Pharmacovigilance of biosimilars – Why is it different from generics and innovator biologics?B Oza, S Radhakrishna, P Pipalava, V Jose
Clinical Development and Medical Affairs, Intas Pharmaceuticals Ltd. (Biopharma Division), Ahmedabad, Gujarat, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.JPGM_109_19
Source of Support: None, Conflict of Interest: None
Keywords: Biosimilars, drug safety, lack of efficacy, pharmacovigilance, regulations
According to the World Health Organization (WHO), pharmacovigilance is defined as the science and activities relating to the detection, evaluation, understanding, and prevention of adverse drug reactions (ADRs) or any other drug-related problems. A good pharmacovigilance practice requires reporting of all types of suspected reactions, suspected drug–drug or drug–food interactions, ADRs associated with drug withdrawal, medication errors or overdose, and lack of efficacy to regulatory authorities. Pharmacovigilance also requires aggregate reports, such as periodic safety update reports (PSURs) and risk management plans (RMPs). The PSUR is an important source for the identification of new safety signals, a means of determining changes in the benefit–risk profile, an effective means of risk communication to regulatory authorities, and an indicator for the need for risk management initiatives, as well as a tracking mechanism of monitoring the effectiveness of such initiatives. The RMP documents the risk management system considered necessary to identify, characterize, and minimize a medicinal product's important risks throughout the product's life cycle, ensuring benefit–risk balance. Global regulatory authorities, such as European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA), have well-structured pharmacovigilance system in place, and India is also moving in that direction. In January 2018, Indian pharmacovigilance guidance for marketing authorization holders (MAHs) was published by Pharmacovigilance Programme of India (PvPI), Indian Pharmacopoeia Commission (IPC).
This review article discusses the importance of pharmacovigilance for biosimilars, how it is different from generics, and provides recommendations to sensitize clinicians and researchers about the requirement of a different approach to improve pharmacovigilance of biosimilars.
The Indian regulatory authority—Central Drugs Standard and Control Organization (CDSCO)—defines biosimilars as a biological product produced by genetic engineering techniques. Biosimilars are claimed to be “similar” in terms of safety, efficacy, and quality to a reference biologic, and they have been granted a marketing authorization in India by the Drug Controller General of India (DCGI) on the basis of a complete dossier and with a history of safe use in India. The US FDA defines biosimilars as a biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences between the biosimilar and the reference product in terms of the safety, purity, and potency of the product. According to the EMA, a biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety, and efficacy based on a comprehensive comparability exercise. In simple terms, biosimilars are substitutable drugs for innovator biologics with expectation of similar efficacy and safety.
In India, the first biosimilar launched was Biovac™ (hepatitis B vaccine, Wockhardt) in the year 2000 followed by Wepox™ (epoetin alfa) in March 2001. In the USA, Zarxio® (filgrastim, Sandoz Inc.) was the first biosimilar, approved in March 2015, followed by Inflectra® (infliximab, Pfizer) in April 2016. In Europe, Omnitrope® (somatropin, Sandoz Inc.) was the first biosimilar product, approved in 2006, followed by Abseamed® (epoetin alfa, Medice Arzneimittel Pütter) in August 2007. Overall, biosimilars are in the market for two decades; therefore, an efficient pharmacovigilance system would ensure safety from the marketed biosimilars.
Copies of small molecule drugs are called generics while copies of biological drugs are called biosimilars. Generic products contain exactly the same active ingredient as the reference innovator drug while biosimilars are variants of the innovator biological drug. Biological drugs are different from small molecule drugs in many ways, including their molecule size and complexity. Small molecule drugs, produced by chemical synthesis, have uniform predictable structure and are generally stable. In contrast, biological drugs are protein-based and large in molecular size.
Manufacturing methods of biologics are more complex compared to small molecule drugs and involve several steps that are subject to variations, which can affect the biological or clinical properties of the product. Biological drugs are manufactured through a highly complex procedure of recombinant DNA technology. The first step is the modification of a cell or microorganism, considered as a host, to introduce a genetic sequence coding for the desired protein. Once the right sequence for the protein is introduced, the host is conserved and a master cell bank is produced from which a seed lot is picked up, cultured, and grown in a bioreactor or fermenter. Then it is harvested to purify the protein. The purified protein is stabilized and then formulated for use as a therapeutic drug. Any change in the processes, such as excursion of temperature, pH of the media, cell culture condition, or storage and transport, may cause partial or full loss of biological activity or enhanced biological activity, which can result in significant difference in the outcome of clinical testing, e.g., safety and efficacy of the biological drug.
