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Regulatory Considerations for Biosimilars



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Biological medicines are already becoming an increasingly important part of health care. With patent expiries on originator biological products, biosimilars are also increasingly become a part of this future. In fact, by 2020 twelve of the top-selling biologicals will have lost patent protection, opening up an estimated US$24 billion in EU sales and US$30 billion in US sales.

Biologicals have potential to reach up to 50% share in global pharmaceutical market in the next few years.

India is one of the leading contributors in the world biosimilar market and is the third-largest in the Asia-Pacific region, after Australia and China. India has demonstrated high acceptance of biosimilars, which is reflected in the 40 biologicals marketed in India, of which 25 are biosimilars The Indian biotechnology industry is also gaining momentum, with revenues of over US$4 billion in 2011, and which are projected to reach up to US$580 million by 2012.

While small molecule drugs are ideal for generics replication, biological drugs are not so simple. Biological drugs are usually large, complex molecular structures derived from or produced through a living organism, making them very difficult to replicate

Currently there is considerable interest in the legislative debate around generic biological drugs or “biosimilars” in the EU and US due to the large, lucrative market that it offers to the industry. While some countries have issued a few regulatory guidelines as well as product specific requirements, there is no general consensus as to a single, simple mechanism similar to the bioequivalence determination that leads to approval of generic small molecules all over the world. The inherent complex nature of the molecules, along with complicated manufacturing and analytical techniques to characterize them make it difficult to rely on a single human pharmacokinetic study for assurance of safety and efficacy.

In general, the concept of comparability has been used for evaluation of the currently approved “similar” biological where a step by step assessment on the quality, preclinical and clinical aspects is made. In India, the focus is primarily on the availability and affordability of life-saving drugs. In this context every product needs to be evaluated on its own merit irrespective of the innovator brand. The formation of the National Biotechnology Regulatory Authority may provide a step in the right direction for regulation of these complex molecules. However, in order to have an efficient machinery for initial approval and ongoing oversight with a country-specific focus, cooperation with international authorities for granting approvals and continuous risk-benefit review is essential. Several steps are still needed for India to be perceived as a country that leads the world in providing quality biological products.

We are now in the twenty-fifth anniversary year of the Drug Price Competition and Patent Term Restoration Act of 1984 (better known as the Hatch Waxman Act), the landmark US regulation that jump-started the generic pharmaceutical industry. The legislation provided the required impetus to make not just cheaper price alternative medicines available to US consumers but stimulated the emergence of the Indian pharmaceutical industry which is now the dominant supplier of generic drugs to the USA.

The regulatory pathway for bringing generic drugs to market is the abbreviated new drug application (ANDA) process which relies on proving bioequivalence to the listed reference product and showing equivalent product quality. Since duplication of proof of safety and efficacy in the preclinical and clinical setting is not required, there are significant cost savings in bringing a copy of a small chemical molecule to market. This model has been so successful in economic terms that almost 7 out of 10 prescriptions in the US are now generic and for the vast majority of products there is no concern in substitution of a generic equivalent for a brand-name prescription.1

The success story of generic small molecule drugs has stimulated interest in the pharmaceutical and biotech industry for applying an analogous approach towards the highly lucrative biologics business. But biologic drugs are very different from small molecules both in their final form and in the process required to produce and control their quality. It is therefore difficult to find a simple, precise “regulatory” definition of biologics. However, biologics are generally understood to be drugs derived from an organic source. Thus, biologics may be obtained or created from living organisms, either naturally or via genetic manipulation or are manufactured from building blocks of living organisms. They demonstrate considerable molecular complexity and may comprise a diversity of molecular forms. Their larger size and heterogeneity make it difficult for complete characterization via physicochemical analysis which is possible for synthetic chemical entities. In general, biologic drugs are more expensive and the cost of a yearly treatment may run into thousands of dollars for some. They are therefore ideal targets for developing cheaper alternatives.

