Biosimilar Markets and Regulation: Which Countries Are Going All In?

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The pipeline of follow-on (biosimilar and biobetter) products in development for the US, EU, and other major markets is very healthy. It includes nearly 800 biosimilars, about three-quarters of which are presumed to be targeted for major markets, and about 500 biobetters in development. Nearly 1,200 follow-on biopharmaceutical products in the development pipeline are intended to compete with more than 100 currently marketed biopharmaceuticals.

This is not just an opportunity in the Western world; biosimilars development is expanding globally. But defining which countries are “all in” strategically with biosimilars depends on what parameters define efforts and progress. Some parameters indicative of a country going “all-in” include the following:

  • Research and preclinical studies, including very expensive analytical studies of target innovator products (to define attributes of biosimilar versions)
  • Preclinical studies and development
  • Clinical trials, accompanied by initial scale-up and process optimization
  • Approval application filings (the number of pending applications)
  • Number of approved products and those that are actually marketed in key markets (instead of being held up, e.g., for resolution of patent issues)
  • Product manufacturing capacity (number of facilities and how much product they can make) and output (how much is actually being made)
  • Imports and exports (whether biosimilars used in a given country are made there or imported)
  • Product revenue (total sales of biosimilars by country) and total profits (whether for domestic or foreign markets, which segments are profiting)
  • Extent of discounts on biosimilar/biogeneric prices relative to reference products (a measure of the benefits to a country’s patients and third-party payers)
  • Extent of governmental involvement, including industry coordination and company funding.

Further, it is important to define the difference between how “biosimilars” are defined for sale in US, EU, and other developed markets compared with those for emerging markets. Some products are on track for approval in major highly regulated markets (e.g., United States and European Union) and are manufactured to good manufacturing practice (GMP) standards, with extensive biosimilarity analytical studies and comparative clinical trials. Other products may be called biosimilars — or similar terms, such as “similar biologics” in India — and those in lesser- and nonregulated international markets are generally classed as biogenerics. Such products generally are not manufactured to the GMP standards of highly regulated countries and lack the documented similarity of extensive biosimilarity analytical studies and comparative clinical trials.

BioPlan Associates has developed unique information resources for comparing biosimilars in different countries: the Biosimilars/Biobetters Pipeline Directory database tracking biosimilar/biogeneric products in research and development (R&D) and marketing (1); the Top 1,000 Global Biopharmaceutical Manufacturing Facilities Index ranking >1,000 bioprocessing facilities worldwide (2); and directories of biopharmaceutical manufacturing facilities in China and India (3, 4).

Overall, the European Union is clearly leading in biosimilar progress, with Germany the leader among EU countries. Europe is where the majority of R&D, clinical testing, applications, approvals, marketed products, manufacturing, product revenue, and profits are currently, all related to genuine biosimilars. It was the first region to develop rigorous guidelines and rack up biosimilar approvals, with more than 20 products on the market now. Other major-market countries lag behind in genuine biosimilar approvals (e.g., only four approved in the United States). Meanwhile, a large number of lesser- or simply nonregulated developing countries consume a large number of biogenerics manufactured in diverse locales worldwide, with suppliers in China and India serving as prominent sources.

Biosimilar activities (development, manufacturing, marketing, and so on) are and will be rapidly increasing in the near term in North America, with the United States running about a decade behind Europe. But the United States will be seeing the most dramatic increase in available biosimilars as most developers increasingly target that market, including favoring market development there above other territories, so it is expected to be the largest and most profitable and competitive biosimilars market (5). The United States already is seeing a few mostly big (bio) pharmaceutical companies pushing to be first to market with biosimilar products. Others are content to let those leaders take the brunt of working things out with the FDA: gaining approvals, being first to market, and setting prices/discounts. In particular, many are depending on big companies to resolve or provide better clarity concerning biosimilars-related patent disputes.

In terms of biosimilar (not biogeneric) research programs and products in the development pipeline, the United States is catching up or overtaking Europe quickly while remaining the largest yet underdeveloped market. EU uptake and market growth of biosimilars is slower than most people expected, whereas the US market is likely to offer higher profit margins. For example, the pipeline database currently reports a comparable number of biosimilar products in the pipeline (Table 1) indexed to companies based in Europe (205) and the United States (224) (1).

