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Regulatory Requirements
The duration of the immunogenicity study 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). The duration of follow- up
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. In the case of chronic administration, 1- year follow- up data will generally be required pre- authorization. Shorter follow- up data preauthorization (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 specic products, refer to product- specic proposed biosimilar
guidelines.
Increased immunogenicity, when compared with that of the reference product, may become
an issue for the benet/ risk analysis and question biosimilarity. However, decreased immunogenicity for a proposed biosimilar is also a possible scenario, which would not preclude approval as a
biosimilar. In case of reduced development of neutralizing antibodies with the biosimilar, the efcacy analysis of the entire study population could erroneously suggest that a proposed biosimilar
is more efcacious than the reference product. Therefore, it is recommended to pre- specify an additional exploratory subgroup analysis of efcacy and safety in people who did not have an antidrug
antibody response elicited during the clinical trial. This subgroup analysis could help establish that
the efcacy of a proposed biosimilar and the reference product is, in principle, similar if not affected
by an immune response.
Immunogenicity depends on several factors, including the route of administration, dosing
regimen, patient- related factors, and disease- related factors (e.g., co- medication, type of disease, and
immune status). Thus, immunogenicity could differ among indications. Extrapolation of immunogenicity from the studied indication/ route of administration to other uses of the reference product
should be justied.
2.5.2 clinical efficacy in Patients
No clinical efcacy and safety testing is required for products that have known PD markers; for
other products, the developer can submit a rationale for waiving these studies.
In the absence of surrogate markers for efcacy, it is usually necessary to demonstrate comparable clinical efcacy of a proposed biosimilar to that of the reference product in adequately powered,
randomized, parallel- group comparative clinical trial(s), preferably double- blind, by using efcacy
endpoints. The study population should generally represent approved therapeutic indication(s) of the
reference product and be sensitive in detecting potential differences between a proposed biosimilar
and the reference product. Occasionally, changes in clinical practice may require deviation from the
approved therapeutic indication, such as 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.
In general, an equivalence design should be used. The use of 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 in instances where the possibility of a signicant
and clinically relevant increase in efcacy can be excluded on scientic and mechanistic basis.
However, as in equivalence trials, assay sensitivity must be considered.
Efcacy trials of the proposed biosimilar product do not demonstrate efcacy per se, as this has
already been established with the reference product. The purpose of the efcacy trials is to conrm
comparable clinical performance between the proposed biosimilar and the reference product.
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In developing a proposed biosimilar product, the choice of clinical endpoints and time points of
the analysis of endpoints may deviate from the guidelines for new active substances. The Committee
for Medicinal Products for Human Use (CHMP) has issued disease- specic guidelines for the
development of innovative products. In the absence of such a guideline, comparability should be
demonstrated in appropriate, sensitive clinical models and certain study conditions. The applicant
should justify that the chosen model is relevant and adequately sensitive to detect potential efcacy
and safety differences. Nevertheless, deviations from endpoints recommended in disease- specic
guidelines need to be scientically justied. Clinical data cannot be used to justify substantial
differences in quality attributes.
The correlation between the “hard” clinical endpoints recommended by the guidelines for new
active substances and other clinical/ PD endpoints that are more sensitive in detecting clinically
meaningful differences may have been demonstrated in previous clinical trials with the reference
product. In this case, it is unnecessary to use the same primary efcacy endpoints as those used in
the reference product’s marketing authorization application. However, it is recommended to include
some standard endpoints (e.g., secondary endpoints) to facilitate comparisons with the clinical trials
conducted with the reference product.
Comparability margins should be pre- specied and justied on both statistical and clinical basis
using the reference product’s data on the choice of the noninferiority margin.
2.5.3 clinical safety
Clinical safety is important throughout the clinical development program and is captured during the
initial PK and PD evaluations and as part of the pivotal clinical efcacy study. Comparative safety
data should generally be collected pre- authorization, and the amount of data depending on the type
and severity of safety issues known for the reference product. The duration of safety follow- up preauthorization should be justied.
2.6 EXTRAPOLATION
The reference product may have more than one therapeutic indication. When the comparability of
the proposed biosimilar has been demonstrated in one indication, extrapolation of clinical data to
other indications of the reference product could be acceptable but needs to be scientically justied.
