1. India’s New Similar Biologic Guidelines: An Overview
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2. he Indian Ministry of Health and Family Welfare and Science and
T
Technology had earlier in the month of June released their guidelines on
biosimilars (similar bilologis in the Indian context) to be implemented
from August 15 2012. These guidelines bring an end to the era of ad-hoc
abbreviated approval pathway under which the Indian authorities had
been approving Indian produced generic biologics with reference products
which were approved in the United States and Europe. There have also been
instances, where biotechnology products were approved without conducting
clinical trials on enough number of patients. The guidelines are applicable for
similar biologics developed in India or imported into the country
The 52-page document, titled, ‘Guidelines on Similar Biologics: Regulatory
Requirements for Marketing Authorization in India’ covers both biosimilars
developed in India as well as those imported into the country. The proposed
norms outline specific requirements for pre-marketing and post-marketing data
apart from guidelines for pre-clinical and clinical trials for biosimilars. The
Indian Guidance lays out the same kind of stepwise approach, starting with
detailed structural characterization of the proposed biosimilar and its reference
product, followed by preclinical then clinical characterizations, and makes
allowances for product-specific differences in analytical techniques and clinical
endpoints.
Salient Features
Definition of Similar Biologics and its Development
As per the guidelines, similar In case the reference biologic is not
biologic includes: a biological authorized in India it should have
product or drug produced by been licensed and marketed for at
genetic engineering techniques and least 4 years with significant safety
claimed to be "similar" in terms of and efficacy data. Under present
quality, safety, efficacy to a circumstances, these guidelines
reference innovator product, which seem to be clearly aimed at
has been granted a marketing encouraging more investment in
authorization in India by a biosimilars in India, both by
competent authority on the basis of domestic and foreign companies.
a complete dossier, and with a However, in case of no medicine or
history of safe use in India. The only palliative therapy is available
definition of similar biologics shows or in national healthcare
that under the regulatory regime a emergency, this period of 4 years
product can be considered as may be reduced or waived off.
similar biologic only if it is proven Since for the foreseeable future,
to be similar, using extensive new biologics will be predominantly
quality characterization against the pioneered in the U.S. and Europe,
reference biologic. there will be a number of recently-
developed products that fall into
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3. this category, and will await either
the approval of the reference drug
in India, or the passage of four
years after approval elsewhere.
Clinical Trials
The guideline suggests that under certain circumstances biosimilars can be
approved without involved clinical trials: The confirmatory clinical safety and
efficacy study can be waived if all the below mentioned conditions are met:
i. Structural and functional comparability of similar biologic and
reference biologic can be characterized to a high degree of confidence by
physicochemical and in vitro techniques
ii. The similar biologic is comparable to reference biologic in all
preclinical evaluations conducted
iii. PK / PD study has demonstrated comparability and has
preferentially been done in an in patient setting with safety
referentially in‐patient
measurement (including immunogenicity) for adequate period
justified by the applicant and efficacy measurements
iv. A comprehensive post marketing risk management plan has been
post‐marketing
presented that will gather additional safety data with a specific
emphasis on gathering immunogenicity data
The confirmatory clinical safety and efficacy study cannot be waived if
there is no reliable and validated PD marker.
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4. COMPARATIVE ANALYSIS
1. Definition of Biosimilar (Similar Biologics)
INDIA UNITED STATES EUROPE
35 U.S.C § 262 (i) Biosimilarity is not explicitly
“A biological product/ Highly similar to a defined, but is situational:
drug produced by genetic reference product licensed “Whether a medicinal
engineering techniques under 262(a) product would be acceptable
and claimed to be notwithstanding minor using the ‘similar biological
“similar” in terms of differences in clinically medicinal product’ approach
safety, efficacy and quality inactive components. depends on the state of the
to a reference biologic, 35 U.S.C § 262 (k)– art of analytical procedures,
which has been granted a Demonstrated the manufacturing processes
marketing authorization biosimilarity to reference employed, as well as clinical
in India by DCGI on the based upon: Analytical and regulatory
basis of a complete studies to show highly experiences.” CHMP/437/04.