Compared with European countries, the United States remains a less regulated market, however, lacking the government controls of price/distribution common in Europe (and most other countries around the world). And in terms of biosimilar approvals and marketed products so far, the European Union remains in the clear lead. Table 1 lists the total numbers of biosimilar product entries in the pipeline database by the country where the manufacturing country is based (where control resides).

In terms of technologies used for biosimilar and biogeneric manufacturing, the United States and Europe also lead, paralleling their overall dominance in biopharmaceuticals manufacturing and innovation. Use of the best-available and most cost-effective bioprocessing technologies and equipment is the general approach for most biosimilar (and many biogenerics) developers. They need low-cost and flexible manufacturing simply to compete with other biosimilars and with legacy reference and biobetter products (6).

FDA Biosimilars and Biologics Nomenclature: Problems Remain
Biosimilars eventually will outnumber innovative products in the US market, with multiple biosimilars expected for most candidate reference products (1). But the FDA continues to move at a slow pace in terms of regulating these products. It has taken over a decade to issue regulations for biosimilar nomenclature. The agency provided a weak compromise involving current names to be somewhat more unique; it did not, however, develop a system suited to provide unique and (bio)generic names for biopharmaceutical products or active agents. Proper names are nonproprietary, freely usable, unchanging names adopted to broadly identify closely related finished biologic products in commerce. Other than their use for marketing and prescription designation, proper names are neither sufficiently unique nor (bio)generic enough for most other purposes, including scientific-technical communications. They also are not associated with definitions/descriptions of what they identify.

The FDA has finally ruled on proper names, creating a divisive issue among those with vested interests in US biosimilars market development (26). The agency has modified its previous proper naming based on the International Nonproprietary Nomenclature (INN) and US Adopted Name (USAN) systems, now appending random four-letter suffixes that identify the biologics license holder to the same problematic USAN/INN names it has used for decades as biologic proper names. This regime does not provide the specificity and actual unique names many need for identifying products.

Committees within the World Health Organization (WHO) and United Nations (UN) select nonproprietary generic INN names for biologics drug substances (active agents). Those almost always are adopted as USAN generic names for the active agents. Then, the FDA rules whether those are to be adopted in the United States as a basis for proper names identifying their related specific finished products. So generic names for biologic active agents form the basis of proper names for finished products, with a modifier for the holder of the biologics license application (BLA). Related to that, it is common practice (derived from generic drugs) for INN/USAN and proper names to be used for both products and active agents. Adding suffixes causes other problems, from looking up and keeping track of them to determining name-based (dis)similarities between US and foreign-distributed products.

FDA has not addressed other nomenclature issues that could cause industry problems: e.g., the lack of names for active agents/drug substances. In fact, no nomenclature systems exist for either unique or (bio)generic names/identifiers either for products or their drug substances (active agents). Related to that, in recent approvals-related documents the agency also has stopped referring to biologics’ active agents by name (7).

For example, Zarxio (filgrastim-sndz) from Sandoz (Novartis) was the first US biosimilar approval. Its product insert does not cite the active agent/drug substance other than to say, “ZARXIO (filgrastim-sndz) is a 175 amino acid human granulocyte colony-stimulating factor (G-CSF) . . . ZARXIO is produced by Escherichia coli (E. coli) bacteria.” But the finished product (tradename = Zarxio; current proper name = filgrastim-sndz) is a complex formulation, not just a G-CSF-class recombinant protein (the active agent). The active agent in filgrastim-sndz is not defined as “filgrastim,” which is the internationally-recognized (INN, USAN, etc.) generic name for all G-CSF–containing products and used extensively by the FDA. Nor is the active agent never cited as N-methionyl-granulocyte colony-stimulating factor, or some other more science-based name, with the FDA simplifying that to “G-CSF.”

If current FDA/INN/USAN biologic-naming conventions are followed, proper names for products also will be used as active-agent names, with significant ambiguity. This may be tolerable with generic drugs, but it is not suitable for biologics. So we now have some rules for official proper names but still lack genuinely unique and (bio)generic names for products or active agents.

Further, in recent years the FDA has stopped disclosing informative definitions or descriptions of what biologic products and their active agents are. There have been no top-level descriptions of the most basic bioprocessing or other chemistry, manufacturing, and controls (CMC) aspects that define each biologic (7). For some products, not even the expression system’s host organism genus (much less species or strain) is identified. Official proper (and any other) names/identifiers for biologics defined by complex manufacturing are not useful without information about what those names/identifiers refer to. That would include clarifying when a product/agent becomes a new/different one or otherwise requires a new name/identifier.

