BIOSIMILARS

Biosimilars are biological products i.e. they are made out of living cells with the help of chemically complicated
procedures and is approved only after proving that is is highly similar to an FDA-approved “reference product”.

When the patent surrounding a biologic's formula is no longer protected and has expired, multiple companies are free
to release a drug with the same chemical recipe, reducing the cost. That new biologic drug is a biosimilar.

In 2010, Congress approved the Biologics Price Competition and Innovation Act (BPCIA), which was proved to be an
abbreviated approval pathway for biosimilars, while maintaining incentives for continued medical advances. This was
established to provide more treatment options, increase access to lifesaving medications, and potentially lower health
care costs through competition. In order to achieve the balance between increased competition among biologics from
biosimilar products with the need for incentives to support future medical innovations, Congress provided
biopharmaceutical innovators with 12 years of data protection for biologic medicines.

DIFFERENCE BETWEEN SMALL- MOLECULE DRUGS AND BIOSIMILARS

SMALL- MOLECULE DRUGS BIOSIMILARS

small and fairly simple in their structure bigger and heavier and complex in structure
synthesized from chemicals in a consistent process
chemically
so much more complicated
that manufacturers can be sure that each pill has the
same effect every time
More stable Often less stable, so they require special handling like
refrigeration.
Ex: Drugs like aspirin (acetaminophen) and commonEx: Neupogen to boost white blood cells for patients
allergy medications (Acrivastine) undergoing chemotherapy.

“HIGHLY SIMILAR”

The developer of a biosimilar has to prove the similarity to its reference product by the extensive characterization of
the structure and function. The comparison of the characteristics of the products is done by using State-of-the-art
technology. Purity, chemical identity, and bioactivity are some parameters that are compared. Only minor changes in
the clinically inactive components are permitted in the biologics. These minor changes include differences in the
stabilizer or buffer compared to what is used in the reference product, etc. Lot-to-lot differences (only acceptable ones)
are carefully evaluated by FDA.

INTERCHANGEABLE PRODUCT
A biosimilar product that meets additional requirements outlined by the BPCIA is an interchangeable product. To
fulfill these additional requirements, information is required to prove that an interchangeable product is expected to
produce the same clinical result as the reference product in any given patient. Also, if the products are administered to
a patient more than once, the risk in terms of safety and reduced efficacy between an interchangeable product and a
reference product will have been evaluated.

If a product has been approved as an interchangeable product, it means that FDA has concluded it may be substituted
for the reference product without consulting the prescriber. If taking a biosimilar instead of the reference product, the
patient may need a prescription from a health care prescriber written specifically for that biosimilar. However, once a
product is approved by FDA as interchangeable, the patient may be able to take a prescription for the reference
product to the pharmacy and, depending on the state; the pharmacist could substitute the interchangeable product for
the reference product without consulting the prescriber.

FDA-APPROVED BIOSIMILAR PRODUCTS TILL DATE

BIOSIMILAR NAME DATE OF APPROVAL

Nivestym (filgrastim-aafi) July 2018
Fulphila(pegfilgrastim-jmdb) June 2018
Retacrit(epoetin alfa-epbx) May 2018
Ixifi(infliximab-qbtx) December 2017
 Ogivri(trastuzumab-dkst) December 2017
Mvasi(Bevacizumab-awwb) September 2017
Cyltezo(Adalimumab-adbm) August 2017
Renflexis(Infliximab-abda) May 2017
Amjevita(Adalimumab -atto) September 2016
Erelzi(Etanercept-szzs) August 2016
Inflectra(Infliximab-dyyb) April 2016
Zarxio (Filgrastim-sndz) March 2015

BIOSIMILAR DEVELOPMENT, REVIEW, AND APPROVAL

To ensure the reliability of the patients on reference, biosimilar, and interchangeable products, they undergo a rigorous
evaluation by FDA. The developer of a proposed biosimilar product has to generate an array of data comparing the
proposed product to the FDA-approved reference product in order to demonstrate biosimilarity. Stepwise, the
comparative data are evaluated, comparative results are produced, moving on to animal studies if necessary and then
to comparative clinical studies.

a manufacturer then shows that its biosimilar product is highly similar to and has no clinically meaningful differences
from the FDA-approved reference. So, lengthy clinical trials are not expected to be performed, leading to faster access
to these products, additional therapeutic options, and reduced costs for patients.

