale batches for the determination of
biosimilarity.
These recommendations are also, in part, the subject of a Citizen Petition filed by the
author to FDA to enact these changes.13
ALLOW WAIVER OF BRIDGING STUDIES
The cost of development of biosimilars is high and requires the developers to formulate a
global strategy where one regulatory dossier can be used to secure regulatory approvals in multiple
jurisdictions. Since the BPCIA requires that a biosimilar to be similar to its locally licensed
originator (that is, a product approved under Sect. 351(a) of the Public Health Service Act of 1942,
as amended), the developers are not allowed to use a Non-US product as a reference product. As
a result, creating a global dossier requires conducting three-way studies (US-licensed product, a
non-US product, and the biosimilar candidate) to develop their regulatory dossier. To reduce this
burden of additional studies, and to reduce unnecessary exposure to humans, several regulatory
authorities have established clear policies on bridging studies as shown in Table 1.
Table 1 Summary of global jurisdictions for bridging data between local and foreign
reference biologic product in the development of biosimilars.14

Jurisdiction Key regulatory texts Regulatory provisions

Australia Regulation of biosimilar For a FAC, a bridging study must be

medicines (guidance)15 provided. This study may be abridged or
omitted if evidence is provided that the drug
is manufactured in a single site for global
sales

Canada Draft—revised guidance
document: information and
submission requirements
for subsequent entry
biologics (SEBs)16
Bridging studies are often not required but
are required when two different references
are used in clinical studies. Each reference
should be shown to be analytically similar to
the biosimilar, or the sponsor should
demonstrate the analytical similarity
between the different references and
perform appropriate clinical bridging studies
(i.e., PK/PD studies)

European CHMP/437/04 Rev 1 Bridging studies required—most commonly

13
https://www.regulations.gov/docket?D=FDA-2018-P-1876
14
BioDrugs (2017) 31:279–286
15
https://www.tga.gov.au/sites/default/files/evaluation-biosimilars-151217_0.pdf
16
http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/consultation/biolog/submission-seb-exigences-pbu-eng.pdf

4
 Jurisdiction Key regulatory texts Regulatory provisions

Union Guideline on similar only analytical data

biological medicinal
products17

Switzerland AW—Administrative Bridging data required

ordinance—Authorization
of similar biological
medicinal products
(Biosimilars)18

United Biosimilars: Questions and Bridging studies required—usually

States Answers Regarding analytical and human PK data
Implementation of the
Biologics Price
Competition and
Innovation Act of 2009:
Guidance for Industry19

WHO Guidelines on evaluation of Bridging studies between RBP/FACs of

similar biotherapeutic different origins not explicitly required
products (2009)20, 21
Key: FAC foreign approved comparators, PK/PD pharmacokinetics/pharmacodynamics, RB Preference biologic
products, WHO World Health Organization
The most stringent requirements are imposed by the FDA that include at least analytical
similarity and PK/PD studies, by the FDA. It is noted that the FDA requirements are not clearly
spelled out as such but accepted as a default position of FDA. There is no legal impediment for
the FDA to changes its position and allow the developers to request a waiver to the use a Non-US-
licensed product alone as the reference product, if certain conditions, enumerated below:
 The non-US reference product meets all statutory requirements as shown above
k.1.2.A.i.II-V;
 The non-US product received approval in its respective jurisdictions by filling essentially
the same original data, including clinical safety and effectiveness, like that of the US-
licensed reference product; or,
 If the non-US reference product was judged to be equivalent to the US-licensed product in
any regulatory filing that presented a bridging study; a few examples include: established

17
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf
18
https://www.swissmedic.ch/ZL101_00_002e_VV
19
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM444661.pdf
20
http://www.who.int/biologicals/areas/biological_therapeutics/biotherapeutics_for_web_22april2010.pdf?ua=1
21
WHO is not a regulatory authority, but its guidance are highly influential on many regulators, especially in the emerging
markets

