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Biosimilars: Impact of Biologic Product Life Cycle and European Experience on the Regulatory Trajectory in the United States

Clinical Therapeutics, Volume 34, Issue 2, February 2012, Pages 400 - 419



Biosimilars are defined as biologic products that are highly similar to reference products, notwithstanding minor differences in clinically inactive components, with no clinically meaningful differences between the biologic product and the reference product in terms of safety profile, purity, and potency. Due to the high cost of innovator biologics, as well as an increase in the number of these products reaching patent expiry, the development of a process for approving biosimilar products has become a crucial regulatory issue in the United States.


This commentary explores the relationship between structural/biophysical variation and the risk/benefit profile of biosimilars and reference biologics that have undergone process changes in the context of the most recent biophysical, nonclinical, and clinical data available.


The search strategy used PubMed, EMBASE, and MEDLINE for the retrieval of documents pertaining to biologic manufacturing, comparative analysis of biosimilars and originator biologics, and relevant review articles on biosimilars. For regulatory documents pertaining to the processes of the approval of biosimilars, biologics, and generics, a search for legislative decisions, briefing summaries, concept papers, guidance, and evaluations of approved and rejected applications for biosimilars published by the World Health Organization, US Food and Drug Administration, European Medicines Agency (EMA), and other national regulatory authorities was conducted. Selected articles from key opinion leaders and manufacturers were also reviewed. These searches were conducted to provide a review of historical and contemporary issues in the consideration of the current status of worldwide biosimilar use and regulation.


A total of 18 marketing applications covering 9 development programs were surveyed. Of these, 14 applications were approved and 4 were rejected by the EMA. None of the biosimilars were reported to have evidence of significant clinical variation relative to reference compounds in the absence of corresponding differences in biophysical properties. A single biosimilar (Omnitrope® [somatropin]) was reported to have evidence of significant variation in both biophysical and clinical parameters in premarketing studies. Biophysical variation in the absence of relevant differences in the efficacy and safety profiles compared with the reference brands was noted for 2 biosimilar epoetin products.


This commentary provides evidence that current EU guidelines have resulted in the approval of biosimilar therapeutics with comparable efficacy and safety profiles for the recommended indications of their respective reference originator biologics. It is anticipated that these precedents will serve as a starting point in the development of a process for approving biosimilars in the United States and worldwide to provide efficacious and tolerable biotherapeutics with a significant cost advantage for national health care programs and consumers.

Key words: biologics manufacturing, biosimilar regulations, biosimilars.


1 Hospira Inc., Lake Forest, Illinois

2 MMS Holdings Inc., Canton, Michigan

Address correspondence to: Uma Sharma, PhD, MMS Holdings Inc., 6880 Commerce Boulevard, Canton, MI 48187

a Adalimumab (Abbott Laboratories Inc., Abbott Park, Illinois).

b Bevacizumab (Genentech USA, Inc., South San Francisco, California).

c Rituximab (Genentech).

d Trastuzumab (Genentech).

e Infliximab (Janssen Biotech, Inc., Horsham, Pennsylvania).

f Denosumab (Amgen Inc., Thousand Oaks, California).

g Ranibizumab (Genentech).

h Etanercept (Immunex Corporation, Thousand Oaks, California).

i Trademark of Janssen-Ortho, Inc., Toronto, Ontario, Canada.

j Trademark of Amgen.

k Trademark of Janssen-Cilag SA de CV, Mexico City, Mexico.

l Trademark of Eli Lilly and Co., Indianapolis, Indiana.

m Trademark of Pfizer Inc., New York, New York.

n Trademark of Sandoz, Holzkirchen, Germany.

o Trademark of Biopartners GmbH, Baar, Switzerland.

p Trademark of Amgen.

q Trademark of Hospira, Inc., Lake Forest, Illinois.

r Trademark of Sandoz, Kundl, Austria.

s Trademark of Teva GmbH, Radebeul, Germany.

t Trademark of CT Arzneimittel GmbH, Berlin, Germany.

u Trademark of ratiopharm, Ulm, Germany.

v Trademark of Sandoz.

w Trademark of Hexal Forschungs Biotech GmbH, Oberhaching, Germany.

x Trademark of Medice Arzneimittel Pütter GmbH & Co. KG, Iserlohn, Germany.

y Trademark of Hospira.

z Trademark of Stada Arzneimittel, Bad Vilbel, Germany.

aa Trademark of BioPartners GmbH.

bb Trademark of Hoffmann-La Roche Inc., Nutley, New Jersey.

cc Marvel LifeScience Ltd., Middlesex, United Kingdom.

dd Trademark of Eli Lilly and Co.