What To Know About Emerging Market Biosimilar Pathways

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

The keynote of the World Biosimilar Congress in San Diego last month was, perhaps surprisingly, not focused on the developing U.S. regulatory pathway or the potential for this market. Rather, it homed in on the emerging markets (i.e., Brazil, Russia, India, China, Mexico, Turkey, Southeast Asia, and Africa). According to the keynote presenter, Jay Kothari of Zydus Cadila, the emerging markets are a powerful tool to leverage in order to build a successful biosimilar portfolio. According to Kothari, products developed in emerging markets are poised to earn positive cash flow by 2019. Compare this to developed nations, in which companies will need to invest heavily through 2020 before finally earning profits in 2021.  

But when it comes to working in these emerging markets, there are a number of regulatory challenges a company will encounter when putting together a dossier for market approval. Dr. Elliot Morales, senior director, regulatory affairs, Dr. Reddy’s Laboratories, presented a thorough and interesting presentation on some of the specific challenges Dr. Reddy’s has faced in the emerging markets.

Follow The Yellow Brick Road — If You Can

A majority of emerging markets have regulatory pathways for biosimilars based around the same structure and framework that WHO has established. “The pathways have a common theme,” Morales said. “They emphasize the reduction of residual uncertainty in a stepwise approach to establishing biosimilarity.” In other words, a biosimilar maker is responsible for performing the physiochemical and biological characterization and nonclinical studies, followed by clinical evaluations to determine biosimilarity. However, the guidelines from pathway to pathway often vary in terms of development. Some may be fully established, closely mirroring other existing frameworks. Others provide manufacturers with the basic breakdown of how to proceed with small molecules or biologics, but not specifically biosimilars. Finally, there are still unapproved drafts of biosimilar guidelines that are not being used regularly.

A pathway can also be impacted by a number of factors, for instance, the exclusivity of the originator in a country. Some countries might require a reference country approval prior to accepting a marketing application. For example, regulators may specify that if a biosimilar has been approved in a specific number of larger territories or jurisdictions, the biosimilar will be accepted for review through an abbreviated pathway.

Familiarity with the molecule or the companies involved in its development can also play a role in a biosimilar’s approval. “It can depend on a regulatory body’s experience with that specific product,” Morales offered. “The agency may have reviewed another therapeutic protein or monoclonal antibody and understood it well — or did not understand it at all. Similarly, having a local partner can impact the regulatory pathway you choose and how you deploy the product in that country.”

A Breakdown Of Emerging Markets

There are several considerations companies need to keep in mind when filing in some of these emerging markets. Morales described the regulatory landscape of several of these markets, including:

• Russia: Biosimilar guidelines were released in Russia in 2014. There were a few biosimilar applications that were filed prior to the release of these guidelines. However, as Morales clarifies, these biosimilars are still being reviewed in accordance with the guidelines as “nothing is grandfathered in.” Though there is an abbreviated pathway for small molecule generics, there is no abbreviated pathway for biosimilar medicines. One unique aspect of filing for approval in Russia is that it requires Russian patients to be included in studies of biological products. “The process that’s followed there is submitting the registration dossier, a Clinical Trial Authorization [CTA], and conducting studies,” Morales explained. “This can either be a global study with local patients or a solely Russian trial. A company can then have its marketing authorization application reviewed by the ministry.”
• Colombia currently has guidance based on WHO guidelines, though it has yet to be formally approved. The review of a biosimilar is a two-step process. First, a pharmacological review is carried out by an external committee of experts, which provides a recommendation to the National Food and Drug Surveillance Institute (INVIMA). Then, INVIMA performs a pharmaceutical review of the biosimilar’s CMC data and other administrative documents. The length of this review can vary, depending on whether INVIMA is reviewing a full dossier that does or does not include comparability data. Similarly, if the company has a reference country approval as discussed earlier, the biosimilar could be placed on an abbreviated pathway.
• Peru ratified legislation for biosimilars in 2016. The country’s regulatory pathway for biosimilars is based on comparability, similar to that of the WHO guidelines. However, there may be flexibility to these guidelines, Morales says. The amount of non-clinical and clinical data that a manufacturer needs to present can be determined on a case-by-case basis, especially depending on the country’s needs for that therapy. As Morales describes, the government in Peru covers the cost of treatments for its citizens. Therefore, the country may be willing to work with a manufacturer to bring the therapy more quickly to market in order to save the government money.
• Malaysia was one of the earlier countries to launch biosimilar guidelines, releasing them shortly after the European Medicines Agency (EMA) in 2008. One of the key things to note about Malaysia is the country’s emphasis on the reference product. According to Morales, the reference product must be representative. “It doesn’t have to be already marketed within the country. It could be representative of that biosimilar in other countries or marketed elsewhere,” he says. There have been instances in which the country has approved a biosimilar based solely on PK/PD data. However, Morales specifies that this is an exception and happens very rarely.

Overall, emerging market regulators have taken some significant steps toward establishing a larger biosimilar market within these countries. However, as the descriptions of some of these markets’ pathways go to show, biosimilar guidelines may not be fully established, nor are they full aligned or implemented from country to country. As Morales emphasizes, “The lack of homogeneity in dossier requirements across the emerging markets poses a challenge to global development programs.” Biosimilar companies planning to approve a biosimilar in an emerging market may face additional quality, nonclinical, or clinical procedures, depending on the country.