No changes are expected in the structure of small molecule drugs over a period of time, unless there are changes in the manufacturing process, manufacturing unit, etc. While in the case of biological products, chances for changes are higher in the structure over a period of time because of larger molecular size, structural complexity, and production by living cells. Biologic agents that undergo several process changes may be more likely to be different from when they were originally tested, approved, and produced more than a decade ago. The manufacturing process of biosimilars is known to affect the level of process-related impurities and post-translational modifications of the product. These characteristics may affect the immunogenicity of the product. Hence, evaluation by characterization (antibody or antibody-derived product); comparison to reference biologic with respect to specificity, affinity, binding strength, and Fc function; and evaluation by animal studies are performed. These changes should be monitored continuously as it may have adverse impact on the safety or efficacy of the product. Although challenging, it may be advisable to compare batches analytically with initial batches of the reference product to detect such changes at a predefined frequency. Furthermore, whenever there are any changes in the volume (scale up or scale down), such comparison should be done, and the comparability data must be evaluated before proceeding for large scale manufacturing for marketing.
Even if the manufacturing of biosimilars are efficient and safe, there is no assurance of safety and effectiveness until the drug is administered to the patient. These mandates need of an efficient and safe device for delivery, supported by a seamless transportation and storage system. As biosimilars are proteins, they need to be administered by injections unlike most of the generic medicines. Usage of parenteral needle-based delivery systems needs more caution than enteral system because of the difficulty in reversibility, postadministration.
Only a vial, prefilled syringe, pen, autoinjectors, or any other such devices can be used as a primary container of the active drug. Due to patent-related concerns, the device used for biosimilars should be different from that of innovator. 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. Though efficient regulations exist for ensuring safety of devices, regular tracking of device manufacturing will complement safety monitoring. While the precision of dosing is a key concern for insulin biosimilars, ease of use, comfort, and convenience of the device are important factors that could potentially influence patient adherence, and so they have an impact on efficacy.
Biosimilars need a temperature-regulated transport and storage system from the manufacturing site to the end user. This may involve transportation in vehicles and storage in refrigerators under strict temperature-regulated environment to ensure maintenance of efficacy and safety. Special care should be followed at the pharmacy to ensure safe delivery of the biosimilars and avoid damage that can be caused by the lack of temperature regulation. The most important environmental parameter that has a significant potential to impact the quality of a pharmaceutical product is probably temperature. Although it may be challenging, pharmacovigilance should cover this area, which generally goes unnoticed until a problem, such as lack of efficacy or immunogenicity, is detected. These aspects are not challenging for most of the generics; hence, such pharmacovigilance practice is not required for generics.
Generics and biosimilars are expected to be cost-effective, and abbreviated development is an acceptable regulatory pathway for these products. For marketing approval of generics, pharmacokinetic (PK) bioequivalence has to be demonstrated with the innovator product. For this, clinical studies in healthy subjects are preferred, and such studies are normally conducted in a controlled manner. For marketing approval of biosimilars, therapeutic equivalence has to be established between the biosimilar and reference biologic by proving comparative PK, pharmacodynamic (PD), safety, efficacy, and immunogenicity profiles. Overall, number of patients and size of studies required for approval of biosimilars are lesser compared to innovator biologics, but larger as compared to generics.
In clinical trials for biosimilars, sample size calculations are based on equivalence or noninferiority demonstration. In most instances, the total number of patients required to be exposed are fewer for biosimilars compared to the innovator products because of the abbreviated development of biosimilars. In addition to proving equivalence or noninferiority, sometimes such equivalence or noninferiority studies also provide an early indication of superiority of biosimilars. In such instances, there may also be a need for closer monitoring of adverse events (AEs), as AEs may also be more frequent.