US FDA definition – A “biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings (Public Health Service Act Sec. 351(i)).

Given the complexity of the final biologic product, it is clear that the nature of the manufacturing process is also complicated. In addition to aspects that are disclosed in regulatory applications, there may still be several aspects which might be held as trade secrets, thereby making it practically impossible for another company to make an identical copy of a biologic drug. While changing a host cell line or vector will definitely impact the product, effects of minor changes like temperature used in the manufacturing process may have an effect on the final characteristics of the biologic drug, including its safety and efficacy. It has been stated often that for a biologic, “the process defines the product”. Thus, while it may be possible to make a similar product, it may not be truly bioequivalent. As a result, even the term used to describe these similar biologic drugs has not been standardized globally. While the parallel term for a biologic generic may intuitively be “biogeneric”, the accepted term in Europe and Canada is “biosimilar” and the preferred term in the US is “follow-on biologic”.

Given these differences among innovator biologics and their “similar” counterparts, there is considerable hesitation on the part of the regulatory agencies to follow an abbreviated approval path similar to one widely used for generic small molecules.

Table 1

Table 1
Some Approved biosimilars

Status of biosimilar regulation in Europe

EMEA Guidelines for Similar Biological Medical Products ( CHMP/437/04, 30 October 2005).2

EMEA’s Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Nonclinical and Clinical Issues (EMEA/ CHMP/BMWP/42832/2005).3

EMEA’s Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Quality Issues, EMEA/CHMP/49348/05.4

In Europe, the Committee for Medicinal Products for Human Use (CHMP), the European Medicines Agency (EMEA) led the way for biosimilars, by issuing its first specific regulatory guidance in October 2005. Two general guidance documents addressing quality and nonclinical and clinical perspectives (June 2006), five product-specific annexes on nonclinical and clinical issues (June-July 2006) and a manufacturing change comparability guideline (November 2007) are now available.

Testing the bioequivalence of biosimilars differs from that of standard generics. Bioequivalence testing procedures for biosimilars are to be performed against the originator product as a control (reference) and include preclinical and clinical testing [2].

In the Biologics Price Competition and Innovation (BPCI) Act, a biosimilar product is defined as a product that is ‘highly similar’ to the reference product, notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences in terms of safety, purity and potency. However, little or no discussion regarding how similar is considered ‘highly similar’ is given in the BPCI Act.

For biosimilars, most of which have long half-lives, crossover study would be ineffective and unethical. This is due to the fact that a crossover study requires a wash-out period (which would be long for biosimilars with long half-lives) where the patient is not allowed to take the drug and therefore will have no treatment for their condition. On the other hand, parallel-group studies are required, but these studies do not provide an estimate of within-subject variation. For a parallel-group study, each drug is administered to a different group of subjects. Thus, we can only estimate total variance (between and within-subject variances), not individual variance components. This makes an evaluation of interchangeability difficult.

Statistical tests that may be used to asses biosimilarity are Shuirmann’s two one-sided tests procedure or the confidence interval approach.

Status of Biosimilar Regulation in US

In US, in March 2009, Representative Henry Waxman introduced H.R. 1427 to the Congress “Promoting Innovation and Access to Life-saving Medicines Act”, which authorizes FDA to approve follow-on biologics in an abbreviated manner. It has market exclusivity clauses with time frames similar to ones used currently for drugs. Other bills are expected to follow in the 2009 legislative agenda in order to establish a pathway for approval of these follow-on biologics. The contentious issues as expected, are focused around the duration of exclusivity benefits granted to innovators. The issue of substitutability of followon biologics for reimbursement is also an important one as the legislators debate the merits of each bill.

