Regulatory Requirements

Unique approval pathways for biosimilars require them to exhibit highly comparable efficacy, safety, and immunogenicity with originators

Because biosimilars are not identical copies of their originators, regulators require extensive investigation to demonstrate that they are sufficiently similar. In addition to a thorough analytical assessment, head-to-head clinical studies versus the originator are needed to obtain approval. Placebo arms are not required in these studies as the aim is to establish comparability to a biologic that is already approved. In most markets, agencies have established or adopted unique regulatory pathways for biosimilar approval.


What testing is required by regulators?   +

Biosimilars represent an entirely new regulatory class. The focus of testing is not to establish patient benefit, as this has already been carried out for the originator. Instead, to gain regulatory approval, biosimilars must exhibit a highly analogous structure and comparable clinical efficacy, safety, and immunogenicity to their already proven originator. By building on the safety and efficacy experience of the originator, biosimilars are able to be licensed on the basis of a reduced and less costly data package.

Biosimilar development is underpinned by four key principles that are unique to this industry.

1. Developers use a “step-wise” approach
2. Candidate biosimilars are compared head-to-head with originators (with no placebo control) and trial endpoints focus on proving similarity

3. Regulators may approve extrapolation to all licensed originator indications, so only one Phase III trial may be needed
4. Regulators make decisions based on “totality of the evidence”

1. Developers are encouraged to use a step-wise approach to biosimilar development where the requirements for each step depend on the extent and quality of the data gained in previous steps.

2.In biosimilar trials, candidate products are compared head-to-head with the originator. There is no placebo arm. Biosimilar trial endpoints may differ from those used in conventional originator trials because they focus purely on proving similarity to the originator. So, for example, while overall survival is a desirable endpoint for a novel oncology biologic, a trial of an oncology biosimilar will use something more directly attributable to the effects of the drug, such as response rate.

3. When regulators approve a biosimilar, they typically allow extrapolation to all approved originator indications provided the Phase 3 trial is conducted in the most “sensitive” indication (i.e. the indication where differences between the biosimilar and originator are most likely to show up).

4. Regulators make decisions to approve biosimilars based on “totality of the evidence,” which means they consider the analytical, non–clinical, and clinical evidence as an overall data package.

Biosimilars undergo rigorous testing at all stages of development – analytical, non-clinical, and clinical – which is significantly more than is required for small-molecule generics but less than required for new biologics. The table below compares requirements across all three categories.

Testing Generics Biosimilars New biologics
R&D objective
  Demonstrate equivalence to approved chemical drug
Demonstrate similarity to approved originator biologic
Demonstrate patient benefit as shown by superiority to placebo
Timeframe and cost for development
  3–5 years1

8–10 years1
10+ years2
$1–5 million (USD)1 $100–200 million (USD)1 Over $2 billion (USD)2
Quality testing Development batches 1 batch >3 batches Multiple batches
Characterization Non-comparative Comparative Non-comparative
Release testing Yes Yes Yes
Non-clinical testing In vitro testing No Extensive structure/function comparisons on multiple batches Extensive characterization of molecule on multiple batches, for prediction of in vivo effects and to inform formulation, delivery mechanism, etc.
Non-clinical animal testing No Extensive comparative PK/PD in non-human primates or other animal models Extensive non-comparative PK/PD characterization in non-human primates or other animal models
Clinical testing Phase I trial PK Large-scale comparative PK/PD and safety Large-scale non-comparative PK/PD and safety
Phase II trial No
Phase III trial


(Typically small comparative trials to confirm therapeutic equivalence) 

Large-scale comparative trials 

If approved for one indication, regulators may allow data extrapolation to other licensed originator indications

Large-scale placebo-controlled trials. Each indication has to be studied to qualify for approval
Pharmacovigilance No



Learn more about Biosimilars by Region >>

Are all copies of biologics considered biosimilars?   +

In some less regulated markets (e.g. India, China, and Mexico), there are a number of non-originator biologics in clinical use that have not been subjected to the level of comparative testing and regulatory scrutiny needed to qualify as a biosimilar, according to the international standards set by the European Medicines Agency (EMA), US Food and Drug Administration (FDA), and the World Health Organization (WHO). Such products are currently loosely termed ‘copy biologics’ (sometimes ‘alternative biologics’), although they go by various local names too (e.g. ‘biolimbos’ in Mexico, ‘biogenerics’ in Iran). In many cases (but not all), copy biologics were approved before country-specific formal biosimilar legislation was introduced. In Mexico the regulatory authorities now require the manufacturers of licensed copy biologics to reapply for approval of their products as biosimilars with all the mandatory comparative data. Other national regulators may follow suit.