Generally, clinical trials for biosimilars include a homogenous patient population with similar disease severity and preclude patients with mild or severe disease to ensure comparable sensitivity of the endpoint. These studies are done in the most sensitive indication, and if the mechanism of action and disease physiology is similar across the indications, approvals for additional indications are based on extrapolation. Therefore, there is a chance for the development of previously unknown AE because of selected disease severity exposure, as well as selective indications exposure in clinical trials. However, the clinical trial data of that particular biosimilar for use in other indications are not available. Though not exactly similar, historically there is an instance where a change in formulations of the epoetin alfa (Eprex®) was responsible for the emergence of pure red cell aplasia, a year after exposure to the product. The Marvel insulin formulations were physicochemically similar, but they had PK/PD and clinical properties that differed substantially from comparator insulins. In clinical studies conducted in cancer patients receiving background chemotherapy along with the biosimilar, there are chances of missing out an AE because of the complex disease course and multiple therapies. Due to the structural and manufacturing complexity of the biosimilar, safety concerns are likely to manifest at different periods, which may be outside the time course of a clinical trial. Thus, there is a need for strict postmarketing vigilance and possibly need of postapproval studies. These studies are required to gather more safety data and evaluate long-term effects associated with the product. From a safety and immunogenicity perspective, a minimum of 300 patients should be treated with biosimilars (includes preapproval and postapproval studies). As per the rule of 3, the adverse reaction with an incidence of 1 in 100 users will be detected only if 300 users are exposed to the drug. Hence, rare AEs will be reported only when a large number of patients are exposed to the drug.
Pharmacovigilance assists to identify unknown ADRs and risk elements that lead to the progress of ADRs. It helps in the assessment of the risk–benefit balance and prescription pattern of any drug. In January 2018, Indian pharmacovigilance guidance for MAHs was published by PvPI, IPC. The CDSCO has published pharmacovigilance guidance for biologics, but it is specific to vaccines. In Europe, 13 modules are available, describing good pharmacovigilance practices. Additionally, specific guidelines for biologics are available, which also discuss good pharmacovigilance practices. In the USA, guidance is available for “Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment” and “Pharmacovigilance Planning”;, and same guidance is being followed for biologic drugs as well.
For reporting of ICSRs for biologics, it is not mandatory to provide a brand name and batch number of the product in India and the USA; however, the European Union (EU) regulations mandate to provide a brand name and batch number of the product. In India, six periodic safety update reports (PSURs) are required to be submitted over a period of 4 years. In Europe, PSURs are termed as “periodic benefit-risk evaluation report” (PBRER), which should be submitted as per the European Union reference dates (EURD) list maintained by the EMA. The EURD list provides information on frequency of PSUR submission, data lock point, submission date and requirements for submission of PSURs for different products. In the USA, PSURs are termed as “periodic adverse drug experience reports” (PADERs), which should be submitted quarterly for first 3 years, and annually thereafter.
The Indian pharmacovigilance guidance highlights the need for an RMP. It should be updated throughout the life cycle of the product and approved by the regulatory authority. As per the European guidance, the RMP should be submitted along with the application for market authorization. The RMP must be approved by the competent authorities prior to the granting of the marketing authorization. All parts of the RMP are required for a biosimilar, with the exception of RMP part II, module SI “Epidemiology of the target population”. The potential for immunogenicity and associated clinical consequences should be fully evaluated and discussed as a part of the initial marketing authorization application (or variation) in the relevant sections of the “Summary of clinical safety” of the application for marketing authorization. In the USA, a similar document is required for particular risks, which is termed as “risk evaluation and mitigation strategy” (REMS).
Per the Indian guidance for biosimilars, all MAHs of biosimilars should have an RMP for their biosimilars. This guidance also states that additional safety data may need to be collected after marketing approval through a predefined single-arm study of, generally, more than 200 evaluable patients and compared to historical data of the reference biologic. The study should be completed preferably within 2 years of the marketing permission/manufacturing license. In Europe, the medicines subject to “additional monitoring” are intensively monitored during the first few years after marketing authorization and are labeled with a black triangle on their package insert together with the sentence: “This medicinal product is subject to additional monitoring”.
Like innovator biologics, biosimilars also require specialized and experienced pharmacovigilance personnel because of the complexity of safety data and challenges in the detection of AEs. MAHs should have an established pharmacovigilance system for collection and processing of ADR reports from all sources. The MAH should sign and implement a safety data exchange agreement (SDEA) with all the distributors to ensure appropriate processing and reporting of ADRs.