5
 by the FDA has determined in the evaluation of a biosimilar candidate such as Remicade22,
bevacizumab23 and insulin glargine24 (under 505 (b)(2) until March 2020).
 Is not used in a study intended to claim an interchangeable status25 to a biosimilar product.
While the statements made by Dr. Scott Gottlieb favor this recommendation, there is a
concern at the FDA that legislative action is required to remove the condition of requiring the
bridging studies.26 The author finds no legal reason why this change will not be allowed.
ENCOURAGE SUBSTITUTION OF A BIOSIMILAR FOR NAÏVE
PATIENTS
The BPCIA creates two categories of biosimilar products: biosimilar and interchangeable
biosimilar. The latter classification was intended to allow automatic substitution of an originator
product with a biosimilar product. The acceptance of a biosimilar product to be labeled as
interchangeable biosimilar requires studies in patients to demonstrate similar efficacy and when a
product is repeatedly administered, the two products are switched and alternated to establish that
there is no reduction in efficacy or an increase in the side effects. As a result, the FDA is yet to
approve a product as an interchangeable biosimilar. However, there is need to take a strategic
approach to allow substitution of biosimilars based on how FDA characterizes a biosimilar FDA.27
“A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences
from an existing the FDA-approved reference product.”

From a scientific and clinical viewpoint, if a product is clinically equivalent, there is no

reason why it should not be prescribed to naïve patients. This view is shared by the FDA
Commissioner, Dr. Scott Gottlieb,28 who said: “payors can also lead the way in formulary design
by making biosimilars the default option for newly diagnosed patients. They can share the savings
with patients, maybe by waiving co-insurance.”
The Author is requesting the FDA:
 To declare an official position that a licensed biosimilar product has no clinically
meaningful difference and that it can be substituted for the originator product when the
originator product is prescribed for a naïve or new patient.
 To engage in educating prescribers that biosimilars are safe and equally effective, without
any risk of additional immunogenicity, when used in naïve or new patients—the most

22
https://www.fda.gov/downloads/%E2%80%A6/UCM484859.pdf
23

https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisor
yCommittee/UCM566365.pdf
24
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205692Orig1s000TOC.cfm
25Draft Guidance for Industry: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price
Competition and Innovation Act of 2009; the FDA, February, 2012:8. https://
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM444661.pdf. Finalized Apr
2015.; Draft Guidance for Industry: Considerations in Demonstrating Interchangeability With a Reference Product; the
FDA, January, 2017, p. 16. https://www.fda.gov/downloads/Drugs/Guidance
ComplianceRegulatoryInformation/Guidances/UCM537135.pdf. Accessed 17 May 2017.
26
http://www.centerforbiosimilars.com/news/gottlieb-fda-considering-an-end-to-biosimilar-bridging-studies-
27

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/Therape
uticBiologicApplications/Biosimilars/ucm580419.htm
28 https://www.fda.gov/NewsEvents/Speeches/ucm599833.htm

6
 significant barrier to the entry of biosimilars into US markets.
 To motivate and enforce adoption of biosimilars by the payors to make the pricing
structure more transparent to demonstrate to patients and prescribers the real cost savings.
ALLOW IN VIVO IMMUNOGENICITY STUDY WAIVERS
Immunogenicity is defined as the propensity of the therapeutic biologics to generate immune
responses to itself and related proteins or to induce immunologically related non-clinical effect or
adverse clinical events. Immune responses to therapeutic biologics may also neutralize their
biological activities and result in adverse events not only by inhibiting the efficacy of the
therapeutic biologics, but also by cross-reacting to an endogenous protein counterpart, leading to
loss of its physiological function (e.g., neutralizing antibodies to therapeutic erythropoietin cause
pure red cell aplasia by also neutralizing the endogenous protein). The effect of immunogenicity
in the therapeutic biologics development can be summarized as follows:
 Effects on bio-availability
 Effect on safety and efficacy
 Effect on PK including potential cross-reactivity to endogenous proteins
 Inhibition of the function of endogenous protein
 Injection site reactions
 Systemic reactions mild or life-threatening
 Formation of ADA (HAMA, HACA, HAHA)
 Formation of neutralizing antibodies
 Formation of immune complexes
 Formation of anti-idiotypic antibodies
Immunogenicity assessment as stated in the FDA guidelines on therapeutic biologics is
investigated in the target population since animal testing and in vitro models cannot predict
immune response in humans. Also, immunogenicity has a role in demonstrating product
comparability following manufacturing changes and similarity in the context of biosimilar
development. Even minor changes can potentially affect the bioactivity, efficacy or safety
including immunogenicity of a therapeutic biologic.
The FDA is making advances in developing this complex science of predicting
immunogenicity using in vitro methods,29 promoting the use of in vitro immunogenicity assays.
The European Medicines Agency provides the following statement regarding use of
alternate methods of testing immunogenicity: “…ongoing consideration should be given to the use
of emerging technologies (novel in silico, in vitro and in vivo models), which might be used as
tools during development or for the first estimation of risk for clinical immunogenicity. In vitro
assays based on innate and adaptive immune cells could be helpful in revealing cell-mediated
responses.30

