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The Biosimilar Boom: Need for Robust Pharmacovigilance
- Dr Rashna Cama, Associate Medical Director, Quintiles Technologies Pvt Ltd

Biosimilars have tremendous potential to improve patient access to modern therapies and improve quality of life in both the developed and developing regions of the world, but the increased risks associated with immunogenicity highlight the need to focus on the pathways of patient care and robust pharmacovigilance legislation and practices.

As biologics worth more than USD 60 million go off-patent in the next decade, we are currently witnessing the blossoming of an era of Biosimilars. Unlike chemically synthesized molecules, “biologic” medicines are large complex molecules that are produced from living cells. The manufacture of biologics is a complex process involving multiple steps of production and purification. The complex structure of the molecule causes it to have different characteristics which may carry different risks. This together with a complex manufacturing process carries the risk of influencing the characteristics of the end product, and possibly the safety profile of the end product.

The first biologic drug to receive approval in the US was recombinant insulin in 1982. Discovery of recombinant DNA techniques more than 25 years ago mushroomed into large-scale production of biologics, which resulted in important new treatments for a variety of chronic and sometimes lifethreatening diseases. Biologics are both therapeutically and economically important. More than 150 reference product biologics have been approved in the US and there appear to be more than 370 in clinical trials targeting a broad spectrum of diseases from cancers to Alzheimer’s, multiple sclerosis, vaccine preventable diseases, and AIDS.

The expiration of patents of some biologics, like growth hormone, granulocyte colony-stimulating factor, and erythropoietin, makes it possible for pharmaceutical companies to produce socalled “biosimilars”, which are also called “subsequent entry biologics” or “follow-on biologics”. Hence, biosimilars are biologic medicines that though not identical to the reference product, are highly similar to the approved biologic, and may have minor differences in clinically inactive components. Biosimilars are defined by the European Medicines Agency (EMEA) as biopharmaceuticals claimed to be similar to a reference medicinal product based on the demonstration of the similar nature of the two products, in terms of quality, safety and efficacy. Since 2007, biosimilars have been approved for use in patients in the European Union (EU) and other regions. According to a 2010 report from India, more than 40 biologics are marketed in India of which 25 are non-innovator biologics manufactured in India including epoetin, filgrastim, Rituximab, insulin and streptokinase.

Regulatory Considerations
The approval of Biosimilars in India today is governed by the ‘Guidelines on Similar Biologics’ issued by DBT and CDSCO in June 2012.

Biosimilars cannot be authorised based on the same requirements that apply to generic medicines for chemically synthesised molecules. Even if a biosimilar and reference drug show similar efficacy, significant differences may exist in its safety profile in terms of type, seriousness or incidence of adverse reactions. As the data from pre-authorisation clinical studies normally are insufficient to identify all potential differences, clinical safety of similar biological medicinal products must be monitored closely on an ongoing basis during the post-approval phase including continued risk-benefit assessment. A lack of similarity in complex drugs can lead to severe consequences, evident only when tested in long-term clinical trials.

The CDSCO ‘Guidelines for Approval of Similar Biologics’ addresses post marketing surveillance requirements which may perhaps augment the pre-approval human clinical data and are in line with the EMEA and FDA requirements. The Guidelines mandate the submission of a post-approval ‘Risk Management Plan’ along with Marketing Authorisation Application. The risk management plan for biosimilars is expected to focus on the pharmacovigilance measures, identify immunogenicity risk and implement special post-marketing surveillance. Thus, it should be designed to monitor and detect the known safety concerns of the biosimilar as well as detect unknown safety signals that may arise. The guidelines stress the need for at least one non-comparative post-marketing study with focus on safety and immunogenicity that will confirm that the biosimilar does not pose any safety concern to the subjects.

The Indian guidelines emphasise that a pharmacovigilance plan must be prepared by manufacturer to further evaluate the clinical safety in all the approved indications in the post marketing phase. The pharmacovigilance plan should include the submission of Periodic Safety Update Reports (PSURs) on a six- monthly basis for the first two years after approval and on an annual basis for the subsequent two years to the DCGI office as per the Schedule Y.

