Gillian Woollett

 Biosimilars Development Raises Research Questions

 FDA, Sponsors Gear Up for User-Fee Action

 Risk & Resources to Shape Trial Operations

Biological medicines (biologics) are drugs derived from living cells. They have been used in medicine for centuries. With the advent of recombinant DNA technology in the late 1970s and early 1980s, recombinant human therapeutic proteins emerged as a new source of biological medicines in the necessary amounts for routine therapy. Before that, therapeutic proteins such as insulin, somatropin, interferons, and blood factors could only be sourced from animal tissues, human body fluids, or cadavers. In some cases, such as epoetin and colony stimulating factors (G-CSFs), recombinant DNA technology made it possible to produce these medicines for the first time. Monoclonal antibodies derived from mice hybridoma cells were first developed in 1975, but failed as therapeutic proteins due to their excessive immunogenicity given that they were essentially mouse xenoproteins. In the 1990s, the first chimeric and humanized recombinant monoclonal antibodies, such as rituximab, infliximab, and trastuzumab, became available. Since then, the number of approved recombinant therapeutic proteins has expanded greatly, and many of these products soon reached blockbuster status. Today's global sales of recombinant therapeutic proteins are above $130 billion, and these sales are expected to grow at least twice as fast as those of small molecule drugs. It is anticipated that by 2016, eight of the top-10 selling drugs will be recombinant proteins—of these, five (Humira® , Avastin® , Rituxan® , Prolia® , and Remicade® ) are monoclonal antibodies, and one (Enbrel® ) is a fusion protein containing antibody components. The others are hormones (Lantus® , Epogen® /Procrit® ). The key patents protecting many of the recombinant human proteins already have (EU), or soon will (US) expire, and from 2013, the first monoclonal antibodies will start losing their patent protection. 

Biosimilars represent a slowly emerging, but steadily growing new field of pharmaceutical biotechnology, analytical development, and clinical research. Their development requires a fundamentally different approach to that used for originator biopharmaceuticals, and analytical design becomes particularly critical. Meanwhile, regulatory authorities are working in each of their jurisdictions, but also collectively worldwide, on the development of guidance documents for biosimilar medicines. However, despite the recognition of the need for global harmonization of pharmaceutical standards, at least three different approaches for the development of biosimilars are observable (Figure 1). In the following discussion, each of these approaches will be reviewed in the context of an evolving global biosimilar market.  

Europe was the first highly regulated region where patents for recombinant protein drugs started to expire from 2000 on. The European Union (EU) has been in the forefront of biosimilar regulation since 2001, when the revisions to the EU laws governing pharmaceuticals created a pathway for the approval of biosimilar versions of biologics. The European Medical Evaluation Agency (then known as EMEA, now EMA) began soon after with the issuance of three over-arching biosimilar guidelines,

  describing general requirements; quality; and non-clinical and clinical development, before they then issued product class specific guidelines for the non-clinical and clinical data requirement for insulin, somatropin, epoetin, G-CSF, interferon-alfa, and LMWH (Table 1). Many EU biosimilar guidelines including the Guideline on Similar Biological Medicinal Products, the Guideline on Non-clinical and Clinical Issues, and the Guideline on Quality Issues are currently under revision to integrate and update the documents based on the experience gained with the approval of the first biosimilars in the European Union (Table 2). Furthermore, draft guidelines for interferon beta, Follicle Stimulation Hormone, and biosimilar monoclonal antibodies have been published and the public comments received are now under review. Based on the successful experiences with the biosimilar regulations in the European Union, other highly regulated markets such as Japan, Canada, and Australia have adopted similar approaches, and approval of a biosimilar based on an EU biosimilar data set and, in some cases, dossier in these countries would require only limited additional efforts. 

Figure 1. Europe has been leading the way in biosimilar standards since 2001. 