29
https://www.fda.gov/BiologicsBloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm246804.htm
30
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/06/WC500228861.pdf

7
 The characterization and screening of biosimilars for physicochemical determinants or
formulation-based factors aid both in the prediction of immunogenicity and in the development of
less immunogenic therapeutic agents, considering impurities, heterogeneity, aggregate formation,
oxidation and deamidation of the molecule. Moreover, predicting potential immunogenic epitopes
in therapeutic biologics is an important and useful strategy to improve their safety and efficacy.
Immunogenicity testing adds substantially to the cost and time for development, like any
clinical study, and the goal of regulatory guidance should be to minimize human testing where
possible. A variety of preclinical immunogenicity assessment strategies are currently used during
therapeutic biologics development as listed in Table 2.
Table 2 Strategies in predicting and reducing immunogenicity to therapeutic biologics
Prediction Reduction
Physiochemical characterization Deimmunization (epitope modifications)
In Silico immunogenicity assessment Humanization
T cell epitope predictions
B cell epitope predictions
In Vitro immunogenicity assessment Purity and formulations
Ex Vivo immunogenicity assessment Purity and formulations
T cell response Modifications
HLA binding assays Fusion proteins
In Vivo immunogenicity assessment Combination biologics or combination therapy

A major advantage of using an in vitro method comes from the ability to test multiple
batches for immunogenicity that is not possible if the immunogenicity is tested in human subjects.
The in vitro tests can be more useful in predicting the difference between a biosimilar product and
its reference product.
There is a clear ethical risk in testing for immunogenicity in healthy subjects, as we can
make them immune positive, as we compare the US-licensed reference to a biosimilar candidate.
For the FDA to move the science of in vitro immunogenicity testing farther, the FDA should:
 Allow developers to present in vitro, in silico, or novel in vivo test methods to request a
waiver from clinical immunogenicity testing.
 Continue its internal development in finding and prescribing testing modalities that reduce
the need for clinical testing of immunogenicity.
MAKE PHARMACOKINETIC PROFILING CLINICALLY
RELEVANT
Bioequivalence is defined in 21 CFR 320.1 (Hatch-Waxman Act31) as “the absence of a
significant difference in the rate and extent to which the active ingredient or active moiety in
pharmaceutical equivalents or pharmaceutical alternatives become available at the site of drug
action when administered at the same molar dose under similar conditions in an appropriately
designed study.” Since the site of action is not known in most cases, and rarely available for

31
https://www.gpo.gov/fdsys/pkg/STATUTE-98/pdf/STATUTE-98-Pg1585.pdf

8
sampling, a surrogate to the site of action was selected as blood level. The PK profile characterizes
the two stages: absorption and disposition (distribution and elimination), making it most relevant
to generic chemical drugs where the disposition is less likely to vary making the PK profile relevant
to absorption, and therefore bioavailability and thus providing validation of bioequivalence.
The PK profiling of biosimilars follows the same testing protocols as used for generic
chemical drugs. However, such extrapolation of testing protocols incurs a significant
misconception; the biosimilar drugs are administered parentally, where the difference in
absorption are least likely to differ but most likely differ in their disposition (distribution due to
binding effects and elimination due to subtle structural differences). This difference between a
generic chemical drug and a biosimilar product needs addressing in the selection of PK parameters
and the statistical models applied to demonstrate similarity.
When the FDA developed the guidance on biosimilars, a new terminology of “clinical
relevance” was introduced—the most pivotal aspect of determining biosimilarity that addresses
the step-by-step approach:32 analytical similarity, non-clinical toxicology, PK/PD profiling,
immunogenicity profiling and if there remains any “residual uncertainty” (another terminology
created by FDA), additional clinical studies (in healthy subjects of patients). The consideration of
“clinical relevance” should be part of the PK/PD analysis.
The Author is suggesting following changes to the criteria of PK/PD profiling of
biosimilars compared to a reference product:
 Waive PK studies where the product is administered by a route (ocular, otic, and possibly
other routes) that does not allow sufficient concentration of the active moiety in blood; an
excellent example of this type of product is the intraocular administration of ranibizumab.33
However, to allow evaluation of the difference in the disposition kinetics, PK studies upon
intravenous administration in an appropriate animal species such as monkeys for
monoclonal antibodies should be required. This study can be made a part of the non-clinical
toxicology assessment. In most instances, a study population of 10-12 animals should
suffice.
 When administered parentally, as most biologicals are, the PK parameters relating to
distribution such as distribution volume and parameters relating to elimination such as
terminal half-life are more clinically relevant than the AUC or even Cmax. Statistical
modeling should include these additional parameters. The distribution volume as a
determinant of clinical efficacy was introduced by the author decades ago, and now this
finds a new application in the evaluation of biosimilars.
 While the acceptance criterion of the confidence interval of the log ratio of Cmax and AUC
(and for any other parameters added as suggested above) to be within 80-125% has worked
well for generic drugs, there is assurance that these intervals are clinically meaningful for
biological drugs. Should the FDA broaden the interval of acceptance or narrow it down
remains to be determined once the FDA begins to consider additional parameters suggested
above are taken into consideration.
 Encourage use of SABE protocols that will allow collection of immunogenicity profiles in