Korea and Singapore have released draft guidelines on biosimilars in 2009. The Singapore guideline is derived mainly from the EMEA guidelines and defines a similar biological/ biosimilar product as “a biological medicinal product referring to an existing registered product, submitted for medicinal product registration by an independent applicant, and is subject to all applicable data protection periods and/or intellectual property rights for the original product”. In addition to specifying the requirements for biosimilars, the guidance requires that the product have prior approval in countries such as Australia, Canada, EMEA or US.

Indian scenario

The Indian biotech industry is a thriving industry which got its start from vaccine manufacturing. In addition to meeting domestic demands, the Indian vaccine industry also fulfils export requirements to a large extent. Therefore it is evident that manufacturing expertise in producing biologic products of required export quality already exists in the country. What is not readily evident is whether these products can prove to be “comparable” to innovator products when we look into all categories of biologics.

The evolution of regulations governing pharmaceuticals in India has historically been driven by the need to make essential medicines accessible to patients. Access encompasses availability and affordability. It applies to medicines for all indications, acute and chronic illness, small molecules and biologics alike. The absence of product patent regulations for drugs marked a period in the country’s history where it was imperative to make inexpensive medicinal products available to the masses – it did not matter whether these products were innovator-made or copies thereof. In the post-TRIPS era however, there is need to offer and enforce adequate protections for patentable drugs, particularly biologics that inherently involve huge investments in R & D, manufacture and clinical development.

Today, several biologics have been approved in India , including recombinant human insulin, recombinant human erythropoietin (EPO), interferon (IFN), granulocyte colony stimulating factor (GCSF). The versions of biologics available in India are typically products whose patents have expired or do not exist in India. Therefore, from a technical standpoint, there is no concern about patent infringement regarding these (there are no patents in India for these products). If a biosimilar results in a price drop of 30%, it is a significant improvement to patients who may now be able to afford this generic version of a life-saving drug. In many ways, the debate about biosimilars that rages across the developed world and regulated markets is irrelevant to India where the central concern revolves around access.

Partly due to the dearth of appropriate resources and experience, Indian regulators have sought to mimic regulations already in use in the developed world without much customization. A host of agencies have been created to address the issues brought forth by biologics.

Basic facts about biosimilars.

Biotechnological drugs have become an essential part of modern pharmacotherapy and are expected to reach a 50% share in the pharmaceutical market in the next few years. The expiry of patent protection for many original biotechnological medicines has led to the development of what are called biosimilars or follow-on biologics. Biosimilars attempt to copy the original technology leading to the production of innovative biotechnological medicines to obtain a product which is similar to the original one. The first two biosimilars have recently been approved in the European Union and one application was rejected. Many more biosimilars will likely see approval in the near future. Our experience with biosimilars has been very limited to date and long-term safety data including immunogenicity are not available. Although biosimilars will likely lower the cost of modern therapies there are issues which have to be discussed at this stage among physicians regarding in particular the differences between biosimilars and generics of the classical chemical drugs, need for appropriate regulations as well as identification of potential problems with biosimilars. Other specific problems which will also be addressed in this review are safety of biosimilars, pharmacovigilance, automatic substitution, naming and labeling/prescription rules. 7

List of agencies

  • Indian Council for Medical Research (ICMR)
  • Central Drugs Standard Control Organisation (CDSCO)
  • Department of Biotechnology (DBT)
  • Genetic Engineering Approval Committee (GEAC)
  • Recombinant DNA advisory Committee (RDAC)
  • Review Committee on Genetic Manipulation (RCGM)
  • Institutional Biosafety Committee (IBSC)
  • National Centre for Biological Sciences
  • National Control Laboratory for Biologicals

Notwithstanding the above, there is clarity on the fact that biologics and drugs need to be scrutinized differently. With this in mind, the DBT has been given the mandate to set up the National Biotechnology Regulatory Authority (NBRA). This is envisaged as an independent, autonomous and professionally led body to provide a single window mechanism for biosafety clearance of genetically modified products and processes.