First and foremost, a biosimilar is a biologic. As such, biosimilar medicines in the European Union must be manufactured following the same quality standards as for all other medicines (e.g., compliance with EU/ICH guidelines for process development and analytics, GMP, GLP, and GCP). EU regulatory authorities also perform regular inspections of the manufacturing sites. A biosimilar, according to the EU definition, is a medicine which is similar to a biologic that has already been authorized in the European Union. The active substance must be similar to the one in the reference biologic. Studies comparing the biosimilar and the reference product have to be carried out systematically in a step-by-step manner, starting with a comparison of the quality of the two products, both at the active substance and at the drug product level. The submission for marketing approval of a biosimilar requires a complete, standalone CMC package as described by Module 3 of the Common Technical Document (CTD). This includes an extensive analytical characterization of the active substance and the drug product. General test procedures and acceptance criteria for characterization and quality control of biopharmaceuticals are described in ICH Q6B.

  In addition, the so-called comparability exercise

 —a data package that is included in a separate chapter of the filing—has to be provided on top of the characterization studies. The importance of the quality comparability exercise cannot be overstated. It builds the backbone of each comparability-based regulatory submission. A successful CMC comparability exercise, demonstrating that the two products are comparable (or in US terminology highly similar), can provide the basis for a significantly reduced pre-clinical and clinical testing program (Figure 2) (this is yet to be confirmed in the United States but is fundamental to the concept of an abbreviated pathway and therefore will always be necessary even if not sufficient). Based on the CMC comparability exercise, a hypothesis is generated that the two products are similar, and it is therefore not necessary to repeat the full preclinical and clinical program of the reference biologic. The FDA has expressed this in terms of it not being necessary for the biosimilar sponsor to re-establish the safety, purity, and potency of the active moiety, but just to confirm biosimilarity, and indeed this is specified in the US Statute.

  The CMC comparability exercise also forms a cornerstone for extrapolation between indications; in this case the indications must share the same mechanism-of-action. 

Table 1. The EMA began its biosimilar regulations with general requirements, quality, and non-clinical and clinical development standards, before issuing product class specific guidelines. 

 Every biologic medicine has a certain degree of batch-to-batch variability. The active ingredients of recombinant protein drugs are produced in a complex multi-step process, including culture of living cells, protein purification, formulation, storage, and distribution. The degree of protein heterogeneity depends on the cell culture manufacturing process, stability, storage, and transport conditions of the biologic drug, as well as the nature of the active biologic moiety itself. Schiestl et al.

 have recently shown analytical data on the acceptable levels of batch-to-batch variability within originator batches of Aranesp® , Rituximab® , and Enbrel® . It is the aim of the quality CMC comparability exercise to demonstrate that the degree of heterogeneity is not significantly different between the biosimilar and the reference biologic. However, it is not expected that the two products are identical. Minor differences are acceptable, if justification can be provided, that these differences have no influence on the clinical activity (safety and efficacy in Europe; safety, purity, and potency in the United States). Justification of minor differences may rely on supplementary biophysical, or in-vitro studies; for some differences, it may require specifically designed in-vivo, toxicology, pharmacokinetic (PK)/ pharmacodynamic (PD) or clinical studies.  

Table 2. The biosimiliar guidelines are under revision in 2012. 

Generally, a physicochemical comparability program will include a determination of the primary structure, composition, and physical properties of the two products. The amino acid sequence should be confirmed by appropriate methods. The variability of N- and C- terminal amino-acid sequences should be analyzed. Free sulphydryl groups and disulfide bridge integrity should be described. The distribution and structure of the glycan structures should be determined. Higher-order structure, biophysical, and biological properties of the products should be characterized by appropriate methodologies. For monoclonal antibodies, antigen binding, epitope specificity, binding to Fc receptors, and complement factors should be evaluated. Finally, a battery of in-vitro potency assays (e.g., tests for ADCC, CDC, and apoptosis), should complement the physicochemical and biophysical comparability exercise. Table 3 shows frequently employed methods for higher-order structure and in-vitro pharmacology. 

Figure 2. It has become expected that for biosimilarity and extrapolation the mechanism of action must be known. 