32
42 USC 262(k)(2)(A)(ii)
33
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Scientific_Discussion/human/000715/WC500043550.pdf

9
 a single study; in those instances where the immunogenicity data are required to be
collected from a patient population, FDA should allow PK/PD profiling in patients,
reducing the number of clinical studies required.
 Allow PK/PD studies to select a population that is likely to have a minimal variation to
reduce the study size. Choosing a specific population should work well to demonstrate
differences between the biosimilar candidate and the reference product.
MODIFY TIER TESTING CRITERIA FOR ANALYTICAL
SIMILARITY
The FDA has recently released draft guidance on “Statistical Approaches to Evaluate
Analytical Similarity” of biosimilars34, one of the most critical components for establishing
biosimilarity, and a component that determines what additional studies, both clinical and CMC-
related that are required. A developer identifies critical quality attributes (CQAs) and tests them
on Tier 1, Tier 2, or Tier 3 level, depending on the nature of data output and the importance of the
attribute to safety and efficacy of a biosimilar product.
For CQAs in Tier 1, equivalence is established by rejecting the interval (null) hypothesis: -
1.5σR ≤90% CI of [µT-µR]≤1.5σ where μT and μR are the mean responses of the test (the proposed
biosimilar) product and the reference product lots, respectively. The suggests the equivalence
acceptance criterion, EAC = 1.5 * σ, where σ is the variability of the reference product, the standard
deviation. A statistical justification for the factor of 1.535 follows the idea of a scaled average
bioequivalence (SABE) criterion for highly variable generic drug products proposed by the FDA.
To achieve a desired power of the similarity test, the FDA further recommends that appropriate
sample size is selected by evaluating the power under the alternative hypothesis at μT − μR = ⅛.
There is no clear relevance of the factor of 1.5 originated to test the most critical of the CQAs.
For example, in presenting the briefing on the approval of Sandoz filgrastim product,36 the FDA
stated that one of the CQA selected was protein content, and it failed initially, requiring additional
batches to be added to statistical analyses to allow passing of the test. While there is a correlation
between the dose and effect for biological products, a small variation, as observed in the Sandoz
data should not have any clinically meaningful difference since the release specification allows
more considerable variability. In essence, a test for analytical similarity may fail, yet such variation
is allowed for the commercial product going to patients.
The test criterion for Tier 1 testing for CQAs can result in misleading results. Let us take an
example of 10 batches (a recommended number by the FDA) of a biosimilar candidate tested
against an equal number of reference product batches for a percentage of the labeled quantity of
protein. If the variation in the reference product is minimal approaching to a value of zero for σ,
then all comparisons will fail even if there is no clinically meaningful difference such as where the
biosimilar candidate has the same average of 100, but one out of ten batches tests at 99 and the

34
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM576786.pdf
35
Chow S-C, Song F, Bai H. Analytical Similarity Assessment in Biosimilar Studies. AAPS J. 18(3) 2016:
670–677; doi:10.1208/s12248-016-9882-5.