DATA ARE REQUIRED FOR APPROVAL OF A BIOSIMILAR OR INTERCHANGEABLE PRODUCT

It includes data from:

Analytical studies demonstrating that the biological product is highly similar to the reference product.
Animal studies, including toxicity assessment; and
Clinical studies to demonstrate safety, purity, and potency of the proposed biosimilar product in one or more of the
indications for which the reference product is licensed. This typically includes assessing immunogenicity,
pharmacokinetics (PK), pharmacodynamics (PD) and may also include a comparative clinical study.

In addition to the data listed above, an application for an interchangeable product must also include information
demonstrating that:
The proposed interchangeable product is expected to produce the same clinical result as the reference product in any
given patient;
In the case of the product administered more than once to an individual, switching between the proposed
interchangeable product and the reference product does not increase safety risks or decrease effectiveness compared to
using the reference product without such switching between products.

ADVANTAGES AND DISADVANTAGES

One can easily obtain biosimilars at a relatively cheaper rate. Moreover, they will work as good as the reference
product. Intellectual property would last longer and their profits would be higher.

But, there is a downside to it. Biologics are often more expensive than small-molecule drugs, and because of the
difficulty in bringing biosimilars to market, they may also have higher profit margins because of which drug
companies have a strong incentive to create the perception [among doctors] that biologics are more effective than
small-molecules.

The nature of biological products, which includes the inherent variations that can result from the manufacturing
process, proves to be a potential challenge in characterizing and manufacturing these products. This is not the case
with the development of small molecule drugs.

GENERIC DRUGS
A generic drug is a pharmaceutical drug having the same chemical substance as the original drug. The generic drug
has the same active pharmaceutical ingredient (API) as the original, but it may differ in characteristics such as
manufacturing process, formulation, excipients, color, taste, and packaging and yields the same therapeutic effect. It is
the same in dosing, safety, strength, quality, the way it works, the way it is taken, the way it should be used, same risks
and the same benefits as the brand name drugs. Generic drugs need not contain the same inactive ingredients as the
brand name product. In the United States, 9 out of 10 prescriptions filled are for generic drugs.

A generic drug can be out for marketing only when the brand name drug's patent has expired, which may take up to 20
years after the patent holder’s drug is first filed with the U.S. Food and Drug Administration (FDA). When patents or
other periods of exclusivity expire, other manufacturers can submit an ABBREVIATED NEW DRUG
APPLICATION (ANDA) to the FDA for approval to market a generic version of the brand name drug. A patent
provides atleast 20 years of protection, although many countries and regions, such as the European Union and
the United States, may grant up to five years of additional protection ("patent term restoration") if manufacturers meet
specific goals, such as conducting clinical trials for pediatric patients.

The law that allows approval of generic products, the Drug Price Competition and Patent Term Restoration Act of 1984,
builds in certain protections for the original drug developer (including patents and marketing exclusivities), but also allows
drug sponsors of identical products to apply for FDA approval without repeating the original developer's clinical trials. The
law also encourages generic firms to challenge innovator patents by awarding marketing exclusivity to the first generic
version challenger.

Not all brand name drugs have a generic drug. Some drugs don’t have a generic because these products may seem
unprofitable or too difficult to manufacture to the manufacturers.

Generics are less costly because the drug manufacturer does not have to duplicate the original clinical trials for
effectiveness and safety, which lowers the cost to bring the drug to market. Generics are not less expensive because
they are lower in quality.

Usually, however the prices may remain high (although less than the brand name drug) for 6 months because the FDA
will give the first generic manufacturer a “180-day exclusivity period”. The “180-day exclusivity” is assigned to the
manufacturer who is the first to file an ANDA and has done the additional work to get the generic drug to market. If
more than one generic manufacturer files their ANDA at the FDA on the same day, these companies would share the
180-day exclusivity, which might lead to somewhat lower prices during the 180-day period due to competition, but
possibly not as low as when several generics enter the market.