Before such an organization can be effectively implemented, it will be necessary to put in place appropriate new legislation, namely the “National Biotechnology Regulatory Act” or the NBR Act. Draft establishment plan and “Draft National Biotechnology Regulatory Bill, 2008” are currently available on the DBT website for comments. The responsibility of consolidating the feedback has been entrusted to Biotech Consortium India Limited (BCIL). The draft bill envisions the scope of this authority to encompass research, manufacture, import and use of genetically engineered organisms and products derived thereof.

Biosimilars: how similar or dissimilar are they?

The imminent expiry of patents on biological medicinal products, such as epoetin alfa in 2006, has significant implications for nephrology in Australia. The purpose of this review is to examine the differences between biosimilars (similar biological medicinal products) and generic low molecular weight (chemical) drugs. The approach that regulatory agencies, including the European Medicines Agency (EMEA) and the Therapeutic Goods Administration (TGA), are taking towards biosimilars is also discussed. Biosimilars differ from generic chemical drugs in many important ways, including the size and complexity of the active substance, the nature of the starting materials (cell banks, tissues and other biological products), and the complexity of the manufacturing processes. Therefore, it has been acknowledged by the EMEA that established legal and regulatory principles of ‘essential similarity’ that are applied to standard chemical generics cannot be readily applied to biosimilars. One of the key areas of concern with the introduction of biosimilars into the field of nephrology will be guaranteeing the safety and efficacy of biosimilars. New manufacturers will need to ensure that their biopharmaceutical has a similar efficacy and safety profile to the innovator product through more extensive clinical trials than the limited testing done for generic versions of low molecular weight chemical medicines. 6

The primary importance of the manufacturing process was highlighted when a slight change in the production process of an originator recombinant erythropoietin resulted in patients developing pure red cell aplasia.

To try to address this possible safety issue, guidelines from EMA on comparability of biosimilars state that preclinical data must be insufficient to demonstrate the immunological safety of some biosimilars. This means that safety must be demonstrated in cohorts of patients enrolled in clinical trials and using post marketing surveillance.

The challenge of biosimilars.

The purpose of this report was to review issues associated with the introduction of alternative versions of biosimilars used in the oncology setting.

Data were obtained by searches of MEDLINE, PubMed, references from relevant English-language articles, and guidelines from the European Medicines Agency.

When biosimilars are approved in EU, they will be considered ‘comparable’ to the reference product, but this does not ensure therapeutic equivalence. Inherent differences between biosimilars may produce dissimilarities in clinical efficacy, safety, and immunogenicity. Switching biosimilars should be considered a change in clinical management. Regulatory guidelines have been established for some biosimilar categories but, because of the limited clinical experience with biosimilars at approval, pharmacovigilance programs will be important to establish clinical databases. Guidelines also provide a mechanism for the extrapolation of clinical indications (approved indications for which the biosimilar has not been studied). This may be of concern where differences in biological activity can result in adverse outcomes or when safety is paramount (e.g. stem cell mobilization in healthy donors). These issues should be addressed in biosimilar labeling.

Biosimilars should provide cost savings and greater accessibility to biopharmaceuticals. A thorough knowledge surrounding biosimilars will ensure the appropriate use of biopharmaceuticals.

Due to the limited clinical database at the time of approval of a biosimilar, vigorous pharmacovigilance is required. EMA guidelines require pharmacovigilance programmes to monitor the safety of biosimilar products post-approval.

For small molecule generics the issue of substitution is easy, since they are considered identical to the originator molecule. This, however, is not the case for biosimilars, which are large complex molecules prone to heterogeneity.

In the US, the BPCI Act gives FDA the authority to designate a biosimilar as interchangeable with its reference product. This means that the biosimilar may be substituted for the originator product by the pharmacist without reference to the prescribing physician. This is not the case, however, in the EU, where decisions on interchangeability are not made by EMA, but at a national level.

