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Why Pharmacovigilance Is Important for Biosimilars


So many factors have the potential to affect the quality and performance of biosimilars that clinicians must be aware of the need for constant pharmacovigilance.

Clinicians and investigators should be aware of how they can improve pharmacovigilance for biosimilars, according to a report by investigators in India who stress the complexity and temperature sensitivity of biosimilars.

“Biosimilars have a large size, complex structure, and complicated manufacturing process, and they are produced in a living organism,” which means they require specialized delivery devices and tighter temperature controls to prevent degradation, according to the authors.

Biosimilars require more extensive pharmacovigilance measures than generics and at least the same level of pharmacovigilance as their reference products, they add. They also recommend that pharmacovigilance studies and monitoring should continue for as long as a biosimilar is on the market, because the makeup of patient populations may change and drug consistency is liable to vary over time.

Proper Reporting and Risk Management Are Essential

“A good pharmacovigilance practice requires reporting to regulatory authorities all types of suspected reactions, suspected drug-to-drug or drug-to-food interactions, adverse drug reactions [ADRs] associated with drug withdrawal, medication errors or overdose, and lack of efficacy,” the authors wrote. Periodic safety update reports and risk management plans should also be part of a comprehensive pharmacovigilance program, they said.

Although biosimilar manufacturing may be efficient and safe, the passage from plant to clinic to patient involves variables that can affect quality of the agent. Patent issues also may affect the type of delivery devices that can be used.

Further, “As the active drug is delivered by the device and is in constant contact with the device, the device can play an important part in the delivered volume and quality of the drug it delivers. Hence, safety of the device delivery system is of utmost importance for biosimilars,” the authors wrote.

The most important environmental parameter is temperature, they said. “Pharmacovigilance should cover this area, which generally goes unnoticed until a problem, such as lack of efficacy or immunogenicity, is detected.” The authors recommend pharmacovigilance with respect to temperature should extend to transportation and storage conditions.

India Has a Longer Experience With Biosimilars

Biosimilars have a longer history in India compared with Europe, where the first biosimilar was marketed in 2000 for hepatitis B, and the United States, which approved its first biosimilar in 2015.

The multistep manufacturing process for biosimilars is prone to variations that affect the final drug, including immunogenicity, a major safety concern associated with biosimilars. “The manufacturing process of biosimilars is known to affect the level of process-related impurities and posttranslational modifications of the product.”

Biosimilars are administered via injection, rather than orally, as generics are, which raises issues of safety and adherence concerning the delivery device. The authors suggest tracking device manufacturing and evaluating factors such as ease of use, which could affect patient adherence.

The authors note that rare adverse events usually are seen when large numbers of patients are using a biosimilar. Therefore, biosimilars require postmarketing vigilance, and perhaps postapproval studies, to assist in the identification of previously unknown adverse drug reactions and to better assess the risks and benefits of a drug.

Adequate pharmacovigilance requires specialized and experienced personnel (as for originator biologics) because of the complexity of safety data and difficulty detecting adverse events. The authors recommend these individuals also regularly search the literature for individual case reports that may be relevant.

How to Put Together a Pharmacovigilance Effort

India, Europe, and the United States each require periodic reports on the safety of biosimilars in the years following market authorization. The authors recommend connecting reported ADRs with specific batches of the biosimilar for comparison with the reference product and documenting patient history with the reference product when assessing immunogenicity or lack of efficacy.

The authors note that a thorough pharmacovigilance program for a biosimilar should include postauthorization safety and efficacy studies, and they said pharmaceutical companies are generally more willing to take these steps than to perform additional testing or larger pre-approval studies that could delay initial approval. Postapproval studies, they note, bolster confidence in prescribers.

“The actual hesitation is in conducting large and multiple preapproval studies, as they carry a nonapproval risk,” they wrote.

Furthermore, they hold that pharmacovigilance should continue as long as a product is on the market, as the risk-benefit ratio at the time of approval is likely to change due to use by a larger patient base with different characteristics than the clinical study population, longer exposure by patients, and potential structural changes to the molecule.

Additional recommendations included using a standard format for prescribing information and regularly updating the prescribing guidelines for the biosimilar, as new safety concerns can arise when the patient population is expanded. They said clinicians should be given latitude to collect blood samples from patients they suspect are having an immunogenic reaction or when there are other quality concerns with a biosimilar.


Oza B, Radhakrishna S, Pipalava P, Jose V. Pharmacovigilance of biosimilars - why is it different from generics and innovator biologics? J Postgrad Med. 2019;65(4):227-232. doi: 10.4103/jpgm.JPGM_109_19.

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