What are Biologics?

Biologic medicines are substances that are made from a living organism or its products. Biologics are produced using living cells grown in culture. Some examples include vaccines and therapeutic proteins that help your body to fight illnesses such as cancer and arthritis. Often, to make biologics, DNA is transplanted into a living cell, which will use its own cell machinery to turn this DNA into a therapeutic protein that will ultimately become a biologic medicine.

Biologic medicines have improved the health of millions of patients worldwide. As the patents for these medicines begin to expire, many companies have begun to develop copies of these medicines, known as biosimilars, similar biotherapeutic proteins, or subsequent entry biologics.

What are Biosimilars?

Unlike generic medicines, which are simple and can easily be copied identically, biologics are large, complex molecules that are made in living cells, and only similar, but not identical copies are possible. The safety and efficacy of the biologic is completely dependent on the type of cells that are used to make the biologic, as well as the manufacturing process. Clinical trials are often required to evaluate how the biologic medicine behaves in the body.

The approach established to evaluate generic medicines is not an appropriate standard for biologics, and agencies responsible for drug approvals around the world, have begun to develop guidelines and standards to evaluate biosimilar medicines.

In general, to be approved as a biosimilar, it is necessary to demonstrate through a series of analytical tests, non-clinical and clinical studies that there are no differences in quality, safety or efficacy as compared to the original, licensed biologic.

WHO guidelines and why they have been used for this analysis

The World Health Organization (WHO) has a mandate to assure global quality, safety, and efficacy of biologic medicines. In 2007, with many biosimilars under development or already licensed in some countries, the WHO convened a group of biologics experts from around the world to discuss the scientific basis for the evaluation and regulation of these important molecules. The group agreed to develop guidelines that could be used by regulators around the world to evaluate these products. The guidelines were drafted and revised with input from global experts, and the final version was published in 2009.

These guidelines are globally accepted as scientifically rigorous and medically appropriate, and serve as a basis for the development of national standards for the production, quality control, and overall regulation of these medicines.

The guidelines address various aspects that should be considered when assessing the safety and efficacy of biosimilar medicines, including what tests and studies should be performed, and how the biosimilar should be compared to the original biologic medicine:

• Scientific considerations
• Key principles
• Quality considerations
• Non-clinical considerations
• Clinical considerations
• Pharmacovigilance
• Product information and labeling

For more information on these guidelines, please go to: WHO guidelines.

Analytical methodology

CBPE evaluated biosimilar guidelines from the 12 countries and regions around the world that had established biosimilar policies at the time of the analysis: US, Canada, EU, South Korea, Taiwan, Japan, South Africa, Argentina, Cuba, Mexico, Brazil, and Columbia. Additional countries, eg Australia, are in the process of being evaluated.

Each country or region was evaluated on 28 aspects of biosimilars policy as outlined by WHO, and rated on a scale of 1-5 (in 0.5 level increments) as follows:

1-2 minimally compliant with WHO regulations
3-4 partially compliant with WHO regulations
4 fully compliant with WHO regulations
5 exceeds the standards set by WHO

The scores across these 28 categories were averaged to give an overall score out of 5. See how your country’s policies line up.

The 28 aspects outlined by WHO are summarized below:

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• Scope – what would be considered under these guidelines
• Concept of biosimilarity – describes what a biosimilar is
• Reference product – outlines what the biosimilar should be compared to: an approved biologic medicine
• Formulation – the mixture that the active biosimilar medicine is produced in, and how this should compare to the original biologic medicine
• Route of Administration – how the biosimilar will be administered to the patient, eg intravenous injection, and how this should line up with how the original biologic medicine is administered to the patient
• Dosage form/strength – the dose that the biosimilar is manufactured in, and how this should compare to the original biologic medicine
• Quality Considerations – this section of the biosimilar guidance reviews the laboratory tests that should be done to show that there are no differences between the biosimilar and the original biologic medicine
• General considerations – in general, describes what the analytical tests used to compare an original biologic medicine and the biosimilar should evaluate
• Isolation of drug substance – outlines how the active ingredient of the original biologic medicine should be isolated for analysis
• Physicochemical analysis – how the structure of the original biologic medicine and the biosimilar should be compared
• Biologic and immunologic analysis – the biologic test will make sure the original biologic medicine and the biosimilar behave in the same way. A further immunologic analysis is done for biologics that have an immune effect, eg antibodies, to ensure the biologic and the biosimilar behave in the same way
• Impurities – outlines how to evaluate any impurities that arise from the biosimilar manufacturing process, and how they compare to impurities arising from the manufacture of the original biologic
• Stability studies- how to compare the relative stability of the original biologic medicine and the biosimilar
• Specifications – Specifications are the parameters that are set and used to ensure a consistently high quality is met in the manufacturing process. In the context of biosimilar policies, this section describes how to set these for producing a biosimilar.
• Non-clinical Considerations – this section of the biosimilar guidance reviews the non-clinical tests that should be done to show that there are no differences between the biosimilar and the original biologic medicine
• General considerations – in general, describes how non-clinical studies used to compare an original biologic medicine and the biosimilar should be done
• Pharmacology, in vitro and in vivo – describes the lab studies (in vitro) and the animal studies (in vivo) that should be done to make sure the biosimilar medicine is behaving as expected. This includes pharmacokinetics, which is a term that describes what the body does with a medicine once it has been introduced.
• Toxicology– describes the studies that should be done to made sure the biosimilar medicine does not have any toxic effects in the body
• Clinical Considerations- this section of the biosimilar guidance reviews the clinical tests (those performed in patients) that should be done to show that there are no differences between the biosimilar and the original biologic medicine
• General considerations – in general, describes what clinical studies should be done to compare an original biologic medicine and a biosimilar
• Pharmacokinetics (PK)/Pharmacodynamics (PD) – describes what clinical studies should be done to evaluate how the biosimilar behaves in the body
• Efficacy – describes what clinical studies should be done to evaluate whether a biosimilar medicine works as well as the original biologic medicine
• Safety – describes what clinical studies should be done to evaluate whether a biosimilar medicine is as safe as the original biologic medicine
• Immunogenicity – describes what clinical studies should be done to ensure the biosimilar medicine is not stimulating an immune response from the body
• Extrapolation of indication – outlines what is needed to be able to demonstrate that a biosimilar tested for one disease will also work in another disease, without additional studies being needed
• Pharmacovigilance– outlines the processes that should be put in place once a biosimilar medicine has been approved by the regulatory agencies and is being used in patients. This includes the implementation of Risk Management Plans, and other methods to track long term safety and efficacy after approval.
• Interchangeability – describes considerations for switching the biosimilar and the original biologic medicine in clinical practice

Product Information and Labeling

Naming – outlines considerations for how biosimilars should be named relative to the original biologic medicine
Labeling – outlines what should be included in the product label for a biosimilar, relative to the original biologic medicine
Manufacturing and Analytical Technology – outlines general considerations for the manufacturing process for biosimilars.