Global concerns regarding product safety and quality

Every drug/biologic manufacturer needs to own the responsibility for putting a high quality, safe drug on the market, after appropriate review and approval by the concerned regulatory authority. While the safety of original biologics products is assured by the innovator by adherence to rigorous standards required for approval, the resistance towards biosimilars on the part of regulators, stems from the concern that an abbreviated approval process may not be adequate to ensure safe performance of the product in the market. For a manufacturer looking to get into the biosimilar market, he needs to overcome major challenges in making a complex product, getting regulatory approval by satisfying stringent criteria and then selling it in the market. Typically, facilities required for manufacture of biologicals are very expensive and the kind of infrastructure required to meet high regulatory expectations is limited to only a few companies. Clinical trial expenditure and ongoing analysis requires compliance to pharmacopoeial monographs when available and access to reference standards, which are not always available.

The cornerstone of generic drug approvals has been the concept of bioequivalence, using equivalence of pharmacokinetic parameters as surrogates for clinical efficacy. But in the context of biosimilars, the concept of comparability is the one used to make such an evaluation. Comparability protocols are used for chemistry, manufacturing and controls (CMC) sections to make the case on the quality aspects of the product. Preclinical testing requires knowledge of study designs used by innovator in order to truly compare performance of the biosimilar. For clinical evaluation, at least one clinical comparability trial is required to demonstrate comparability (non-inferiority in terms of efficacy to innovator and comparable safety profile). But long term safety issues remain unaddressed for biosimilars, requiring thorough postmarketing studies and pharmacovigilance and adequate risk management plans.

In terms of preclinical studies, for biologics, pharmacodynamic endpoints are more relevant than pharmacokinetics, which is the key measure with small molecules. For animal safety studies, choice of appropriate animal species and duration of studies are important criteria for proving comparability. Clinically, comparative PK/PD study is required to compare the reference and biosimilar product. However, clinical trial design selection and a thorough understanding and a priori statement of margins chosen for comparability must be stated for meaningful evaluation of data.

Follow-on biologics: challenges of the “next generation”.

The imminent patent expiration of many biopharmaceutical products will produce the possibility for generic versions of these therapeutic agents (i.e. biosimilars). However, there are a number of issues that will make approval of biosimilars much more complicated than the approval of generic equivalents of conventional pharmaceuticals. These issues centre on the intrinsic complexity of biopharmaceutical agents, which are recombinant proteins in most cases, and the heterogeneity of proteins produced by different manufacturing processes (i.e. differences in host cells, purification and processing, formulation and packaging). The increased occurrence of antibody (Ab)-mediated pure red cell aplasia (PRCA) associated with a change in the formulation of one particular epoetin-alpha product highlights the potential for increased immunogenicity of recombinant proteins with different formulations, or those manufactured by different processes. Thus, verification of the similarity to or substitutability of biosimilars with reference innovator biopharmaceutical products will require much more than a demonstration of pharmacokinetic similarity, which is sufficient for conventional, small molecule generic agents. Regulatory requirements for the approval of biosimilars have not yet been fully established, but preliminary guidelines from the European Agency for the Evaluation of Medicinal Products (EMEA) state that the complexity of the product, the types of changes in the manufacturing process, and differences in quality, safety and efficacy must be taken into account when evaluating biosimilars. For most products, results of clinical trials demonstrating safety and efficacy are likely to be required. In addition, because of the unpredictability of the onset and incidence of immunogenicity, extended post-marketing surveillance is also important and may be required. 10

Statistical assessment of biosimilar products.