The comparability exercise should be conducted as a head-to-head comparison of the two products, namely the biosimilar and the originator reference, if the performance of the assays allows it. Some of the highly sophisticated analytical methods may only be applicable to the purified active ingredient, since the non-active constituents of the formulation may interfere with the assay. The revised version of the over arching EU biosimilar quality guideline will also provide guidance on this topic.  

Table 3. Frequently employed methods for higher-order structure and in-vitro pharmacology. 

 Results from the physicochemical, biophysical, and in-vitro biological comparability studies should be reviewed for potential impact on efficacy and safety. If animal studies are determined to be necessary for further confirmation of biosimilarity, such studies should be performed in a relevant species. Where possible, PK and/or PD effects relevant to the clinical application should be investigated. At least one repeat dose toxicity study, including toxicokinetic measurements and determination of antibody titers, including cross reactivity and neutralizing capacity, should be performed. Toxicity of monoclonal antibodies is mainly target related. For a biosimilar monoclonal antibody, it may be acceptable to perform the toxicity study as a single arm, non-comparative, one gender study. This topic will be further addressed in the final biosimilar monoclonal antibody guideline. Local tolerance can be addressed in the same repeat dose toxicity study. Other routine toxicological studies, which are normally required for the development of a novel biologic, such as safety pharmacology, reproduction toxicology, mutagenicity, and carcinogenicity studies are not required for similar biological medicinal products in the European Union. 

 A clinical comparability exercise has been expected for European biosimilars to date, but the extent of the data required has varied considerably even for biosimilars made by different sponsors to the same reference product.

  These studies should begin with PK and PD studies followed by clinical efficacy and safety trial(s) or, when validated surrogate parameters for clinical endpoints are available, PK/PD studies for demonstrating clinical comparability. Dose finding studies are generally not required for biosimilars. In certain cases, where validated surrogate PD parameters exist, comparative PK/PD studies between the similar biological medicinal product and the reference medicinal product may be sufficient to demonstrate clinical comparability. According to the EU product specific biosimilar guidelines, the case for insulin and filgrastim, and indeed a biosimilar filgrastim, has been approved on this basis. The European Union has yet to approve a biosimilar insulin. Clinical comparability margins should be predefined and justified based on ICH topic E10.

 For a biosimilar and the reference biologic, the same dose needs to result in the same effect, and in many cases not only a lower margin but also an upper margin for the equivalence studies needs to be defined. One big advantage of pursuing the development of a biosimilar over a standalone biologic in the European Union is the opportunity to extrapolate to other indications. For a biosimilar, it is not necessary to demonstrate comparable safety and efficacy in every indication. The sponsor of a biosimilar development program should carefully select the indication, patient population, and dosing regimens for the pivotal Phase III study. These parameters need to be based on sensitivity for expected side effects and potential dose-efficacy differences, and regulators will likely require this justification by the sponsor. Based on the demonstration of comparable safety and efficacy in a carefully designed pivotal Phase III trial, other indications of the reference biologic can be approved if they share the same mechanism of action (Figure 2). Unlike the use of comparability for the support of manufacturing changes where the mechanism of action does not need to be known for extrapolation between indications, it has become expected that for biosimilarity and extrapolation, the MOA must be known. This is one area where the use of the same standard does not apply in Europe to all biologics, and likely will not in the United States either. Immunogenicity has been a major concern for all protein drugs, irrespective of whether they are originator or biosimilar, and at least 12-month immunogenicity data will be required pre-authorization for most chronically administered biosimilars. Traditionally, these studies have not had to be repeated after manufacturing changes, even though the most oft-cited case of an immunogenicity problem

One outstanding issue recognized as critical in all the highly regulated markets is the challenge facing biosimilar sponsors: the appropriate choice of the reference product. Each biosimilar law only applies to the jurisdiction for which it is written. The way most are configured states that the reference product has to have been approved in the same jurisdiction to be available as a reference for a biosimilar. And it is the label on the product that determines its approval status, rather than what is in the vial itself. Thus many of the head-to-head studies expected for a biosimilar may have to be repeated with locally-labeled reference product (even if the source of all the reference product in the world is a single factory). It is not clear how this will be managed and whether the bridging of reference products in dossiers for different jurisdictions will be allowed, which would enable a single global development program for a biosimilar. Absent some resolution, the need to repeat studies will hamper any economies of scale otherwise expected for the biosimilar. Given that originator products can now be developed for a global market, this would be particularly unfortunate. 