In case it is unclear whether the safety and efcacy conrmed in one indication would be relevant for
another indication, additional data will be required. It is expected that the safety and efcacy can be
extrapolated when the comparability of the proposed biosimilar has been demonstrated by thorough
physicochemical and structural analyses as well as by in vitro functional tests complemented with
clinical data (efcacy and safety and PK/ PD data) in one therapeutic indication. Additional data are
required in certain situations, some of which are listed below:
• The active substance of the reference product interacts with several receptors, which may lead
to a difference in the effects on the tested and nontested therapeutic indications.
• The active substance itself has more than one active site, and each site may produce a different
effect in different therapeutic indications.
• The studied therapeutic indication is not relevant for the other indications in terms of efcacy
or safety, that is, it is not sensitive for differences in all relevant aspects of efcacy and safety.
2.6.1 PhaRMacovigilance
While a pharmacovigilance program does not satisfy any residual uncertainty in biosimilarity,
in some cases, pharmacovigilance may provide additional condence to regulatory agencies; for
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Regulatory Requirements
example, if the formation of antidrug antibodies is dependent on the demographic aspects, then
only a large- sample study can provide reliable data, and such information can be collected through
a pharmacovigilance plan, among other routine and common attributes.
2.7 INTERCHANGEABILITY AND SUBSTITUTION
A generic drug is generally considered interchangeable with its reference (brand- name) product and
other generic products that use the same reference product. However, because a proposed biosimilar
is not structurally identical to its brand- name biologic, assessing interchangeability is a separate
process. In the US, the FDA regulates the drug product, but the states regulate pharmacies and pharmacy practices. According to the National Conference of State Legislatures (NCSL), as of October
22, 2018, “at least 49 states have considered legislation establishing state standards for substitution
of a proposed biosimilar prescription product to replace an original biologic product.” The NCSL
indicates that 45 states and Puerto Rico have enacted legislation; the provisions of state legislation vary.
The US FDA has issued its nal guidelines on demonstrating the interchangeability of a proposed
biosimilar with its reference product to assist sponsors in showing that a proposed therapeutic protein product is interchangeable with the reference product. There were two citizen petitions by the
author (Niazi), wherein suggestions were mostly considered in the nal guidelines.
It is important to reiterate that the FDA guidelines are not binding, and for the same reason, they
do not preclude a sponsor from making an alternate proposal to the FDA, even though most sponsors
would hesitate to do so.
The FDA is yet to approve the rst interchangeable product. As the FDA gains more condence
in the evaluation of interchangeability, after approving a few products, the guidelines will change
substantially.
Data from pre- authorization clinical studies are usually insufcient to identify rare adverse
effects. Therefore, the clinical safety of the biosimilars must be monitored closely on an ongoing
basis during the post- approval phase, including continued benet- risk assessment.
Within the authorization procedure, the applicant should present a description of the
pharmacovigilance system and a risk management plan following the current EU legislation and
pharmacovigilance guidelines. The risk management plan should consider identied and potential risks associated with the use of the reference product and should detail how these issues will
be addressed in the post- marketing follow- up. Immunogenicity should specically be addressed
in this context. Any specic safety monitoring imposed on the reference product or product
class should be adequately addressed in the biosimilar pharmacovigilance plan. Applicants are
encouraged to participate in already existing pharmaco- epidemiological studies in place for the
reference product. However, new studies might be needed. Risk minimization activities in place
for the reference product should, in principle, also be included in the risk management program
of the biosimilar.
For suspected adverse reactions relating to biopharmaceutical products, the denite identication
of the concerned product about its manufacturing is of particular importance. Therefore, all appropriate measures should be taken to identify any biopharmaceutical product, which is the subject of a
suspected adverse reaction report, based on its brand name and batch number.
2.7.1 Miscellaneous
2.7.1.1 Naming
Biosimilars should have a brand name and share the same International Nonproprietary Name as
that of the reference product and any additional designations required in the local jurisdiction.
Biosimilars should also have a different brand name.
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Regulatory Requirements
2.7.1.2 Label
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The label must, without exception, include all risks related to the reference product and the same
indications as well as be formatted and specied following this guideline. All indications issued to
the reference product are permissible once a biosimilar candidate is highly comparable to it, so long
as they are not covered by market exclusivity or patents. The developer is not permitted to ask for
fewer or more indicators.
