Regulatory Requirements

Regulators have established unique approval pathways for biosimilars, which require them to exhibit a highly analogous structure and comparable clinical efficacy, safety and immunogenicity to their 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 which 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.

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.

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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). 

Where have biosimilars been approved?   +

As of August 2016, biosimilars have been approved in highly regulated markets for relatively few biologics (see table below), but the range is expected to expand in the near future. The earliest biosimilars were versions of biologics with fairly simple molecular structures, such as somatropin (growth hormone), erythropoietin and filgrastim, but since then, monoclonal antibodies have been increasingly targeted and are seen by many to be the key growth area.

The EU is in the lead, with the greatest number of approvals and commercialization of biosimilars. The table below lists biosimilars approved in highly regulated markets (as of August 2016); it does not include all markets that have adopted biosimilar guidelines, but lists those that are generally recognized to be frontrunners in terms of biosimilar legislation and licensing.

Biologic Australia Canada* European Union Japan South Korea United States 

Epoetin alpha

 3  1    
Epoetin lambda
Epoetin zeta

 1    2  
Filgrastim (G-CSF)
3 1  9  3    1
Follitropin alpha (FSH)
 2  3  1  1  1
Insulin glargine
 1  1  1  2     1 
 2  1  2  1  1  1
11   5

* In Canada, biosimilars are known as subsequent entry biologics (SEBs)
 Approved via 505(b)(2) pathway before the dedicated biosimilars 351(k) pathway was established. In 2010 the FDA also approved a low molecular weight heparin (LMWH) via 505(b)(2) but considers this a generic rather than a biosimilar (a view the EMA does not share).
ǂ Two later withdrawn within EU for commercial reasons (one filgrastim, one somatropin)

In both China and India, formal biosimilar regulatory frameworks have now been introduced.  However, it is important to note that numerous biologic copy products – often referred to as biosimilars in the media and the literature – were brought to market before this time. Because these products have generally not been developed according to rigorous international standards, they should be regarded as ‘copy biologics’ rather than biosimilars. 

Learn more about Biosimilars by Region >>

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.


Video Spotlights
Industry perspective: How can biosimilars influence innovation and regulation?
Industry perspective: How can biosimilars influence innovation and regulation?
Quintiles perspective: How does the regulation of biosimilars differ from that of small-molecule generics?
Quintiles perspective: How does the regulation of biosimilars differ from that of small-molecule generics?
Investigator perspective: Extrapolation: Gaining approval for additional indications
Investigator perspective: Extrapolation: Gaining approval for additional indications