Risk management program and pharmacovigilance. 

As required in general for all recombinant protein drugs, the sponsor should provide a risk management program (RMP) and pharmacovigilance plan at the time of submission of a biosimilar marketing authorization dossier, in accordance with current EU legislation and pharmacovigilance guidelines. Any specific risk identified during development of the biosimilar must be taken into account. In the case where specific safety monitoring is required for the reference product or class, this must be considered also for the biosimilar. In many cases, at least one Phase IV study will be part of the RMP. 

Experience with EU biosimilar approvals. 

Omnitrope®  (somatotropin) was the first biosimilar recombinant protein approved in the European Union in 2006. The first biosimilar glycoprotein was epoetin alfa, approved in 2007, it is marketed under three names: Binocrit® , Epoetin alfa Hexal® , and Abseamed® . Just as is the case for small molecule generics, biosimilar companies submitted multiple applications with different names for one development program. In the future, only one marketing authorization per development program will be allowed per company. So far, 10 different development programs for somatropin, epoetin, filgrastim, and insulin have been submitted to the EMA, comprising 19 product names. Seven programs have been approved (Table 4). Two applications (interferon alfa and interferon beta 1a) have been rejected, and two other applications (insulin and epoetin alfa) have been withdrawn. This suggests that the same rigorous standards are applied to biosimilars and originator biologics, and there is no reason to expect any difference in the quality of a biosimilar and an originator biologic. Five biosimilar marketing authorization applications are currently under review (three human insulin, one follitropin alfa, and one infliximab). 

Table 4. Biosimilar development programs submitted for marketing approval at EMA. 

While the scientific principles are universal, and the United States led with the development of comparability, implemented by guidance in 1996 (neither statutes nor regulations being considered necessary at the time), the FDA waited for formal legislation before allowing biosimilars to be considered for the majority of biologic products approved in the United States. The terminology used in the US legislation, BPCIA enacted March 23, 2010, is "highly similar,"

 which is a perfect match for the definition of comparable in ICH Q5E.

  (Table 5). Nonetheless, many stakeholders expect a substantial public process to ensue before FDA approves biosimilars, or interchangeable biosimilars. This is even though neither regulations nor new guidances are required by the statute, and biosimilar applications could have been filed from the day of enactment. FDA has been given a unique authority by Congress, in having the ability to designate biosimilars as interchangeable with their reference product. This occurs nowhere else in the world. For instance, in Europe, while comparability is the standard used to establish biosimilarity, the final marketing authorization is silent on the interchangeability of a biosimilar with its reference product (albeit the EPAR says that the active ingredient in each product is similar that in its reference). 

Table 5. Comparable and biosimilar are the same as a matter of science. 

FDA held a public meeting in November 2010 to hear stakeholder opinions on how they should implement BPCIA, has subsequently received many written comments to the docket, and has initiated a formal public process concerning biosimilar user fees

  which has recently passed Congress. The agency published its scientific principles for biosimilars in August 2011

  and eventually released three draft guideline documents on February 9, 2012 (Table 6) which are currently under stakeholder discussion. Although it is not expected that the US guidelines will exactly match the EU biosimilars system, the scientific foundations will be the same. This has already been the case in the FDA's approval of subsequent versions of those biologic drugs that happen to have been approved under the Federal Food Drug & Cosmetic Act as opposed to the Public Health Service Act. 

Table 6. FDA draft guidance on biosimilar product development, February 9, 2012. 