Biological products or medicines are therapeutic agents that are produced using a living system or organism. Access to these life-saving biological products is limited because of their expensive costs. Patents on the early biological products will soon expire in the next few years. This allows other biopharmaceutical/biotech companies to manufacture the generic versions of the biological products, which are referred to as follow-on biological products by the U.S. Food and Drug Administration (FDA) or as biosimilar medicinal products by the European Medicine Agency (EMEA) of the European Union (EU). Competition of cost-effective follow-on biological products with equivalent efficacy and safety can cut down the costs and hence increase patients’ access to the much-needed biological pharmaceuticals. Unlike for the conventional pharmaceuticals of small molecules, the complexity and heterogeneity of the molecular structure, complicated manufacturing process, different analytical methods, and possibility of severe immunogenicity reactions make evaluation of equivalence (similarity) between the biosimilar products and their corresponding innovator product a great challenge for both the scientific community and regulatory agencies. In this paper, we provide an overview of the current regulatory requirements for approval of biosimilar products. A review of current criteria for evaluation of bioequivalence for the traditional chemical generic products is provided. A detailed description of the differences between the biosimilar and chemical generic products is given with respect to size and structure, immunogenicity, product quality attributed, and manufacturing processes. In addition, statistical considerations including design criteria, fundamental biosimilar assumptions, and statistical methods are proposed. The possibility of using genomic data in evaluation of biosimilar products is also explored.15

A way forward for India

In today’s scenario, India needs to focus on quality of each biological product per se, whether that is demonstrated through comparability or by its own merit; and assurance of safety through appropriate regulatory review and approval of available data.

Irrespective of the authority entrusted to oversight of biologics, the debate on appropriate level of regulatory scrutiny for biologics will continue to focus on requiring adequate characterization while balancing cost, with the overall goal of having a much needed product on the market with reasonable assurance of efficacy and safety. Intense discussion on publication of appropriate monographs in the Indian Pharmacopeia and availability of reference standards continues amidst regulatory circles. Indian manufacturers have always sought to enter new markets and have voluntarily raised the bar in order to secure approvals for their products in the regulated markets where profit margins are high. From a facility infrastructure and systems point of view, most companies eyeing the regulated markets for their products will most likely fulfil expectations. State-of-the art analytical techniques are available within the industry. Therefore from a quality standpoint, biologic products made in India should not have any trouble in meeting market expectations. However, physicochemical characterization of a biologic product and compliant facilities form only one part of the evaluation required to demonstrate product comparability.

The practical way forward for approval of biosimilar products in India would have to be unique to the Indian context while staying rooted to scientific basics and keeping in mind the needs and limitations of the country. The large majority of biosimilars introduced in India would be products whose patents have expired and where the “original innovator” product may not be approved in the country. It is also possible that no patent exists in India for some products and therefore , originator and similars coexist. For all products, the question of available reference standards and monographs would continue to remain. The next wave of biologics of commercial interest to the industry will become a burning issue where the regulator cannot expect to wait to see how the legislation is crafted in the US or elsewhere before making a move.

In my opinion, it seems that India, having the benefit of in-house (in-country) expertise in the area, should utilize the various agencies currently entrusted with splintered tasks and responsibilities to come up with working group or taskforce whose goal is to develop product-specific guidelines for approval. These can be developed using available worldwide regulatory knowledge by signing appropriate MOUs if necessary, studying the scientific literature and current industry standards and practice with respect to characterization, focusing on specific areas of unique concern for each product and proposing an approval path. These guidelines can be widely disseminated in the community. There will still be grey areas that need clarification and in such cases, a system for formal meeting with members of the working group/taskforce can be instituted, similar to the scientific advice that is currently available through the EMEA or individual European country competent authorities.

As a nation that takes pride in being the “exporter to the world” in the arena of pharmaceuticals, it behooves not just the regulators but all those in the regulatory affairs profession in India to support such initiatives to make life-saving products available to our countrymen that are unquestionably of the highest standards in terms of quality, safety and efficacy such that we become the supplier of choice when it comes to exporting biosimilars to markets in every corner of the world.

Biosimilar therapeutics-what do we need to consider?