2.7.1.3 Substitution
The reference product and other biosimilars authorized using the same reference product can be
replaced or interchanged with biosimilars as most recently conrmed by the EMA.
2.7.1.4 Pediatrics
For biosimilars, no pediatric compliance studies are necessary.
2.7.1.5 Human Factors Studies
These investigations are necessary to ensure that the appropriate dose is administered when a patient
receives a product. However, these studies are not required if the device utilized for the biosimilar
is very similar to that of the reference product. Furthermore, no such studies are necessary when a
healthcare expert uses the product.
2.7.2 RisK ManageMent
A biosimilar product uses the same risk management strategy as that used for the reference product.
Additionally, accurate biosimilar traceability must be ensured using the brand name and batch
number. Post- market surveillance data submission is not required. Safety pharmacology, reproduction toxicology, and carcinogenicity are not required for biosimilars. Local tolerance studies are
usually not required unless new excipients are introduced, for which no or little experience exists
with the intended clinical route of administration.
2.8 DOCUMENTATION
The development and documentation for the proposed biosimilar should cover two distinct aspects:
• Molecular characteristics and quality attributes of the target product prole should be comparable to those of the reference product.
• Performance and consistency of the manufacturing process of a proposed biosimilar on
its own.
The QTPP of a proposed biosimilar should be based on data collected on the reference product,
including publicly available information and data obtained from the reference product’s extensive
characterization. The QTPP should form the basis for the development of a proposed biosimilar
product and its manufacturing process. This QTPP should be considered a development tool for
which some target ranges may evolve during development as further information on the reference
product becomes available.
A proposed biosimilar is manufactured and controlled according to its development, considering
state- of- the- art- art information on manufacturing processes and consequences on product
characteristics. As for any biopharmaceutical product, a proposed biosimilar product is dened
by the molecular composition of the active substance obtained from its manufacturing process,
which may introduce its molecular variants, isoforms, or other product- related substances as
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Regulatory Requirements
well as process- related impurities. Consequently, the manufacturing process should be appropriately designed to achieve QTPP. The expression system should be carefully selected, considering
differences in the expression system that may result in undesired consequences, such as atypical
glycosylation pattern, higher variability, or a different impurity prole, than those with the reference
product.
The formulation of a proposed biosimilar does not need to be identical to that of the reference
product. Regardless of the formulation selected, the suitability of a proposed formulation regarding
stability, compatibility (i.e., interaction with excipients, diluents, and packaging materials), integrity, activity, and strength of the active substance should be demonstrated. In case a formulation
and container/ closure system different from those of the reference product is selected (including
any material in contact with the product), then its potential effect on the efcacy and safety of the
proposed biosimilar should be appropriately justied.
The stability of a proposed biosimilar product should be determined according to ICH Q5C. Any
claims about stability and compatibility must be supported by data and cannot be extrapolated from
the reference product.
It is acknowledged that a proposed biosimilar will have its lifecycle. When changes to the manufacturing process (active substance and nished product) are introduced during product development, a comparability assessment (as described in ICH Q5E) should be performed. For clarity, any
comparability exercise(s) for process changes introduced during development should be identied
in the dossier and addressed separately from the comparability exercise performed to demonstrate
biosimilarity versus the reference product. Process- related changes may occur during the development of a proposed biosimilar product. However, it is strongly recommended to generate the required
quality, safety, and efcacy data to demonstrate biosimilarity with the reference product using the
product manufactured through the commercial manufacturing process and therefore represent the
quality prole of the batches to be commercialized.
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for the Biosimilar
3.1 CHOICE OF THE PRODUCT
Most of the proposed biosimilar developers face a dilemma when choosing to develop the product
because of cost and time constraints for taking the product through regulatory approval. Traditional
business development teams follow hard rules of the market; competitors, including both preapproval and post- approval phase competitors; and cost of goods in order to decide which product
to manufacture. While these considerations have survived the test of time, there are many reasons
why these rules do not always apply to select a proposed biosimilar product for development.
3.1.1 coMPetition
First, unlike chemical generics, competitors’ eld will always be much smaller, not so much for a
nancial reason but for the need for deep science that is not available to many. Hence, regardless of
the nature of the product, the competition will always be limited. Given that almost every proposed
biosimilar product can become a blockbuster biologic, a different type of projection is required to
qualify a product regardless of the competitors.