Reporting ADR is an essential component of pharmacovigilance. Therefore, following a good practice while reporting an ADR can improve the pharmacovigilance system. ADRs should be reported to the MAH or regulatory authority as soon as possible so that actions can be taken faster, if necessary. While reporting an ADR, it is a good practice to provide the brand name and batch number in the ADR form; this can help the manufacturer in tracking the ADR. The batch number will be helpful to identify if there is an increased number of events reported with a particular batch. If there is a sudden increase in the ADR reports with a particular batch of the product, it will require urgent attention and quick action; hence, it is advisable that clinical complaints are handled and monitored by a medical doctor. If complaints are related to the quality of the product, such complaints should be handled by the quality personnel.
Patients treated with biologics often have multiple diseases and are treated with multiple drugs, which may hamper adequate causality assessment. Comparison of the frequency and severity of the known ADRs of the reference product with that of the biosimilar is important to detect possible differences between the two products. If possible, the trend of ADRs reported with specific batches should be calculated and compared with the frequency of the reference product.
While reporting an ADR, it is essential for the reporter to provide details about the history of administration of the same biosimilar or innovator product. This will be helpful in cases of immunogenic reactions or lack of efficacy issues. Lack of efficacy cases should be evaluated thoroughly along with immunogenicity assessment. As biosimilars are protein, there are inherent chances for development of neutralizing antibodies, leading to immunogenicity. Increased tungsten levels leading to immunogenicity associated with epoetin alfa is known. Such reactions are very rarely seen with generics. Mandatory blood collection and testing in case of immunogenicity can solve this concern. MAHs should develop a method for detecting antidrug antibodies from patient's blood sample.
In PSURs, postmarketing patient exposure data are crucial, considering the limited exposure during clinical trials. All dosage forms, presentations, and strengths should be included in a single PSUR. In case of approval of a new strength/dosage form, the PSUR cycle should start again for the next 4 years. The regulatory authority may ask for an extension of the PSUR if the product has safety issues or it is under close monitoring.
It is essential that MAHs have an RMP for all biosimilars. Most widely accepted RMP format is the EU RMP template (in integrated format). The most important safety issue for biosimilars is immunogenicity; therefore, the RMP should address the risk of hypersensitivity and immunogenicity. Additional pharmacovigilance and risk minimization activities should be proposed and implemented when appropriate. These details are available in the European public assessment reports. Details of postauthorization safety studies should be captured in the RMP. The RMP should be updated whenever there are significant safety updates in the prescribing information.
The MAHs should do regular literature search to identify potential individual case safety reports. Apart from journals, focus should be on newspapers and other media, which will provide intimation in case of any issue with the product. As under-reporting is highly prevalent, it is possible that cases are not submitted to the MAH, rather it will gain attention in the public media. Signal detection activity should be performed by MAH on regular basis to identify any new safety concern with the product. The pharmacovigilance program of biosimilars can be expanded to include both postauthorization safety studies and postauthorization efficacy studies. As the number of patients exposed to the biosimilars are relatively less, data and publications demonstrating efficacy and safety are also less. Generally, pharmaceutical companies are not hesitant to conduct postapproval studies, as it helps the marketing team to buy confidence of investigators. The actual hesitation is in conducting large and multiple preapproval studies, as they carry a nonapproval risk.
Prescribing information/package insert is an essential document mentioning safety profile of the product. The MAHs should keep it in-line with the reference safety information (EU summary of product characteristics or US FDA prescribing information) of the innovator. A standard format for prescribing information is presented in the new drugs and clinical trials rule published by CDSCO in March 2019. Prescribing information/package insert should be updated regularly and should be approved by the regulatory authority.
One of the greatest concerns about biological drugs is the risks associated with these products over time because of the structural changes in the molecule, as these are derived from microorganism. It is highly possible that the risk–benefit profile established at the time of approval will change over time through expanded use, patient characteristics, and patient exposure. Therefore, pharmacovigilance should be continued for biosimilars as long as the product is in the market.
Pharmacovigilance for biosimilars is more important than it is for generics because of the need of strict temperature regulation, a specialized delivery system in the form of device, and the risk of post-translational changes over a period of time compared to generics. Pharmacovigilance for biosimilars is as important as it is for innovator biologics because there is a potential for minor structural or constituent-related changes in biosimilars. Efforts should be made by the MAHs and regulatory authorities to maintain the risk–benefit balance of biosimilars. There is a scope for further improvement in the pharmacovigilance practice of biosimilars.
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Conflicts of interest
All the authors are employees of Intas Pharmaceuticals Ltd., India.