In Europe, the pharmacovigilance legislation which came into force in July 2012, has been upgraded to increase the scrutiny and robustness of the pharmacovigilance system. The European Directive 2010/84/EU requires that with regard to the reporting of adverse events, biologics must be identified by the trade name and batch number in addition to the International Nonproprietary Name (INN). The legislation recognises that biosimilars, and other biological medicinal products, present distinctive safety challenges and aims to guarantee their traceability after they have been dispensed, through the provision of product information and identification.

Safety and Pharmacovigilance
Though biosimilars are expected to behave like their reference biological product, differences in manufacturing and purification processes may induce differences in their safety and immunogenicity profile. As approval of Biosimilars is based on an abbreviated dossier based on equivalence in terms of pharmacokinetics (PK), pharmacodynamic (PD), efficacy and safety data between the biosimilar and the reference product in a relatively small number of subjects, the importance of post-marketing studies and surveillance cannot be over-emphasised.

The most critical safety concern relating to biopharmaceuticals (including biosimilars) is immunogenicity. The development of anti-drug antibodies and antibodies with cross-reactivity may affect the PK/PD characteristics of the biosimilar and may have potentially serious effect on its safety and efficacy profile. Hence the importance of post-marketing studies which must be appropriately designed taking into consideration the above factors.

Continuing immunogenicity assessments post approval of a biosimilar are required as often the incidence of anti-drug antibodies and neutralising antibodies in controlled clinical studies may not reliably reflect that seen during the post-approval stage due to a larger numbers of exposed subjects, more concomitant medications, repeated drug re-exposures, and possibly reduced patient treatment compliance

Strict post-marketing surveillance and potentially large post-marketing studies are necessary to provide reassurance regarding the safety of biosimilars. In June 2013 at ASCO, Hospira declared the results of the first ever post marketing study of their EPO biosimilar. This European prospective, observational study included 2,310 patients with solid tumors, lymphomas or myelomas who received their EPO biosimilar for chemotherapy induced anemia. The majority of patients (>80 per cent) enrolled in this study achieved a pre-defined haemoglobin response in a real-world clinical setting and the biosimilar was well tolerated in this study with an overall rate of thrombotic events at 3.5 per cent. In this observational study, no biosimilar-related deaths were reported. This post-marketing study reinforces the acceptability of biosimilars and reassures the treating physician regarding their efficacy and safety.

Besides the safety and immunogenicity concerns regarding biosimilars, concern has also been expressed about using biosimilars in other indications on the basis of extrapolation of efficacy and safety data, ie, in indications that are approved for the reference biological but for which the biosimilar has not been investigated. The efficacy and safety of biosimilars in these extrapolated indications can only be confirmed by robust post marketing surveillance studies.

With increasing use of biosimilars, another concern which bears highlighting is that of switching among biosimilars or between the reference biologic and a biosimilar. It is possible that repeated switches between the biosimilar and the reference biological may increase immunogenicity with potentially negative effects on the safety and/or efficacy of the products. Data from large-scale robust post-marketing programs will ascertain the justification or otherwise of these concerns.

Pharmacovigilance processes for biosimilars should be designed to adequately address the specificity of the respective type of medicinal product. Although International Nonproprietary Names (INNs) served as a useful tool in worldwide pharmacovigilance, for biologicals they should not be relied upon as the only means of product identification. Biologicals and biosimilars should always be commercialised with a brand name or the INN plus the manufacturer's name, which can assist in tracing them back in case of adverse event. Some Pharmaceutical companies are working to improve patient safety by applying bar codes to all injectable drugs and intravenous solutions, and incorporating bar code-reading technology into several infusion devices, in order to help ensure that patients receive the right dose of the right medicine.

Conclusion
Post-marketing studies and pharmacovigilance of biosimilars are necessary tools to ensure their long-term safety and reassure the treating physician on their safety and efficacy in all the approved indications.

(The author would like to thank Dr Charu Manaktala, Medical Director, Quintiles.)
Contact: rashna.cama@quintiles.com