3.1.2 cost of goods
Cost of goods can be controlled: most products will cost the same within a small range of variation
if the development cycle is followed to reduce your future cost of goods. The cost of goods is often
considered a selection criterion, but this is a poor indicator because the production cost of biological
drugs is relatively uniform, such as 150– 300 USD per gram of the proposed biosimilar developed
from monoclonal antibodies (mAbs); cytokines have not shown much variation in their category.
Most of the production cost is attributed to the cost of cell culture media, as production involves
producing a carbon- based entity, since, the carbon- in and carbon- out exchange occurs in carbon
cycle. More details about the cost of goods are provided in the section on the manufacturing process.
3.1.3 ManufactuRing Plan and facility
It is important to create a manufacturing plan involving the utilization of a similar cell line as that
used for the reference product, although this requirement is unnecessary. The developers should
know that using novel cell lines will inevitably increase the burden of proof required to establish
the safety and efcacy of a proposed biosimilar product. The developers should also realize that the
cell lines used for the reference product are often decades old when the productivity was not high;
DOI: 10.1201/9781003392026-3
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Development of a Master Plan
however, manufacturers do not change cell lines to avoid safety and efcacy concerns. The use of a
similar cell line, despite the availability of cell lines that provide much higher productivity, can be
challenging. Two key elements should be considered when choosing a cell line: First, cell lines with
lower productivity generally yield more consistent products because of reduced pressure; second,
the actual cost savings achieved when using a high productivity cell line may not reduce the overall
cost signicantly. Most of the production cost is attributed to the cost of the cell culture media used
proportionally to the protein output; a higher productivity cell line reduces the capacity of the bioreactor. The developers are advised to carry out a detailed analysis before using newer cell lines with
a very high yield.
Developers must assure the regulators that there are no cross- contamination possibilities between
the facilities used for bacterial processing and mammalian cell processing to avoid the risk of viral
contamination. The upstream and downstream manufacturing areas should be class 100,000 (Class
8) and 10,000 (Class 7) facilities, respectively. Maintaining a single- pass system of personnel and
material is recommended. Additionally, innovating clean area engineering designs based on the
single- pass system with only minimal air replaced to meet the OSHA requirements can help reduce
the CAPEX of heating, ventilation, and air conditioning systems by 50%– 70% and the OPEX by a
similar margin.
Most of the large pharmaceutical companies will have xed- pipe stainless steel systems in place
and are less likely to adopt the single- pass systems; for newly emerging pharmaceutical companies,
the single- pass system should be the only choice, as it eliminates the need for cleaning validation, a
process that adds more than just cost— the risk of contamination causing alterations in the molecular
structure of the biosimilar is a serious consideration.
3.1.4 exPRession systeM
Generally, some quality attributes are strictly related to the expression of proteins and the selection
of cell lines. When a new biological product is developed, the product of the selected cell line is
characterized and evaluated through all three phases of product development. For a biosimilar, the
cell line must produce a similar product as that of the reference product, and this process can be
challenging if the product has many post- translational modications, a higher molecular weight,
and a highly complex structure. When designing mAbs, a single cell (monoclonal) is used to create
a uniform cell line, which may not necessarily be the best choice. The developers should rst conduct analytical testing of the reference product to establish the quality attributes required before
selecting a cell line to avoid extensive testing at a later stage to justify any analytical differences in
the expression of proteins from the selected cell line. It is also important to understand that a hightiter cell line reduces only the capacity of the bioreactor; for low- yield products such as cytokines,
the titer differences do not affect the size or cost as much as it is touted by the suppliers of new
cell lines.
3.1.5 batch size
As a proposed biosimilar product may likely be approved without extensive comparative clinical
safety and efcacy studies, the rst clinical study, that is, pharmacokinetics (PK)/ pharmacodynamics
(PD) studies, must use a commercial- scale lot. If single- use upstream processing is chosen, then the
size of the bioreactors available have limitations. The developers may choose a smaller- sized bioreactor for manufacturing clinical lots, and then, after approval of the product, they may use ICH
Q5E to scale up the process. The developers may also combine several smaller- scale upstream lots
to remove the scale- up issues and decrease the burden of ICH Q5E compliance. Generally, the
downstream process is less likely to cause signicant changes to the product than the upstream process, where post- translational modications to the protein commonly occur.
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When conducting similarity testing of the analytical prole, it is recommended to include at least
one commercial- scale lot even at this stage, as the lot may not have undergone PPQ qualication.