Patents for the first generation of approved biopharmaceuticals have either expired or are about to expire. Thus the market is opening for generic versions, referred to as ‘biosimilars’ (European Union) or ‘follow-on protein products’ (United States). Healthcare professionals need to understand the critical issues surrounding the use of biosimilars to make informed treatment decisions.The complex high-molecular-weight three-dimensional structures of biopharmaceuticals, their heterogeneity and dependence on production in living cells makes them different from classical chemical drugs. Current analytical methods cannot characterize these complex molecules sufficiently to confirm structural equivalence with reference molecules. Verification of the similarity of biosimilars to innovator biopharmaceuticals remains a key challenge. Furthermore, a critical safety issue, the immunogenicity of biopharmaceuticals, has been highlighted in recent years, confirming a need for comprehensive immunogenicity testing prior to approval and extended post-marketing surveillance.Biosimilars present a new set of challenges for regulatory authorities when compared with conventional generics. While the demonstration of a pharmacokinetic similarity is sufficient for conventional, small-molecule generic agents, a number of issues will make the approval of biosimilars more complicated. Documents recently published by the European Medicines Agency (EMEA) outlining requirements for the market approval of biosimilars provide much-needed guidance. The EMEA has approved a number of biosimilar products in a scientifically rigorous and balanced process. Outstanding issues include the interchangeability of biosimilars and innovator products, the possible need for unique naming to differentiate the various biopharmaceutical products, and more comprehensive labelling for biosimilars to include relevant clinical data. 5

Biosimilars: policy, clinical, and regulatory considerations.

The regulatory background surrounding biosimilars (biopharmaceuticals that are considered similar in composition to an innovator product, but not necessarily clinically interchangeable); equivalence, interchangeability, and unique considerations associated with biopharmaceuticals; the biopharmaceutical protein production process; scientific facts for use in the policy discussion about biosimilars; the European Union system for biosimilars; and the current status of biosimilars legislation in the United States are described.

An abbreviated regulatory pathway for the approval of biosimilars, and a process for safely demonstrating the therapeutic interchangeability of these proteins, has the potential to provide meaningful cost savings. This economic advantage to patients can translate into important public health benefits. But to date, no formal regulatory process exists in the United States for bringing these drugs to market. In addition, the current tools for fully characterizing biopharmaceuticals are not–in certain cases–well developed, especially for proteins that have complex structures or are heavily glycosylated. In addition, using “similar” but not completely “identical” proteins interchangeably raises concerns about potentiating immunogenicity. The bottom line is that demonstrating therapeutic equivalence and interchangeability for biosimilars is not a straightforward matter–it cannot be based on the same criteria as for conventional small-molecule drugs. The science, while obtainable, is more complex. For example, it is assumed that showing that a biosimilar protein can be safely used interchangeably with an innovator protein would require, at the least, some limited clinical data and interchangeability studies. Notwithstanding the more complex scientific and clinical issues particular to protein products, most believe that a process for enabling the approval of safe and effective biosimilar proteins is not only possible, but an important public health goal. The European Union system for biosimilars may provide a model for anticipating and resolving the scientific and policy issues related to biosimilars in the U.S. 

The legal and regulatory status of biosimilars remains to be resolved in the United States as policymakers address the scientific and policy issues surrounding product manufacturing, patent terms, and clinical use.

Biosimilars: it’s not as simple as cost alone.

Biosimilars or follow-on biologics (FoB) are biopharmaceuticals that, unlike small molecule generic products, are copies of larger, much more complex proteins. As such, data generated from one biopharmaceutical cannot be extrapolated to another. Unlike small molecule generics, FoB require a full developmental programme, albeit smaller than for an originator product. This has been recognized by European regulatory authorities and it is becoming clear that accelerated processes for FoB marketing approval are not feasible.

To determine the balance between costs surrounding FoB (including relatively extensive developmental programmes and subsequent price to the market) and the necessity to ensure efficacy and safety.

It is important that FoB are sufficiently tested to ensure patient safety is not compromised. Conducting such a development programme followed by sound pharmacovigilance is very challenging and costly.