36
http://patentdocs.typepad.com/files/briefing-document.pdf

10
other is 101. This is not a hypothetical presentation. The Author has come across these situations
where an attribute is tightly controlled in the originator product based on decades of manufacturing
experience. The question arises if this is a clinically meaningful difference or merely a routine
observation. For example, a biosimilar product that is allowed a range of 97-103 or even 95-105%
in the COA, based on the history of manufacturing, yet all of these samples will fail if the σ of the
reference product is minimal. On the other hand, where an attribute has high variability (σ) for the
reference product, the test passes, while failing in a Tier 2 test where we have 90% of all values
within 3*σ. It is for this reason that the FDA requires a Tier 2 testing for all Tier 1 attributes. To
resolve these inconsistencies, the Author is suggesting the following changes to statistical
modeling of CQAs in the analytical similarity testing:
 Do not include any quality attributes for testing of analytical similarity that are part of the
Certificate of Analysis; If the FDA is accepting the variability as shown in the ranges of
acceptance provided in the COA, then it does not make sense to accept or reject a product
based on statistical limits of analytical similarity otherwise. The COA is clinically relevant,
the tiered testing of these attributes is not. Critical quality attributes of importance are
primary, secondary and tertiary structure, receptor binding, impurity profile of timed
samples, and many more that are pertinent to differences in the molecules, albeit small and
subtle.
 Allow the developers to use of Identify CQAs and also their range of variability based on
clinical meaningfulness rather than an arbitrary factor (e.g., 1.5) for Tier 1 testing.
 If a product fails Tier 1 test but passes the Tier 2 testing, allow this as acceptance of
similarity.
CLARIFY ANALYTICAL TESTING VALIDATION
Whereas it is clearly understood that all analytical methods including the bioanalytical
methods must be validated, a provided in a recent (May 2018) final guidance on bioanalytical
methods37. The analytical similarity testing requires using test methods that are often difficult or
impossible to validate based on the guidance provided, without incurring high cost and time, such
as NMR, mass spectrometry, etc. Whereas all analytical test methods used for the release of a
product should be validated, the test methods to demonstrate other analytical similarity attributes
may be acceptable if they are suitable, a vocabulary often used in the FDA guidance but not entirely
made clear.
ENCOURAGE DEVELOPMENT OF NOVEL TESTING METHODS
The current testing methodologies for evaluating differences between a biosimilar
candidate and a reference product are based on methods for characterizing new molecules; there
is a need to develop technology that will be more sensitive to determine differences in the structure
of large molecules, both at steady state and during activity within the body. One such method, as
recently reported, involves a thermodynamic approach to stressing the three-dimensional structure
and studies its interaction with its surrounding by a simple fluorescence technique developed by
the author.38 Several new techniques have come into practice recently including modified capillary

37
https://www.fda.gov/downloads/drugs/guidances/ucm070107.Pdf
38

https://static1.squarespace.com/static/55354388e4b044cf6c8d051e/t/5ab7b49188251b198c35fa0c/1521988753676/b
iomolecule+patent.pdf

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electrophoresis, Chip-based (Bioanalyzer) Protein Electrophoresis Assays (CPEA), and many
variations involving mass spectrometry.39
The FDA defines a fingerprint-like similarity as: “the results of integrated, multi-parameter
approaches that are extremely sensitive in identifying analytical differences (i.e., fingerprint-like
analyses) permit a very high level of confidence in the analytical similarity of the proposed
biosimilar product and the reference product, and it would be appropriate for the sponsor to use a
more targeted and selective approach to conducting animal and/or clinical studies to resolve
residual uncertainty and to support a demonstration of biosimilarity. 40” Introduction of new
methodologies is most likely to demonstrate a clinically meaningful lack of difference that will
lead to requiring fewer additional studies.
ACCEPT SMALLER BATCH SIZES AS COMMERCIAL SCALE
Unlike the development of new drugs or biologics, the development of biosimilars requires
at-scale or commercial scale batches to begin testing for similarity. The rationale for this
requirement comes from the assertion that there may not be any efficacy study required where
commercial scale batches are tested, so the development exercise must begin with fully scaled
batches. This requirement creates a huge cost and time burden on the developers, disqualifying
large number of developers to enter the market. While the FDA has not identified what it considers
to be a commercial scale, these conversations come up early in Type 2 meetings with FDA. The
author is suggesting the FDA to require a batch size that is adequate to provide samples for testing,
for stability testing and for the clinical or other testing required, instead of making any market
projections to justify the size of a commercial batch. Should the developer decide to change the
batch size after the product has been approved, the developer may use the Comparability Protocol
for Biological Drugs41 to make this post-approval change. The impact of this clarification by the
FDA will be large on the industry, allowing small developers to offer products ready to go to
market using small batches at a much lower cost. The developer may also use novel techniques of
scaling up where the output from several small batches is combined as described by the author in
several US patents.42
MINIMIZE CLINICAL STUDIES
The largest contributor to cost and time to market comes from the clinical studies required
to establish biosimilarity. When clinical studies are required in patients, the cost and timeline
stretch further. The current mindset of establishing biosimilarity follows the phase 1 to 3 testing
that is not relevant to establish non-inferiority status of a biosimilar candidate with the reference
product. Here are some recommendations:
 If it is determined a priori that studies are required in patients, then allow
developers to conduct PK/PD profiling in patients as well.
 Allow statistical models of PK/PD studies to allow determination of
immunogenicity within the same study.