3.1.6 Residual unceRtainty
After completing all the testing, the developer should prepare a detailed report to justify to the
agency that the proposed biosimilar product possesses the required biosimilarity to allow licensing
(in the US) or authorization (in other countries). This is the most critical stage where a developer can
save 24– 36 months and scores of millions of dollars from securing approval. Most of the proposed
biosimilar developers are too eager to carry out safety and efcacy studies to support their marketing
efforts based on their archaic understanding of selling biopharmaceuticals through prescribers. If the
developer can demonstrate that there is no residual uncertainty through a strong argument, then it is
highly likely that any additional clinical testing will not be required, and even if it requires, this may
be limited to additional clinical pharmacology studies.
The developers should present an argument afrming that the totality- of- the- evidence provided
is sufcient to determine that the proposed biosimilar product is highly similar to the reference
product. The arguments should include a description of any differences in the analytical assessment,
nonclinical assessment, and clinical pharmacology assessments in this specic order, realizing that
any residual uncertainty must be removed (either proving it nonconsequential or demonstrating
that it does not affect the clinical safety and efcacy of the biosimilar). One argument favoring the
developer is that additional testing may not necessarily remove any marginal residual uncertainty.
3.1.7 clinical safety and efficacy
The developers should realize that if a PK/ PD study has failed and any residual uncertainty related
to the failure is not resolved, then the agencies will not approve conducting a clinical safety and
efcacy assessment to provide additional proof of biosimilarity, regardless of the size of the clinical
efcacy study proposed by the developers.
However, where an efcacy study is conducted, the study design must provide justication of the
indicators chosen to test the product where multiple indications are allowed through extrapolation.
The study size should rst present the effect size analysis (M1) based on public domain data. An
equivalence interval (M2) was decided based on clinical judgment, and a rational argument was used
to justify the M2 value. The choice of the study model, that is, equivalence margin vs. noninferiority,
should also be explained. A critical element of these studies is the population demographic, and
making it a practical choice is often difcult, particularly for anticancer drugs. While treatmentnaïve patients’ option is always desirable, it is often not possible to achieve these criteria. Some
complications emerging from safety and efcacy studies make the study results less reliable than
the outcomes of PK/ PD/ immunogenicity testing. When safety and efcacy studies are conducted,
the developers are encouraged to use clinical markers rather than hard efcacy results where possible, realizing that the study’s purpose is not to demonstrate that the proposed biosimilar product
is effective, rather that the biosimilar is equally effective to the reference product. Clinical markers
that are relatively easier to evaluate provide greater robustness to the study than the hard efcacy
results. Finally, the purpose of a safety and efcacy study is to remove any residual uncertainty and
not provide proof of biosimilarity based on the study results alone.
3.2 HISTORICAL DATA ON REGULATORY COMPLIANCE
The developers’ common practice is to examine the public domain data, particularly the BLA
documents available (www.acc essd ata.fda.gov/ scri pts/ cder/ daf/ ). However, a critical analysis of the
developers’ studies showed that the data vary widely in number and detail.
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A detailed analysis of the regulatory submissions that led to the approval of these products
showed high diversity, frequent redundancy, and reliance on studies that may not assure the safety
and efcacy of the biosimilars. The paradigm of stepwise development and evaluation suggested by
the Food and Drug Administration (FDA) has not worked well. We have sufcient data available to
indicate that a signicant change in the biosimilar approval guidance is required to remove redundant testing and reduce the risk of approval of unsafe biosimilars.
