Regulators expect that during the postauthorization pharmacovigilance stage, unpredicted adverse results from differences
in manufacturing process could be detected. Incorrect extrapolations from nonclinical or clinical data during comparability
assessments could also be revealed.
The EU's pharmacovigilance legislation, approved in 2010, simplifies reporting of adverse drug reactions and the submission
of periodic safety update reports (PSURs), data from both of which will be held centrally.
Postauthorization safety and efficacy studies can be requested from drug-licence holders by the authorities. Applicants for
marketing approvals of medicines will have to submit postauthorization risk-management plans.
For biosimilars, particularly mAbs, pharmacovigilance requirements will be tougher than for conventional medicines. "The pharmacovigilance
system is an essential part of monitoring biosimilars after approval," says Morrison. "[The legislation] provides for additional
monitoring for biological products, including biosimilars."
The mAb guideline states that applicants for marketing authorization of their mAbs or other biosimilars will have to provide
a "comprehensive concept" of how further postauthorization safety studies will be carried out. The safety plan will cover
safety claims based on extrapolations of efficacy and safety data during the comparability exercise and occurrences of rare
and particularly serious adverse effects.In addition, because adverse reactions to biosimilars could be due to defects in
manufacturing processes, the products should be clearly identifiable by name and batch number, according to the mAb guideline.
A GLOBAL ENTERPRISE
Because of the high expenditure necessary on manufacturing facilities, development, and pharmacovigilance activities, biosimilar
producers are looking for ways of curbing costs. Merck Serono and Dr. Reddy's are among pharmaceutical companies that have
formed an alliance in the production and development of biosimilars, mainly mAbs, to spread the risk. DSM of the Netherlands
and Crucell, a Dutch subsidiary of Johnson & Johnson, have reduced the scope of Percivia, their US-based joint venture in
biosimilars by ending in-house product development.
"In order to reduce the overall development costs, we need in the EU and in the US a scientific framework which allows global
development," says Kox. The European Commission has appeared to be acknowledging the need for global development of biosimilars
when it recently announced it would accept applications for approvals of biosimilars containing data from reference products
that come from outside the EU.
"[With this announcement] a new regulatory paradigm is born, which is a great achievement after years of discussion," says
Kox. "The issue of the reference product is not the only one to achieve global development. But for companies to be able to
use data from tests from reference products that are not sourced from the EU constitutes a major and far-reaching regulatory
The European Commission has yet to finalize details on how a comparability exercise with a reference product outside the EU
would work. But the decision does seem to show that the EU is intent on continuing to take a lead on biosimilar regulatory
matters without waiting for US guidance on the development of biosimilars to be formally adopted. FDA issued three draft guidance
documents earlier this year to assist companies in developing biosimilars for the US market (5–7). Under the Patient Protection
and Affordable Care Act of 2010, biosimilars are due to be allowed to be marketed in the country by 2014.
Sean Milmo is a freelance writer based in Essex, UK, firstname.lastname@example.org
1. EMA, Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies—Non-Clinical and Clinical Issues (London, June, 2012).
2. EMA, Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality
Issues, revision 1 (London, May 2012).
3. EMA, "Multidisciplinary: Biosimilar,"
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c, accessed Oct. 13, 2012.
4. EMA, Guideline on Immunogenicity Assess-ment of Monoclonal Antibodies Intended for In Vivo Clinical Use (London, June, 2012).
5. FDA, Guidance for Industry: Q & As Regarding Implementation of the BPCI Act of 2009 (Rockville, MD, Feb. 2012).
6. FDA, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (Rockville, MD, Feb. 2012).
7. FDA, Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product (Rockville, MD, Feb. 2012).