Learn more about Biosimilars by Region >>

What regulatory pathways have been established for the approval of biosimilars?   +

The European Medicines Agency (EMA) set the precedent in 2005 and others followed. 

Agency Year Milestone

European Medicines Agency


Adopted overarching guidance for biosimilar approvals
Issued updated guidelines (to learn more click here)

US Food and Drug Administration

<2010 (mainly)

Approved a few "follow-on proteins" via the Food, Drug & Cosmetic Act 505(b)(2) pathway
Received authority to regulate biosimilars via a new dedicated route: the Public Health Service (PHS) Act 351(k) pathway
Began issuing biosimilar guidance (to learn more click here)

World Health Organization


Adopted biosimilar guidance to encourage regulatory harmonization across markets

Learn more about Biosimilars by Region >>

How do biosimilars obtain extrapolation to other indications?   +

Once a biosimilar is clinically tested and approved for a particular indication, extrapolation to other approved indications needs additional consideration by regulators. The sponsor is required to provide scientific justification as to why extrapolation to other indications should be allowed. The type of data required includes mechanism of action, pharmacokinetics and bio-distribution of the product in different patient populations, as well as toxicity profiles for all relevant indications.

Which countries are adopting biosimilar guidelines?   +

The WHO and a number of ex-EU nations have followed the EMA’s lead by adopting similar principles in their guidelines. Many developing countries that have approved ‘copy biologics’ in the have now established (or are in the process of establishing) formal biosimilar guidelines. This global map gives a snapshot of the countries that have finalized their guidelines as of September 2015 (it is not intended to be fully comprehensive). 

What real-world evidence exists to support the use of biosimilars?   +

Numerous real world studies have confirmed the safety and efficacy of licensed biosimilars compared with originators and evidence continues to accumulate. Key examples include:

  • 2017: A study in patients with breast cancer receiving neoadjuvant myelosuppressive chemotherapy (n=218) showed that alternating back and forth between originator filgrastim (Neupogen®) and biosimilar filgrastim (Zarxio™) over six cycles of treatment was no less effective or well tolerated than receiving either Neupogen or Zarxio throughout all six cycles.3

  • 2017: One-year outcomes from the nationwide DANBIO registry in Denmark reported sustained efficacy and safety after 802 patients with inflammatory arthritis were switched within routine care from Remicade® to biosimilar infliximab (CT-P13, Remsima®) without a prescriber-led decision in each case.4

  • 2017: A meta-analysis of results from 11 published real-world studies including 829 patients showed that biosimilar infliximab has “excellent clinical efficacy and safety” in patients with Crohn’s disease or ulcerative colitis.5

  • 2016: Delegates at the annual European Crohn’s and Colitis Organisation (ECCO) Congress heard that ten real world studies, involving nearly 600 patients with inflammatory bowel disease, all showed highly similar efficacy and safety following a switch to biosimilar infliximab from the originator.6

  • 2016: At the Annual European Congress of Rheumatology (EULAR), data were presented on patients transitioned from originator etanercept (n=254) and infliximab (n=396) to their biosimilar counterparts. In both cases there were no treatment-emergent safety or immunogenicity issues, and efficacy was sustained for up to 2 years.7,8

  • 2016: The triple-switch EGALITY Study was a randomized, double-blind study involving 531 patients with chronic plaque psoriasis that compared biosimilar etanercept with the originator, Enbrel®. Patients underwent three switches back and forth between the originator and biosimilar with no loss of efficacy or increased safety issues.9