BRANDED GENERICS

Generic drugs that have a brand name developed either by a generic drug company or the original manufacturer after
the patent expires for the original product. IMS Health defines a branded generic as:

 Prescription products that are either novel dosage forms of off-patent products produced by a manufacturer
that is not the originator of the molecule, or;
 A molecule copy of an off-patent product with a trade name.

Birth control pills are an example of a branded generic drug made by several manufacturers. For example, Aviane is
the branded generic name for a formulation of oral contraceptive that contains ethinyl estradiol and levonorgestrel.
Other branded generics are the same as Aviane, but with different proprietary names, and include products such
as Orsythia and Vienva.

Branded generics are not always as affordable as a true generic. By sporting a brand name, some consumers may
incorrectly assume that the branded generic is a higher quality product than a true generic, but that is not usually the
case. However, branded generics may be less expensive than the original brand.

Authorized generics

An "authorized generic” is an exact copy of the brand name version authorized by the original patent holder of the
drug product. It is identical to the branded product in appearance (shape, color, markings) and unlike a generic; the
authorized generic has exactly the same inactive ingredients. For example, atorvastatin calcium by Greenstone is an
authorized generic and exactly the same drug as the Lipitor brand cholesterol medication by Pfizer.
 First Generic Drug Approvals
Each year, FDA’s Center for Drug Evaluation and Research (CDER) approves a wide range of new drug products.
FDA provides the scientific and regulatory advice required to bring safe, effective, high-quality generic alternatives to
market, which in turn creates more affordable treatment options for patients. “First generics” are the first approval by
FDA which permits a manufacturer to market a generic drug product in the United States.
“Approved drugs are not always available on or after the listed approval date”
Few first generic drugs are:

ANDA number Generic name ANDA applicant Brand name ANDA approval ANDA indication
date

203153 TemsiroLimus Injection,Accord

25 7/30/2018
Torisel(Temsirolimus)Injection, For the treatment of advanced renal cell
mg/ml Single Dose Vial Healthcare Inc
25mg/ml carcinoma.

207568 Epinephrine Injection,Luitpold

1 Adrenalin (Epinephrine)
7/6/2018 To reduce the risk of COPD
mg/mL Pharmaceuticals,
Injection, 1 mg/mL exacerbations in patients with severe
Inc COPD associated with chronic bronchitis
and a history of exacerbations

206223 Fresenius Kabi 1/16/2018

Ultiva® Injection, 1 mg/vial, 2 For intravenous administration as: an
USA,
Remifentanl Hydrochloride LLC mg/vial, and 5 mg/vial analgesic agent for use during the
for Injection, 1 mg/vial, 2 induction and maintenance of general
mg/vial, and 5 mg/vial anesthesia for inpatient and outpatient
procedures; for continuation as an
analgesic into the immediate
postoperative period in adult patients
under the direct supervision of an
anesthesia practitioner in a postoperative
anesthesia care unit or intensive care
setting; as an analgesic component of
monitored anesthesia care in adult
patients

DIFFERENCE BETWEEN BIOSIMILARS AND GENERICS

BIOSIMILARS GENERICS
A Biosimilar is a medicinal product of biological origin, withChemically
a derived medicinal product, usually a simple, homogeneous
complex structure, and large proteins. small molecule, whose bioequivalence must be demonstrated.

Very complex molecules with many post-translational Simple molecules those are easy to characterize and have a small, well-
modifications. They can exceed 150,000D in size in the case defined structure (approximately 180D on average).
of monoclonal antibodies. They require a lot of analytical work
for their structural and functional characterization.
Biosimilars are very sensitive to storage and handling Very stable molecules, making them easy to store.
conditions

Could be immunogenic. Have virtually no immunogenic potential.

Biosimilars require an investment of around 3 billion dollars Require an investment of around 2-3 million dollars for their
development.
For biosimilars, phase IV studies need to be conducted in order to test their Once on the market, generic drugs require a
safety, and a risk management plan created. standard pharmacovigilance process