Until the end of 2020, more than 1100 studies on analytical similarity, 96 studies on animal
pharmacology, 42 in vitro/ ex vitro studies on pharmacology, 52 studies on clinical pharmacology,
and 32 studies on clinical efcacy studies were submitted. The highlights of these submissions are
as follows (Table 3.1):
TABLE 3.1
Testing Approaches Submitted for Licensing of Biosimilars Approved by the Food and Drug
Administration
Animal
Licensed Product Analytical
Adalimumab- atto 41 2 0 1 2 46
Adalimumab- adaz 52 5 1 4 1 63
Adalimumab- adbm 70 6 (2) 26 (10) 2 1 105
Adalimumab- afzb 25 1 0 3 2 31
Adalimumab- bwwd 38 2 0 2 2 44
Bevacizumab- awwb 56 7 (2) 0 1 1 65
Bevacizumab- bvzr 42 2 4 1 1 50
Epoetin alfa- epbx 32 15 (13) 0 4 0 79
Etanercept- szzs 53 5 0 4 1 88
Etanercept- ykro 52 3 0 1 1 57
Filgrastim- aa 38 1 0 3 0 42
Filgrastim- sndz 41 5 0 5 1 52
Iniximab- abda 52 3 0 1 1 57
Iniximab- axxq 61 1 2 1 1 66
Iniximab- dyyb 33 4 (2) 2 4 5 48
Iniximab- qbtx 51 2 0 2 1 80
Peglgrastim- bmez NA 13 (8) 0 2 2 17
Peglgrastim- cbqv 31 1 2 2 0 36
Peglgrastim- jmdb 31 2 0 2 1 36
Rituximab- abbs 50 1 1 1 1 171
Rituximab- pvvr 40 2 0 1 2 98
Trastuzumab- anns 27 5 2 1 1 111
Trastuzumab- dkst 37 2 2 1 1 84
Trastuzumab- dttb 48 2 0 1 1 99
Trastuzumab- pkrb 44 2 0 1 1 48
Trastuzumab- qyyp 44 2 0 1 1 48
Pharmacology
In Vitro/ Ex Vitro
Pharmacology
Humira
Avastin
Epogen
Enbrel
Neupogen
Remicade
Neulasta
Rituxan
Herceptin
Clinical
Pharmacology
Clinical
Efficacy Total
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• Twenty- seven animal pharmacology studies were not reviewed by the FDA, labeling them as
redundant or unnecessary.
• No animal pharmacology or in vitro/ ex vitro study demonstrated failed results.
• A few clinical pharmacology studies had to be repeated to meet the acceptance criteria because
of the wrong choice of the study population. However, none demonstrated failed results.
• No clinical efcacy studies have failed, even if the primary endpoints did not meet by
conducting post hoc analysis to add scientic justication for their approval. In two cases,
higher immunogenicity was overcome by making minor changes to the manufacturing process. No product was rejected based on a failed efcacy study.
• No correlation existed between submissions for the same molecule; a total of 48– 111 studies
on trastuzumab were conducted by different developers.
In summary, all analytical similarity testing met the acceptance criteria, and animal pharmacology
studies contributed only little to available evidence; all clinical pharmacology studies reached the
acceptance criteria, and even though differences prevailed among clinical efcacy studies, these were
overcome through discussion and consensus decision- making, allowing marketing authorization.
Given these observations, the developers of a proposed biosimilar have an opportunity to present
testing protocols to the FDA that may not be as extensive as used in the approval of all current
products.
Table 3.1 lists the testing approaches used by the developers for licensing of biosimilars approved
by the FDA. First, the developers should meet with the FDA at a Biosimilars Advisory Meeting
that requires having expressed the biological entity at a small scale with initial analytical similarity
testing. This meeting should be followed by type 2 meetings to secure an agreement with the FDA
on the minimal testing studies required.
3.3 PLANNING FOR MANUFACTURING
Establishing a manufacturing plan for biosimilars is essential to enable accessibility to biological
drugs; unlike chemical generic drugs, there is no option of operating a ll and nish operation, as the
drug substance constitutes the main product. This practice, carried out in several developing countries, should be discouraged to ensure safety of the product.
The denitions of terms are provided below:
3.3.1 Qualified PRoduct
A qualied product is a product that has a reference SRA product currently distributed in the country
of origin; the proposed biosimilars should have the same mechanism of action, dose, frequency,
route of administration, and concentration (strength).
3.3.2 RaPPoRteuR
Using rapporteurs is a standard practice in the European Union (EU); the FDA also accepts thirdparty audits. Rapporteurs are members of the Committee for Medicinal Products for Human Use
or the Committee for Medicinal Products for Veterinary Use, assigned to assess applications for
marketing authorization. They play a critical role in evaluating and monitoring medicines in the
EU. The competent national authorities of the EU Member States appoint the rapporteurs. The
European Medicines Agency (EMA) generally identies the rapporteurs and co- rapporteurs for specic medicines in its assessment reports as well as maintaining the identities of the rapporteurs and
co- rapporteurs condential in certain situations. For example, a list of 61 rapporteurs for biosimilars
is available at the EMA.
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