In the last ten years bio similar program have progressed significantly both in EU and US. Several products were approved by these Agencies as shown in Table 1. Several submissions are pending to be approved. In the meantime FDA issued two important long waited guidance [1-3]: one on labeling and the other one in inter changeability of drug product. Several organizations from both countries commented on the labelling and inter changeability [3-5]. According to these comments it is important to provide complete, accurate, transparent prescribing and dispensing information of bio similar and interchangeable biological products [5-9]. If the information is limited about the bio similar product in the labeling for that particular product it is difficult for healthcare providers to prescribe safely and effectively. Several considerations are required to maintain good supply chain reliability and patient support programs. In case of the post-approval requirements, both EMA agree that the post approved biosimilar is not linked to the reference product. Furthermore, any changes to the product have to be evaluated in accordance with the post-approval guidance. The FDA, on the other hand, is working on post-approval guidance for biosimilar products.
The above issues are also reflected in a few approved biosimilars. In order to bring more confidence in these biosimilar products new approaches are required to perform post approval research on the safety and effectiveness of biosimilars compared with their branded products.
Biosimilar drugs, which are supposed to be the economical version of branded biotherapeutics, started in getting market approval both in EU and US [1,2]. As the use of biotherapeutics continues to expand within pharmaceutical marketplace, the development of biosimilars represents great potential or vast expansion within the industry. Unfortunately, biosimilar manufacturing is often different from the brand name drug
due to variances in preparation starting from raw materials to finalized products [3,4]. As a result, such variations may trigger unwanted adverse events. In this regard US Food and Drug Administration (FDA) issued several draft guidance’s. Related to quality consideration, reference product, labeling, and inter changeability in the last three years, shown in Table 1. But still there are a number of issues with biosimilars, which are discussed in this paper.
EU guideline states that, the biosimilar’s summary of
product characterization (SmPC) has to be derived from the
reference product [5-7]. According to EMA the information from
the reference product’s SmPC that applies to biosimilar should
be included in the SmPC of the biosimilar. SmPC also refers to
detailed information being available in EMA website whereas
comprehensive and transparent information of biosimilar is
presented in European Public Assessment Reports (EPAR). The
critics of this program claim that it does not highlight sufficiently
the inherent difference between biosimilars and their reference
products. Since they are biological, as discussed earlier [3,4] they
cannot be identical with their originals. Instead, a biosimilar has
to demonstrate similarity to the reference product in terms of
quality characteristics, biological activity, safety, and efficacy
based on the comprehensive comparability exercise [8,9].
Implementation of the Biologics Price Competition and
Innovation Act (“BPCIA”) and subsequently FDA’s issuance of the
long-awaited draft guidance on labeling of biological products
licensed under section 351(k) of the Public Health Service Act
(42 USC 262(k)) is a significant event .
FDA issued guidance , which includes the data and
information related to the reference product instead of the
information about the biosimilar. According to FDA the data
from clinical studies, which support biosimilarity, are not likely
to be relevant to a health care practitioner’s consideration
regarding safe and effective use of the biosimilar product.
Several organizations including BIO comment that it is important
to provide complete, accurate, transparent prescribing and
dispensing information of biosimilar and interchangeable
biological products .
If the information is limited about the biosimilar product
in the labeling for that particular product it is difficult for
healthcare providers to prescribe safely and effectively for an
individual patient, as well as for formulary and other decision
makers who mainly depend on the label to determine the use of
the biosimilar. If multiple biosimilars are approved for the same
reference product and each has been approved based upon its
own unique bio similarity data, the patients and the prescribers
should have access to all important information, including the
nonclinical and clinical data which will allow to understand how
the data were collected.
FDA proposes that the biosimilar product conform to
the requirements of the Physician Labeling Rule (PLR) and
Pregnancy and Lactation Labeling Final Rule (PLLR), regardless
of whether the reference product is required to meet the PLR
and PLLR requirements at the time of licensure of the biosimilar
product10Several organization including BIO are concerned that
requiring the biosimilar product labeling to conform to content
and format requirements which do not apply to its reference
product may result in confusion to prescribers and patients [9-
Moreover, updates to the PLR or PLLR format and content
may require input of the reference product sponsor. Therefore,
the guidance should provide that the biosimilar label be
approved consistent with the same PLLR format and content
labeling requirements as applicable currently to the reference
product and be updated when the reference product label is
modified to conform to the new implementation requirements
The US has a somewhat different approach for establishing
inter changeability compared to Europe. FDA has jurisdiction
to classify biosimilars as ‘interchangeable’, and this designation
then enables substitution at the pharmacy level without the
consent of the prescribing physician - provided that state
legislature permits such substitution and that the prescribing
physician has not indicated in the prescription form that the
prescribed product must not be substituted .
FDA, in its draft guidance , recommended “switching”
studies, which rotate patients between the biosimilar and the
reference product multiple times and monitor the patient’s
response for any differences with the use of two drugs. FDA
has taken in consideration the issues that can be raised from
the container-closure, storage condition and the method of
application for the drug. The purpose of this consideration is to
provide confidence to the patients and their doctors with regard
to safety and efficacy of the interchangeable biosimilar.
Some may disagree with the FDA’s preference for using U.S.
products in the studies required to show that the patient can
switch from the original biologic to the biosimilar safely and with
no loss of efficacy . Further they think that the draft guidance
should discuss the labeling and naming of interchangeable
biosimilars. The US biosimilar pathway does not define the
amount of data required for interchangeable biosimilar product
which ‘can be expected to produce the same clinical result as the
reference product in any given patient’ and ‘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’ [10,11].
In case of the post-approval requirements, EMA agree that
the post approved biosimilar is not linked to the reference
product6. Furthermore, any changes to the product have to
be evaluated in accordance with the post-approval guidance.
If needed, the sponsor may use a “quality-by-design (QbD)”
approach to the development of biosimilar products to meet
compliance and reduce any post-approval changes16. The
FDA, on the other hand, is working on post-approval guidance for biosimilar products. It’s also important for the FDA to
provide specific recommendations about how interchangeable
biosimilars should be named and what kind of information
should be included on their labels.
As mentioned earlier, EMA permits biosimilars to use same
active ingredient (API) name as their brand name counterpart.
On the contrary, US naming is not final, but in the interim they
are adding a suffix like Sandoz “sndz” for Filgratism biosimilar.
This may help both patients and prescribers to distinguish
biosimilars. But this may add some confusion later when the
different versions of the same API will be in the market. “For
reimbursement of provider-administered biologics, payers
customarily require a Healthcare Common Procedure Coding
System “J code”. The Centers for Medicare and Medicaid Services
is currently considering requiring unique J codes for biosimilars
under Medicare Part B. It should be strongly encouraged to do
so; private payers would follow suit, and the requirement would
facilitate rigorous, product-specific surveillance of biologics
through the FDA›s Sentinel system” .
The issues as discussed above are reflected in the number
of approved biosimilars. In order to bring more confidence in
these biosimilar products new approaches are required to
perform post approval research on the safety and effectiveness
of biosimilars compared with their branded products.