the approval process
The Science

The approval process

Before biosimilars can be marketed (or sold), they have to be registered with or approved by the relevant Regulatory Authority of the specific country or region. In South Africa, the SA Health Products Regulatory Authority is responsible for registration (or approval) of all medicines, including biosimilar medicines.

Sufficient controls and standards

The USA Regulator, the Food & Drug Administration (FDA), specifically states that the biosimilar approval pathway was established as a means to provide more treatment options, increase access to life-changing medicines, and potentially lower healthcare costs through price competition.2 In Europe, the very term ‘biosimilar medicine” had its origins in European Union legislation that governs this approval process. All over the world, including South Africa, this rigorous approval process has regulations and guidelines in place to ensure the quality (methods of control and manufacturing), safety (risk/benefit assessment), and efficacy (desired effect) of biosimilar products.1,2

It should be borne in mind that there is a natural variability in the manufacturing of all biologics, (including originator/reference products) and that stringent quality control measures are therefore required to help ensure a high similarity between even different batches of the same biologic.2,3 To guarantee quality, there must be sufficient controls and standards that are consistently applied during all manufacturing, preparation, and processing of the biosimilar.

To this end, the following fundamental quality aspects are critical:

Potency of the product
Purity of the product

Both of the above must fall within the limits set by the original product (also called the reference product) during the approval process.1

Comparison of data requirements for approval of a biosimilar versus the reference medicine

Comparison of data requirements for approval of a biosimilar versus the reference medicine

A biosimilar medicine will not be registered (or approved for use) unless it has been shown that it has the same quality, safety, and efficacy profiles as those of the originator/reference product.1,2 This is true for all countries where the use of medicines is regulated, as in South Africa. To this end, biosimilar medicines are thoroughly evaluated for their comparability with the reference product. It is also important to bear in mind that the same Regulatory Authority which approved the originator/reference product, is responsible for the evaluation and approval of the biosimilar. Hence the same rigour and approval standards apply to both biologics and biosimilars.1,2


An important part of the approval process is to check the potential of the biosimilar product to elicit an unwanted immune response that may have a negative effect on safety and efficacy. Although conventional medicines also have the ability to do so, biopharmaceuticals, since they are proteins or polypeptides, demonstrate a greater capacity to cause an immune reaction. This capability of a specific substance to induce an unwanted immune response that is triggered by more than one factor is termed the substance’s immunogenicity.

Although such immune responses may have no clinical consequences in some patients, in others it may lead to allergic reactions or even anaphylaxis (a severe, potentially life-threatening allergic reaction). In other instances, the body may produce neutralising antibodies rendering the biopharmaceutical ineffective or the biopharmaceutical may give rise to an enhancement of immune activity.1,2,3

Factors that influence immunogenicity

the approval process

Immunogenicity is not only influenced by factors related to the biopharmaceutical (such as the manufacturing process and formulation), but also by patient-related factors. These include the individual susceptibility of the patient, the disease and its treatment method, the immune status of the patient (e.g., compromised immune systems of cancer patients) and the route of administration.

Since immunogenicity is difficult to predict from pre-clinical studies (work done in the laboratory or sometimes in animals), it is usually necessary to perform clinical studies to evaluate the immunogenetic potential of biopharmaceuticals. The results of such studies will form an important part of the approval process. In some instances, the Regulatory Authority may request that further immunogenicity studies are performed following approval.1,2

Post-approval surveillance

Once a Regulatory Authority has approved a biosimilar, the medicine will be permanently monitored to ensure continued safety.1,2 In South Africa, SAHPRA will collect data from suppliers of the medicine through pharmacovigilance activities, which will include routine measures, but which may also include a Risk Mitigation Plan, depending on the biosimilar in question. Such pharmacovigilance monitoring allows the Regulator to keep track of adverse reactions to the biosimilar.

Scientist analyzing experiment apparatus

Another way of keeping track of how patients respond to biological medicines, inclusive of biosimilars, is to enter patient details into a formal patient registry. Such registries are in essence a database of information about patients, their treatments, and their responses to treatment. When it comes to biopharmaceuticals, their aim is to evaluate and improve outcomes for patients suffering from the same condition (e.g., rheumatoid arthritis) or receiving the same or similar treatments (e.g., a biosimilar such as infliximab). Because these registries contain patient data, they have to be registered with SAHPRA and an established Ethics Committee (such as Pharmaethics) need to provide ethical approval. The latter is to ensure that the information is obtained in an ethically sound way and that it complies with current legislation. Patient participation is voluntary and no information can be entered into a registry without a patient’s formal consent. When the information from the registry is analysed, it is not possible to identify or link information back to a specific patient. 10,11

One such registry is the SARAA Biologics Registry. SARAA is the SA Rheumatism and Arthritis Association, and they established a national database to capture information on patients with rheumatic disease receiving a biologic disease modifying anti-rheumatic drug in 2008. This registry is specific for SA patients and allows the Association to, amongst others, monitor a biosimilar’s safety and efficacy in the South African setting. Capturing and analysing information on patients with rheumatic disease and their response to treatment ultimately enables SARAA to assist with improving the management of these patients.10

In a similar fashion, the South African Gastroenterology Society (SAGES) have established a registry for patients suffering from inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis.11 Through sharing outcomes and adverse events from a large number of patients, these registries are invaluable when it comes to providing an overall view of the success of biopharmaceuticals in the treatment of many challenging and life-threatening diseases.