Cost-savings associated with FoB may be limited. 10

Recommendations regarding technical standards for follow-on biologics: comparability, similarity, interchangeability.

Policy makers around the world are currently considering the creation of a regulatory pathway for follow-on biologics (FOB), which will have to account for the substantial technical challenges associated with FOB development. These challenges will likely involve more complexity than comparability assessments of process changes made by the same manufacturer. The history of industry-regulator comparability discussions helps explain why the same degree of testing and flexibility now applied to change-control within a manufacturer’s own process, at this time, cannot be extrapolated to the observed and possibly unknown differences between two manufacturing processes that are independently developed by different (non-collaborating) parties.

This commentary provides recommendations on the technical aspects that should be considered in the creation of an approval pathway for FOB products.

In the authors’ view, analytical methodology in its current state cannot alone provide full assurance that the FOB is sufficiently similar to the innovator product. Moreover, the FOB manufacturer will not have access to the extensive knowledge accumulated by the innovator manufacturer from early development through marketing. Thus, extensive clinical evaluation will likely be necessary to provide assurance that the FOB is safe and efficacious. If such testing demonstrates the FOB is safe and efficacious per existing regulatory standards, the product should receive marketing approval as a ‘similar’ product. Since ‘similarity’ is a fundamentally different determination than establishing interchangeability between the two products, an interchangeability determination must be based on additional testing and market experience to ensure patient safety. Post-marketing surveillance of the FOB should be conducted to ensure that the approved molecule has similar clinical safety and efficacy as the innovator product, prior to any consideration of interchangeability 11

European regulatory guidelines for biosimilars.

The impending arrival en masse of biosimilars on Western markets is placing drug regulatory agencies under pressure to realign their policies. Biosimilars require more rigorous assessments than traditional chemical generics. This is because of the molecular complexity of recombinant proteins, and the complexity of biological manufacturing processes. Small differences can arise in a recombinant protein product which are hard or impossible to detect with even state-of-the-art analytical techniques. Yet, these differences can have significant impact on the safety and efficacy of the drug. The European Medicines Agency (EMEA) has taken the lead in issuing guidelines, most of which are still under review. The guidelines advocate pre-clinical and clinical testing of biosimilars prior to market authorization, complemented by tailored pharmacovigilance plans. These guidelines provide a valuable base from which to develop in this evolving regulatory environment.12
Legislative initiatives in Europe, Canada and the US for market authorization of follow-on biologics.

The formulation and application of legal and regulatory requirements for the market authorization of follow-on versions of biological drugs present challenges. This review discusses relevant regulatory guidelines and legislative initiatives related to market authorization for follow-on biologics in Europe, Canada and the US. The respective positions of these three markets is analyzed with regard to several factors: criteria for the choice of reference products; requirements for the comparability exercise between a candidate follow-on biologic and the selected reference product, with an emphasis on considerations of quality, safety and efficacy data; the interchangeability of a reference product with related follow-on drugs; data exclusivity provisions; and the application of specialized patent enforcement mechanisms to follow-on biologics.13

Quality, safety and efficacy of follow-on biologics in Japan.

Recently, WHO, EU, Japan and Canada have published guidelines on biosimilar/follow-on biologics. While there seems to be no significant difference in the general concept in these guidelines, the data to be submitted for product approval are partially different. Differences have been noted in the requirements for comparability studies on stability, prerequisites for reference product, or for the need of comparability exercise for determination of process-related impurities. In Japan, there have been many discussions about the amount and extent of data for approval of follow-on biologics. We try to clarify the scientific background and rational for regulatory pathway of biosimilar/follow-on biologics in Japan in comparison with the guidelines available from WHO, EU and Canada. In this article, we address and discuss the scientific background underlying these differences to facilitate the harmonization of follow-on biologic principles in the guidelines in future.14



  1. excellent article, very comprehensive!! Great work Dr Anthony.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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