Standard and Abbreviated Pathways for Drug Approval in the United States9-12
Small molecules
Biologics
Approved via Food, Drug, and Cosmetic Act (FDCA)
Approved via Public Health Service Act (PHSA)
Generics
Biosimilars
New drug application (NDA)
Abbreviated new drug application
(ANDA),“Hatch-Waxman”
Biologics license
application (BLA)
Biosimilar biologics license
application (BPCI Act)
Safety and efficacy
must be demonstrated
Bioequivalence must
be demonstrated
Safety and efficacy
must be demonstrated
Must demonstrate high
similarity to reference / No clinically
meaningful differences
ADDITIONAL SOURCES
In addition to already-gained experience with abbreviated
applications for protein products regulated as drugs, the
FDA is following guidance from several other key sources
in regulating biosimilar products. One source is the FDA’s
previous experience with manufacturing changes proposed
for currently marketed biologic products. Comprised of living
cells, variability is inherent in the manufacture of biological
products, both batch-to-batch and after a manufacturing
change.13 Since the mid-1990s, the FDA has required
physicochemical and functional assays to characterize the
effects of manufacturing changes in biologics. Any remaining
uncertainties about the comparability of pre- and postchange products are then addressed by conducting animal
or clinical studies to provide the FDA with sufficient
confidence that safety and efficacy are not diminished as
a result of the manufacturing process change.14
Through comparative testing, the FDA also may be able to
ascertain when additional clinical testing is unnecessary,
allowing the drug to be brought to market more quickly.15
Another source of FDA guidance in regulating biosimilars
comes from European regulation, which has been in place
since 2005. Available guidelines include those that define
principles (Guideline on Similar Biological Medicinal Products);
general comparability guidelines (immunogenicity assessment,
quality issues and nonclinical/clinical issues); and productspecific comparability guidelines. More than 7 years of
experience with biosimilars in Europe have not shown any
unusual or unexpected effects with their use compared with
their reference biologics.16,17
Leveraging this European experience with biosimilars, along
with its own extensive experience in regulating biological
products, has left the FDA well-positioned to oversee the
introduction and utilization of these much-anticipated
biosimilar products in the United States. Both the European
experience and expert FDA oversight should give providers a
high level of confidence to prescribe biosimilar products.
The approval of the first biosimilar is
a milestone for the agency [FDA] and
a significant positive development as
patients and their physicians will have
more treatment options. 18
— Alliance for Safe
Biologic Medicines
References: 1. U.S. Food and Drug Administration (FDA). Biosimilars. FDA [website]. April 28, 2015. Available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm. Accessed April 24, 2015. 2. European Medicines
Agency (EMA). Questions and answers on biosimilar medicines (similar biological medicinal products). EMA [website]. September 27, 2012. Available at http://www.ema.
europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdf. Accessed April 24, 2015. 3. WHO: Definitions of biosimilars. Generics and biosimilars
initiative (GaBi); 2012. GaBi [website]. Available at http://gabionline.net/Biosimilars/General/WHO-definitions-of-biosimilars. Accessed July 23, 2015. 4. U.S. Food and
Drug Administration (FDA). Drug approvals and databases. February 2, 2012. FDA [website]. Available at http://www.fda.gov/drugs/informationondrugs/ucm079436.
htm. Accessed April 24, 2015. 5. Institute for Healthcare Informatics. The global use of medicines: Outlook through 2017. November 2013. Parsippany, NJ: IMS Institute for
Healthcare Informatics. 6. US Government Accountability Office. Medicare: Information on the Highest-Expenditure Part B Drugs. GAO-13-739T. June 28, 2013. 7. Miller S.
The $250 billion potential of biosimilars. April 23, 2013. Express Scripts [website]. Available at http://lab.express-scripts.com/insights/industry-updates/the-$250-billionpotential-of-biosimilars. Accessed July 7, 2015. 8. Federal Trade Commission Report. Emerging health care issues: Follow-on biologic drug competition. Washington, DC:
Federal Trade Commission; June 2009. 9. U.S. Food and Drug Administration (FDA). New drug application (NDA). February 3, 2015. FDA [website]. Available at http://www.
fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/NewDrugApplicationNDA/. Accessed April 28, 2015. 10. U.S.
Food and Drug Administration (FDA). Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Amendments) [FDA testimony before the Senate
Committee on the Judiciary]. August 1, 2003. FDA [website]. Available at http://www.fda.gov/newsevents/testimony/ucm115033.htm. Accessed April 29, 2015. 11. U.S. Food
and Drug Administration (FDA). Frequently asked questions about therapeutic biological products. May 22, 2015. FDA [website]. Available at http://www.fda.gov/Drugs/
DevelopmentApprovalProcess/%20HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm113522.htm. Accessed April 30, 2015.
12. U.S. Food and Drug Administration (FDA). Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference
product. April 2015. 13. Shiestl M, Stangler T, Torella C, et al. Acceptable changes in quality attributes of glycosylated biopharmaceuticals
[letter]. Nature Biotechnol. 2011;29(4):310-312. 14. Kozlowski 2