Proper names serve some marketing and prescription needs but are ill-suited for others, including technical communications (for which they are neither unique nor generic enough). These deficiencies will pose problems for the industry. For biosimilars, such names do not describe what’s unique about each product, and needed names/identifiers and information are unavailable. Further complications will come from the FDA assigning proper names based on BLAs rather than a product or active agent, which can apply to multiple products. For example, Amgen’s Epogen and Janssen’s Procrit recombinant epoeitin alfa products are blockbusters marketed by different companies but have the same singular BLA. So will they be assigned the same or different names (suffixes)? More complications will come when the agency assigns new proper names to interchangeable, authorized biologics and deals with names for cellular and gene therapies, alternative antibody structures, and other new product classes. Even more problems are foreseeable if the FDA deals with needs for reporting excursions in product attributes relevant to public health (8).

Next steps regarding biologics names/identifiers could involve an industry-grounded committee providing ingredient names and definitions to the agency, much as the cosmetic industry has been doing for over 40 years. In our work tracking biopharmaceutical and biosimilar products (9, 10), we have documented how the FDA and preceding regulatory agencies (e.g., the National Institutes of Health, NIH) have failed to assign unique names to biologic products for the over a century.

References
1
Rader RA. An Analysis of the US Biosimilars Development Pipeline and Likely Market Evolution. BioProcess Int. 11(6) 2013: S16–S23.

2 CDER/CBER. Nonproprietary Naming of Biological Products: Guidance for Industry. US Food and Drug Administration: Rockville, MD, January 2017.

3 Rader RA. Nomenclature of Biosimilars Will Be Highly Controversial. BioProcess Int. 9(6) 2011: 26–33.

4 Rader RA. What Is a Generic Biopharmaceutical? Biogeneric? Follow-On Protein? Biosimilar? Follow-On Biologic? Part 1: Introduction and Basic Paradigms. BioProcess Int. 5(3) 2007: 28–38.

5 Rader RA. What Is a Generic Biopharmaceutical? Biogeneric? Follow-On Protein? Biosimilar? Follow-On Biologic? Part 2: Information, Nomenclature, Perceptions, and the Market. BioProcess Int. 5(5) 2007: 20–28.

6 Rader RA. Biopharmaceuticals: Lack of Information Disclosure Confounds Public Trust, Particularly in the Context of Biosimilars. BioWorld Perspectives 2(18) 2008.

7 Rader RA. Biologics Nomenclature and Public Information: Suitably Descriptive Names/Identifiers and Public Disclosures Are Needed. Citizen Petition 21 July 2013, www.biopharma.com/biopharmacopeia/petition.pdf.

8 Ramanan S, Grampp G. Drift, Evolution, and Divergence in Biologics and Biosimilars Manufacturing. BioDrugs 28(4) 2014: 363–372; doi:10.1007/s40259-014-0088-z.

9 Rader RA. Biopharma: Biopharmaceutical Products in the US and European Markets (database). BioPlan Associates: Rockville, MD, 2017; www.biopharma.com.

10 Rader RA. Biosimilars/Biobetters Pipeline Directory (database). BioPlan Associates: Rockville, MD, 2017; www.biosimilarspipeline.com.

Important Biosimilars Regions
Among up-and-coming countries and regions pursuing the most aggressive biosimilar development and manufacturing, South Korea deserves mention, particularly for Samsung Biologics and Celltrion. Noting their new, state-of-the-art, supersized facilities (e.g., Samsung with >300,000 L of total bioreactor capacity), BioPlan studies have shown that those companies are now attaining the lowest estimated costs for biosimilar MAb manufacturing — ≤$100/g — whereas most others struggle (and are happy to) attain multiples of that (e.g., <$300–500/g). With their dominant manufacturing capabilities, both companies are developing their own portfolios of biosimilars for worldwide marketing in addition to partnering and contract manufacturing with others. They also are developing and will be commercially manufacturing biosimilars for other companies.

Biosimilar approvals aren’t always followed immediately by product launches. Particularly in the United States, only one of four approved biosimilars is on the market. Launch of the others currently is held up for resolution of related patent disputes. When it comes to expected patent disputes and related disruptions of development pipelines — e.g., as has happened with Enbrel (etanercept) — the United States is leading because it provides more patent-protection options than other countries. For example, US process patents are strictly enforceable, unlike those in most other countries. It is still too early to make conclusions about the extent to which patent challenges will succeed in keeping biosimilars off the US or other major markets.