Only about 15% of the world population lives in highly regulated countries, while 85% live in less- or un-regulated countries. To increase the access to affordable, safe, and effective biological medicines in all countries is therefore of utmost importance. Emerging countries, such as Brazil, Russia, Korea, India, and China have defined local requirements for development and manufacturing of follow-on versions of biologics. These jurisdictions address the unmet medical need in each of these countries, but they are not biosimilars according to the standards in highly regulated markets. For these products, the term "alternative biologics" have been used.

  Each is developed with a specific structure and function in mind to the standards of that country, but not based on a thorough comparison to a specific individual product already approved in that country. Also, the stringent ICH development guidelines and GLP and GMP requirements of the highly regulated markets are not a basis of marketing approval. Cost of development for such alternative biologics may be less than 10% of the development costs for a biosimilar in the highly regulated markets. Also, the development timelines are much shorter. This has raised some questions as to the level of comparability between an alternative biologic and an innovator reference biologic. Several alternative recombinant erythropoietins manufactured in Asia analyzed with isoelectric focusing gels were not comparable with recombinant erythropoietin preparations licensed in the EU.

  This is unlike approved EU biosimilars, which are highly similar to a specific identified originator reference marketed in that same jurisdiction.

It can be expected that many more emerging countries will soon issue country-specific biosimilar guidelines. India has specific guidance documents for generics, but these do not apply for alternate biologics. In the past, these products were approved in India on a case-by-case basis, and clinical studies for biologics required only a limited number of patients; Phase I and Phase II trials were typically not required. The Department of Biotechnology approves protocols up to animal toxicity studies, and the Drug Controller General of India approves clinical trials and final product for marketing. The Indian Food and Drug Control Administration issues the manufacturing license based on a local GMP audit.  

The World Health Organization (WHO), while not a formal regulatory authority, in October 2009 created a guideline on similar biotherapeutic products that will raise the standards for alternative biologics in the emerging markets.

  However, although the standards are largely derived from biosimilar guidelines in the European Union, Australia, Canada, and Japan, this WHO standard alone will not be sufficient to achieve a biosimilar approval in highly regulated markets. Nonetheless, companies from emerging countries may soon reach the standard of the highly regulated markets, as for instance some companies from Korea and India have recently formed alliances with US pharma companies for the development of global biosimilars. 

It is anticipated that by 2016, eight of the top-10 selling drugs will be recombinant proteins. The size of the current global market for recombinant proteins is more than $130 billion. With the loss of patent protection for most of these products starting in 2013, the development of follow-on versions of recombinant proteins, so called biosimilars, becomes a steadily growing new field of biopharmaceutical development and clinical research. In contrast to small molecule generics, pre-clinical and clinical studies will be required for most biosimilars. The biosimilar regulations are currently evolving in Europe, the United States, and in many emerging countries. For the successful development and commercialization of biosimilars in a global market, it will be important to understand the specific requirements for clinical development of biosimilars in these regions—where they are the same and especially where they differ. Clinical development managers will also need to understand the concepts of quality CMC comparability, the value of in-vitro pharmacology, and non-clinical studies, since this will form the basis for each biosimilar clinical development program. 

PhD, is Owner and Managing Director of Brockmeyer Biopharma GmbH, Luetjen Feldsweg 28, 37081 Goettingen, Germany, e-mail: 

 MA, Vice President, FDA Regulatory Strategy and Policy at Avalere Health.

*To whom all correspondence should be addressed. 

1. European Medicines Agency, "Multidisciplinary: Biosimilar," 

2. International Conference On Harmonization, "Specifications: Test Procedures and Acceptance Criteria for Biotechnical/Biological," (1999), 

3. International Conference On Harmonization, Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process," (2004),  

4. One Hundred Eleventh Congress of the United States of America, "The Patient Protection and Affordable Care Act (PPACA),"  (2010) 

5. M. Schiestl et al., "Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals," 

6. European Medicines Agency, "European Public Assessment Reports,"  

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