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After India flooded the world market with
affordable medicine, it is now trying to its hand on
biosimilars. These are medicines purposely designed to have
the same action for the same disease as the original
pharmaceutical drugs but are produced differently.
The world market for biosimilars is expanding
very rapidly. According to Datamonitor, biosimilars is worth
$245 million in 2010 and will easily reach $3.7 billion in
2015. But at present, only EU and the US have established
regulatory guidelines for the approval to market these drugs.
In the US, there are two ways for FDA drug approval. First is
through the Public Health Service Act and the second is
through the Food, Drug and Cosmetics Act. In 2010, President
Obama sined into law the Biologics Price Competition and
Innovation Act of 2009 which is considered as the legal
pathways for biosimilar in the US. Unfortunately, a practical
pathway defined by the FDA is not yet in place. Many doubt
that the US regulatory and intellectual property barriers are
not favorable to biosimilar pathways. The Biologic License
Application will be used instead of the abbreviated BLA to get
around the 12-years exclusivity requirement in the BPCI Act
for biosimilars. BPCIA covers anything for which a BLA is
filed; a virus, therapeutic serum, toxin, antitoxin, blood or
blood component or derivative, allergenic product, or
analogous product… applicable to the prevention, treatment, or
sure of a disease or condition of human beings. Recently,
proteins have been included except for chemically synthesized
polypeptides.
According to the FDA’s reference products
exclusivities, a biosimilar application will only be accepted
4 years after the approval date of the reference product.
Approval of a biosimilar will happen only after 12 years from
the date of first approval for reference product.
There are two biologic types in the US; a
biosimilar product which is highly parallel to the reference
product with no significant clinical differences in terms of
safety, purity and potency; and an interchangeable biosimilar
which may be substituted for the reference product without the
intervention of the health care provider who prescribed the
reference product.
A biosimilar product must have gone through
analytical studies showing that the product is close to a
reference despite differences in clinically inactive
components, animal studies, clinical studies to demonstrate
safety, purity and potency. Labeling must match the reference
product’s approved indication, as well as route of
administration, dosage form, and strength. Manufacturing
facility must also be approved following criteria already
set.
The 12-year exclusivity does not apply to a
supplement for the biological product that is the reference
product or subsequent application filed by the same entity for
a change resulting in new indication, route of administration,
dosing schedule, dosing form, delivery system, delivery
article or strength or structural modification that does not
change safety, purity and potency. Although it is not clear
which FDA regulation applies to this, a structural
modification to change safety, purity and potency is needed.
There are regulatory guidelines established in
EU, with both general guidelines and product specific
guidelines in place. For example, there is an 8-year data
exclusivity for a reference product, a further 2-years
marketing protection and an additional 1-year marketing
protection for a new therapeutic indication during the first 8
years of exclusivity.
To date, 14 biosimilars have been approved by
the Committee for Medicinal Products for Human Use(CHMP),
taking into consideration the legislative guidelines under the
DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE
COUNCIL of 6 November 2001 on the Community code relating to
medicinal products for human use as amended by DIRECTIVE
2004/27/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL.
Under this guideline, an applicant is not required to provide
clinical and pre-clinical data if he can demonstrate that the
medicinal product is a generic of the reference product. CHMP
is further guided by the following guidelines on
biosimilars namely; guideline on similar biological medicinal
products, guideline on similar biological medicinal products
containing biotechnology-derived proteins as active
ingredients, guideline on similar biological medicinal
products containing biotechnology-derived derived proteins as
active substance (currently under revision to take into
account the lifecycle of biosimilars), and the guideline on
immunogenicity assessment of biotechnology-derived therapeutic
proteins.
The specific guideline for
biotechnology-derived proteins says that the product must
demonstrate comparable profiles in terms of
quality, safety and efficacy. Possible safety issues in
different subpopulations should be addressed, non-clinical
studies must have been conducted, immunogenicity must have
been investigated in humans using state-of –the-art methods to
characterize immune response, clinical safety and
pharmacovigilance.
EMEA/CHMP/42832/05/ also known as the Guideline
on similar biological medicinal products containing
biotechnology-derived proteins as active substance: clinical
and non-clinical issues lay down the non-clinical and clinical
requirements for a biological medicinal product claiming to be
similar to another one already marketed. The non-clinical
section addresses the pharmaco-toxicological assessment. The
clinical section addresses the requirements for
pharmacokinetic, pharmacodynamic, efficacy studies. The
section on clinical safety and pharmacovigilance addresses
clinical safety studies as well as the risk management plan
with special emphasis on studying the immunogenicity of the
similar biological medicinal product.
The
regulatory frameworks for biosimilars are largely established
in Europe, in fact, covering human insulin, somatropin, human
growth hormone, erythropoietin, interferon-alpha,
low-molecular weight heparin and monoclonal antibody.
Currently, they are working on guidelines to include a number
of other products like interferon-beta and follicle
stimulating hormone.
In India, concerns have been
expressed on the existing regulatory approval process for
biosimilars. Manufacturing processes must strictly adhere to
perfection as minor changes could greatly affect safety and
efficacy. Biosimilar products must only be approved after a
well established regulatory pathway in India. Due to the
susceptibility of biologics, it is not impossible for two
different manufacturers to come up with two identical
biopharmaceutical drugs. Present marketing approval in the
country follows bioequivalence model in the Schedule Y of the
Drugs and Cosmetics Act for small molecule chemical entities
only. Drugs and Cosmetics Act of India do not differentiate
between large and small molecular drugs. It is the Central
drugs Standard Control Organization and the Drugs Controller
General of India who are responsible for approvals of new drug
applications, however, each state regulatory authorities are
responsible for granting manufacturing licenses. These
practices may lead to regulatory oversight and weaker
enforcement of the guidelines.
It is high time that
India must come up with its own regulatory guidelines for
biosimilar drugs to be enforced by a specific agency. In
addition, regulatory control over mistakes and offences for
manufacture of unapproved drugs are equally as important as
the guidelines. The present Review Committee on Generic
Manipulation discusses current guidelines by the EMEA and FDA.
They take approvals of biosimilar drugs in case by case basis.
It is very urgent that India must have its own
guidelines for biosimilars, both for manufacturing and
marketing, which conforms to international safety and quality
standards. A lot of people around the world depend on India to
deliver safe and effective life-saving medicines. Painful,
debilitating, and deadly diseases such as rheumatoid
arthritis, chronic lymphocytic leukemia, vasculitis,
References:
- Biosimilars in Europe, by Dr. Kati Hudson
- Biosimilars in the United States, Presented at
the 10th Annual Forum on Pharma Patent Lifecycles (London),
Dr. Rouget F. Henschel, RHenschel@foley.com
- www.gabionline.net/Policies-Legislation/UK-s-NICE-issues-first-biosimilars-recommendation
- McGraw-Hill Science & Technology Dictionary
- European Medicines Agency; Pre-authorization
Evaluation of Medicines for Human Use
- http://www.emea.eu.int
- http://www.tapanray.in/profiles/blogs/patients-safety-regulatory
- http://en.wikipedia.org/wiki/biosimilar
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