39
https://www.agilent.com/cs/library/primers/Public/5990-8561EN_LO.pdf
40
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm397017.pdf
41
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM496611.pdf
42

https://static1.squarespace.com/static/55354388e4b044cf6c8d051e/t/58858321d2b857134e45071c/1485144867139/
US9469426.pdf

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  Allow use of in vitro models of immunogenicity testing to reduce exposure to
healthy subjects.
 Allow use of animal models to establish differences in the PK (and where possible
PD profile) where the blood concentrations are not measurable.
SUMMARY
In creating the methods for evaluation of biosimilars, the FDA has created a highly specific
and scientifically important vocabulary such “no clinically meaningful difference” and “residual
uncertainty” that are highly relevant and represent a creative approach to assuring the safety of
biosimilars. However, not all guidance of the FDA takes these two considerations into account
adequately.
The following is a summary of the recommendations made based on clinical relevance:
 Remove default requirements of conducting bridging studies for non-US reference product
where the reference product meets specific criteria.
 Declare that biosimilars have no clinically meaningful difference from the originator
product and therefore, substitutable for naïve patients should be allowed.
 Remove default requirements of conducting in vivo immunogenicity testing and allow
developers to offer alternate in vitro and silico testing instead of clinical testing.
 Modify PK/PD protocols and statistical analysis to make the outcome clinically
meaningful.
 Modify testing of critical quality attributes by separating them from release specification
to demonstrate analytical similarity.
 Minimize clinical studies by combining studies.
 Clarify the type of validation required for analytical similarity testing.
 Allow approval of products based on small-scales sufficient for the study only.
The FDA has recognized the need for changes to the FDA guidance, as communicated by
the Commissioner of FDA, Dr. Scott Gottlieb,43 expressing the willingness of the FDA to respond
to the urgent needs to reinterpret the FDA’s guidelines for the approval, as well as wider adoption
of biosimilars.
CONFLICT OF INTEREST STATEMENT
The author is engaged in the development of biosimilars.
ABOUT THE AUTHOR
Prof. Sarfaraz K. Niazi has authored several textbooks and handbooks in the field of
biosimilars and bioprocessing;44 he has submitted serval citizen petitions to FDA suggesting
methodologies to modernize the regulatory approaches to the approval of generic and biosimilar
43
https://www.fda.gov/NewsEvents/Speeches/ucm599833.htm
44
Sarfaraz K. Niazi, Handbook of Biogeneric Therapeutic Proteins, CRC Press, 2006; ISBN-13: 978-0849329913;
Sarfaraz K. Niazi, Biosimilars and Interchangeable Biologicals: Strategic Elements. CRC Press, 2015; ISBN 9781482298918;
Biosimilars and Interchangeable Biologics: Tactical Elements. CRC Press, 2015; ISBN 9781482298918; Biosimilarity: The the
Agency Perspective, CRC Press, 2016, 978-1498750394; Biosimilars and Interchangeable Biologicals: Analytical Elements.
CRC Press., 2016; Frontiers of Bioprocessing—Immune and Gene Therapy, CRC Press, 2019

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products. Prof. Niazi has hands-on experience in developing and taking a large number of
biosimilar products to market globally. Prof. Niazi is an Adjunct Professor of Biopharmaceutical
Sciences at the University of Illinois and the University of Houston and Founder and Executive
Chairman of Karyo Biologics, LLC (www.karyobio.com) , a company developing biosimilars for
the US and EU markets in the creative model to reduce the cost and time to market. Prof. Niazi
also the founder of Adello Biologics (www.adellobio.com) that has several biosimilar products at
various stages of FDA approval. Prof. Niazi is also helping biosimilar companies around the world
in developing their development plans (www.pharmsci.com) and (www.niazi.com). He can be
contacted at niazi@karyobio.com.

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