Based on devoted capacity and product output volume, Europe currently leads in biosimilar manufacturing. Much production for the United States and other major, non-EU markets will continue to happen there (primarily by EU-based companies). But US biosimilar manufacturing is likely to catch up over the next five years as many more biosimilars and players enter its market.

India currently leads the rest of the world for current and upcoming biogenerics and intends to graduate into biosimilar products. China is rapidly catching up and expected to surpass it over the next 5–10 years. Recent BioPlan Associates studies show that China has now largely caught up with India in capacity (total bioreactor volume), but it is growing much more rapidly as many new biogeneric (and some genuine biosimilar) developers enter the field (2, 3). These and most other developing countries are involved with biogenerics primarily over biosimilars, which are harder to develop and manufacture. Both India and China have large domestic markets satisfied by domestically manufactured biogenerics that generally are not manufactured to US- and EU-level GMP standards and aren’t subject to rigorous analytical and clinical studies. Biosimilar manufacturing will grow rapidly in China, India, and other Asian and developing countries if only just to serve their own large markets.

Nearly all (>90%) biosimilar/biogeneric products currently under development in developing countries are biogeneric rather than genuine biosimilars. India and China are the current leaders in biogenerics. The former’s “similar biologics” development is slowing in numbers of new players and capacity expansions, which are much higher in the latter. Chinese biopharmaceutical companies also are more aligned toward bringing biosimilars (and innovative biopharmaceuticals) to Western markets. Compared with India, China has better infrastructure (electricity, water, waste treatment, and so on). The Chinese government is much more involved than its Indian counterpart, including centralized planning and even government investment. China is addressing its own business-culture–based quality issues, and it is a more “open” market (India has more pharmaceutical price controls). So China is on track to surpass India in biogenerics (and eventually biosimilars), beginning with addressing its own domestic market needs.

So far, China has attained its position as a manufacturer of many biogenerics for domestic and export markets without much involvement by Western biopharmaceutical companies — and notably, without any real contract manufacturing industry. Only recently has the country implemented a trial program to allow third-party manufacturing of biopharmaceuticals. Its own current contract manufacturing organizations (CMOs such as WuXi) possess the most bioprocessing capacity there, whether for R&D or making products for export. Once Chinese regulations allow domestic companies to use CMOs for clinical and commercial manufacturing, we should see the Chinese CMO sector and its activities (primarily biogenerics/biosimilars development) expand rapidly. That is likely to include many current major-market CMOs (e.g., Boehringer Ingelheim) partnering or themselves developing commercial manufacturing-capable facilities in China.

By contrast, successful Indian (bio)pharmaceutical companies (primarily those involved in generic drug fill–finish) prefer to invest in building and acquiring capacity/facilities in the United States and other major markets. Eventually, it seems likely that China will become a world leader in biogenerics and a serious contender for genuine biosimilars. Many other countries are making concerted “all in” efforts to develop a domestic biosimilars industry, often starting with biogenerics. But the overall current and likely future leaders include the European Union, United States, South Korea, China, and India.

References
1
Rader RA. Biosimilars/Biobetters Pipeline Directory (database). BioPlan Associates: Rockville, MD, 2017; www.biosimilarspipeline.com.

2 Top 1,000 Global Biopharmaceutical Manufacturing Facilities Index (database). BioPlan Associates: Rockville, MD, 2017; www.top1000bio.com.

3 Top 60 Biopharmaceutical Manufacturing Facilities in China. BioPlan Associates, Inc.: Rockville, MD, February 2017; www.bioplanassociates.com.

4 Langer ES, et al. Directory of Top 60 Biopharmaceutical Manufacturers in India (database). BioPlan Associates: Rockville, MD, September 2008.

5 Rader RA. An Analysis of the US Biosimilars Development Pipeline and Likely Market Evolution. BioProcess Int. 11(6) 2013: S16–S23.

6 Rader RA, Langer ES. Future Manufacturing Strategies for Biosimilars. BioProcess Int. 14(5) 2016: S26–S29.

Ronald A. Rader is senior director of technical research at BioPlan Associates, as well as editor/publisher of the Biosimilars/Biobetters Pipeline Directory and Biopharmaceutical Products in the US and European Markets; 2275 Research Boulevard, Suite 500, Rockville, MD 20850; 1-301-921-5979 info@bioplanassociates.com.

 

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