Biosimilars – Modest Challenges And Possible Resolutions: A Pharmacovigilance Perspective

As the generics are the copies of small molecule chemically originated pharmaceutical products, the biosimilars are the copies of biologics.

Biological medicines (Biologics) are the large sized, complex structured medicines produced via a complicated manufacturing process in a living organism, which are administered via a specialized delivery device. Biologics are used to treat a range of chronic and serious diseases, including cancer and rare genetic disorders; they also provide therapeutic benefits for limited alternative treatment options.

As the generics are the copies of small molecule chemically originated pharmaceutical products, the Biosimilars are the copies of biologics. Biosimilars are very similar to licensed biologics, despite modest changes in clinically inactive ingredients. Patients in the India, European Union (EU) and United States of America (USA) have been using Biosimilars since 2000, 2006 and 2015 respectively1.

Biosimilars as a Cost-Effective Alternative to Biologics

Biologics are relatively new and exceptionally expensive for the vast majority of patients who require them but are out of reach because of their high cost. Many biologics are still protected by patents, which is one of the main reasons for their high cost. End-of-patent exclusivity, as well as breakthroughs in biotechnology that make manufacturing them easier, have created tremendous prospects for Biosimilars, to enter the market and fulfill the demands of patients across the globe in a cost-effective way.

Although the pricing difference between innovative products and Biosimilars is not as great as it is with generics, the price of a biosimilar is generally between 10% and 35% less than the reference product.

Biosimilars and follow-on biologics development is an indisputable fact. However, biosimilar regulatory rules and standards are still changing.

Probable challenges

Even though a biosimilar and the innovator drug show similar efficacy, the biosimilar may generate a different safety profile. The patients using biosimilar may have co-morbid conditions and other confounding factors which makes causal association of Adverse Event (AE) with biosimilar product much more difficult to associate. This would be immensely challenging if Biosimilars were named like the chemical generics i.e., with their international non- proprietary names (INNs) alone. This requires a highly professional staff to collect accurate and detailed information from reporters, which helps to identify the safety of product.

Manufacturing process of biologics is much more complex compared to generics and involves multiple steps subject to variations which can affect the biological, clinical properties of the biosimilar which could result in change in affinity, specificity, binding strength (affinity), pharmacological response (efficacy) and immunogenicity of biosimilar compared to reference biologics.

Despite the equivalence of a Biosimilar to reference drug, its safety and effectiveness depends on its administration. It mandates need of an efficient and safe device for delivery,

supported by a seamless transportation and storage system (temperature controlled). The active drug is in constant contact with administration device, which is equally important for quality of drugs. Since the Biosimilars are proteins molecules, they require a temperature regulated transport and storage system. Deviations from the standards in their transportation and storage may result in unexpected outcome post administration.

Due to the small size of the studies required for approval of Biosimilars, any differences in the safety profile or novel adverse effects not seen with the reference product can only be discovered after the biosimilar has been on the market through the tedious collecting and examination of post-marketing data.

A pharmaceutical product's labeling is crucial to its safe and successful use. When a patient has an AE to a drug, the label information is reviewed to determine whether a specific AE/safety concern has already been identified as a risk or is a new possible safety issue. Hence, Warnings on labels of Biosimilars must assert that the information only applies to a specific product and that “changing to another biological medical product must be approved by the prescribing practitioner, who must record the product name prescribed for PV reasons."

Pharmacovigilance (PV) Considerations for Biosimilars

Major regulators like EMA, United States Food and Drug Administration (USFDA) and India i.e., Pharmacovigilance Programme of India (PvPI) has published guidance related to PV of Biologics and Biosimilars.

Ø For reporting of Individual Case Study Report (ICSR), brand name and batch number were made mandatory by EU while it is not mandatory for USA and India.

Ø Lack of efficacy of Biosimilars should be thoroughly assessed for immunogenicity.

Ø Different regulators have their own requirement of aggregate reports to be submitted within stipulated timeline in different format, which include the cumulative data collected for the reporting period.

Ø Data from clinical studies are usually not enough to identify all potential gaps between the biosimilar and its innovator product. So, clinical safety of similar biological medicinal products must be monitored closely on an ongoing basis during the post-approval period, including continued risk-benefit assessment. EU and India require that the biosimilar applicant must submit a Risk Management Plan (RMP) and PV program with its application while USA requires Risk Evaluation and mitigation Strategies (REMS).

Ø The biggest issues with biosimilar are the risks associated with these products over time because of the structural variations in the molecule, as these are derived from microorganism.

It is highly anticipated that the risk–benefit ratio proven at the time of authorization may change over time by expanded use, patient characteristics, and exposure. So, pharmacovigilance should be continued for Biosimilars as long as the product is in the market.


PV and risk management for Biosimilars presents several unique and significant challenges. The adoption of routine PV processes may address these issues. Moreover, the end-of-patent exclusivity in near future and technological advancements will open the new horizons for other manufacturers to sell which eventually would lead to strengthen the PV system including its quality management system for biologics.

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