  • 2016: The NOR-SWITCH Study – a non-commercial switching study sponsored by the Norwegian government – was a Phase 3 randomized trial of 481 patients at 40 sites who were on stable treatment with originator infliximab (Remicade®) for at least 6 months. Participants were randomized to either continue Remicade® or switch to the biosimilar, and followed-up for 52 weeks. Switching to biosimilar infliximab was found to be safe and non-inferior to continued treatment with Remicade® across multiple indications, including inflammatory bowel disease, rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, and chronic plaque psoriasis.10

  • 2016: A major Johns Hopkins Bloomberg systematic review of 19 studies, published in the Annals of Internal Medicine, reported that tumor necrosis factor-α (TNF-α) inhibitor biosimilars for the treatment of rheumatoid arthritis and other autoimmune diseases, appear to be as effective and safe as their branded equivalents.11  

  • 2015: A real-world prospective study in over 1,400 patients with chemotherapy-induced febrile neutropenia confirmed the clinical similarity of biosimilar filgrastim to the originator Neupogen®.12

References   +

1. Federal Trade Commission, 11 June 2009. Follow-on biologic drug competition. Accessed 1 April 2016.

2. PhRMA, 2015. Biopharmaceutical research & development: The process behind new medicines. Accessed 1 April 2016.

3. Krendyukov A, Harbeck N, Gascon P et al. Safety and efficacy of alternating treatment with EP2006, a filgrastim biosimilar, and reference filgrastim for the prevention of severe neutropenia, in patients with breast cancer receiving myelosuppressive chemotherapy. Poster presented at the American Society of Clinical Oncology (ASCO) 2017. Abstract no. 10116. J Clin Oncol (2017) 35.

4. Glintborg B, Sørensen IJ, Loft AG et al. A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry. Ann Rheum Dis (2017) May 4; doi: 10.1136/annrheumdis-2016-210742 [Epub ahead of print].

5. Komaki Y, Yamada A, Komaki F et al. Systematic review with meta-analysis: the efficacy and safety of CT-P13, a biosimilar of anti-tumour necrosis factor-α agent (infliximab), in inflammatory bowel diseases. Aliment Pharmacol Ther(2017) 45:1043–1057.

6. BioPharmaDive, 18 March 2016. Data presented at ECCO congress in nearly 600 patients with inflammatory bowel disease (IBD) supports switching from Remicade® to biosimilar infliximab. Accessed 26 May 2017.

7. Emery P et al. Long-term safety and efficacy of SB4 (etanercept biosimilar) in patients with rheumatoid arthritis: comparison between continuing SB4 and switching from etanercept reference product to SB4. Poster presented at the Annual European Congress of Rheumatology (EULAR) 2016 by Samsung Bioepis. 9 June 2016.

8. Smolen JS et al. Comparable safety and immunogenicity and sustained efficacy after transition to SB2 (an infliximab biosimilar) vs ongoing infliximab reference product in patients with rheumatoid arthritis: results of phase III transition study. Poster presented at the Annual European Congress of Rheumatology (EULAR) 2016 by Samsung Bioepis. 9 June 2016.

9. Griffiths CEM, Thaçi D, Gerdes S et al. The EGALITY Study: A confirmatory, randomized, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, vs. the originator product in patients with moderate-to-severe chronic plaque-type psoriasis. Br J Dermatol (2017) 176:928–938.

10. Jørgensen KK, Olsen IC, Goll GL et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial.Lancet (2017) May 11; doi: 10.1016/S0140-6736(17)30068-5 [Epub ahead of print].

11. Chinqcuanco F, Segal JB, Kim SC, and Alexander GC. Bioequivalence of biosimilar tumor necrosis factor-α inhibitors compared with their reference biologics: A systematic review. Ann Intern Med (2016) 165:565–574.

12. Gascon P, Aapro M, Ludwig H et al. Treatment patterns and outcomes in the prophylaxis of chemotherapy-induced (febrile) neutropenia with biosimilar filgrastim (the MONITOR-GCSF study). Support Care Cancer (2016) 24:911–925.