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

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:

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).

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 [email protected].