dossier, and with a similar, Animal studies, “Comparability studies are
history of safe use in and Clinical study(ies) needed to generate evidence
India.” Indian Guidelines substantiating the similar
at 22. nature, in terms of quality,
safety and efficacy, of the
new similar biological
medicinal product and the
chosen reference medicinal
product authorised in the
Community.” CHMP/437/04
2. Developing a Biosimilar
INDIA UNITED STATES EUROPE
Similar biologics are A stepwise approach to “A stepwise approach
developed through demonstrating should be undertaken to
sequential process to biosimilarity, which can justify any differences in
demonstrate the similarity include a comparison of the quality attributes of the
by extensive the proposed product and similar biological medicinal
characterization studies the reference product with product versus the
revealing the molecular respect to structure, reference medicinal
and quality attributes with function, animal toxicity, product in order to make a
regard to the reference human pharmacokinetics satisfactory justification of
biologic. Indian Guidelines (PK) and the potential implications
at 5. pharmacodynamics (PD), with regard to the safety
clinical immunogenicity, and efficacy of the
and clinical safety and product.”
effectiveness Guidance CHMP/BWP/49348/2005
“Scientific Considerations” at 5.
at 2.
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5. 3. Reference Products
INDIA UNITED STATES EUROPE
Licensed in India or in “To obtain licensure … a No provision for non-EMA
“Similar biologic can only sponsor must demonstrate licensed reference
be developed against an that the proposed product products.
authorized reference is biosimilar to a single
biologic that has been reference product that
approved using a complete previously has been
data package in India. In licensed by FDA. . . .
case the reference biologic However, under certain
is not authorized in India, circumstances, a sponsor
it should have been may seek to use data
licensed and marketed for derived from animal or
at least 4 years with clinical studies comparing
significant safety and a proposed product with a
efficacy data.” Indian non-U.S.-licensed
Guidelines at 3. product….. In such a case,
the sponsor should provide
“The products, where the adequate data or
reference biologic is not information to scientifically
authorized in India shall be justify the relevance of this
considered on a case by comparative data to an
case basis if such products assessment of biosimilarity
have been granted and to establish an
marketing approval in acceptable bridge to the
countries with well U.S.-licensed reference
established regulatory product.” Guidance for
systems such as US FDA, Industry Scientific
EMA etc. and have been in Considerations in
wider use for a minimum of Demonstrating
four years.” Id. at. 22 Biosimilarity to a Reference
Product at 6
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6. 4. Safety and Efficacy Trials
INDIA UNITED STATES EUROPE
Potential for “As a scientific matter, “Usually comparative
omission of safety comparative safety and clinical trials will be
and efficacy trials. effectiveness data will be necessary to demonstrate
See quote above necessary to support a clinical comparability
demonstration of biosimilarity if between the similar
there are residual uncertainties biological and the reference
about the biosimilarity of the two medicinal product.”
products based on structural EMEA/CHMP/BMWP/4283
and functional characterization, 2/2005 at 6.
animal testing, human PK and
PD data, and clinical
immunogenicity assessment. A
sponsor may provide a scientific
justification if it believes that
some or all of these comparisons
on clinical safety and
effectiveness are not necessary.”
FDA Draft Guidance for
Industry:
Scientific Considerations in
Demonstrating Biosimilarity to a
Reference Product at 12.
5. Exclusivity Period
INDIA UNITED STATES EUROPE
India provides for no A section (k) application “8+2+1.” A biosimilar
market exclusivity period may not be filed until 4 application may not be
beyond patent rights. years after reference filed until 8 years after the
product approval. A reference product approval.
biosimilar may not be A biosimilar may not be
approved until 12 years approved until 10 years
after reference product after reference approval.
approval. 42 USC 262 The market exclusivity may
(k)(7). be extended by an
additional year if the
reference product sponsor
obtains approval for a
second significant new
indication during the data
exclusivity period.
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