From The Editor | July 19, 2017

The Thai FDA's Approach To Biologics And Biosimilars

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By Anna Rose Welch, Editor, Biosimilar Development
Follow Me On Twitter @AnnaRoseWelch

Biosimilar industry

During my time in the biosimilar space, I’ve occasionally come across the name “Siam Bioscience” in lists of companies working on biosimilars. But I knew little to nothing about the company, its pipeline, or its progress. When I signed on to visit Thailand, the preliminary agenda of site visits did not include any biosimilar companies (though that certainly didn’t dissuade me from going). However, to my surprise, Bangkok’s own Siam Bioscience, which has released two biosimilars to market and is currently developing a pipeline of biosimilars, earned a place on the final agenda.

Compared to other developing nations, Thailand hasn’t made headlines in terms of biosimilar development or uptake. But this certainly doesn’t mean the Thai government and pharma industry don’t have biosimilar ambitions. Siam Bioscience provided a wealth of information about the country’s existing biologics industry and the emerging biosimilar industry. This article — the first of two parts based on my visit to Siam Bioscience’s facility — will examine the country’s history with biologics and biosimilars, as well as the company’s perceptions of the current Thai FDA biologics and biosimilar regulations in relation to the U.S. and EU.   

The Evolution Of Thailand’s Biosimilar Market

Around 2010, The Thai FDA released updated biologics guidelines to be in line with WHO standards and Association of Southeast Asian Nations (ASEAN) harmonization. This biologics guideline set in motion the release of the country’s first biosimilar guidelines in October 2013. Though, as Songpon Deechongkit, Ph.D, the managing director of Siam Bioscience, described, prior to 2010, the lack of guidelines enabled some companies to release poorly characterized biologics and “not-exactly biosimilars” onto the market.

“I personally would refer to the universe of these products as non-original biologics, rather than calling them all biosimilars,” Deechongkit said. “The availability of both the biologics and biosimilar guidelines allows us to now categorize them. Very few of them were indeed biosimilar according to U.S. and EU standards. Most of them were developed as “stand alone” products, which meant they did not comprehensively compare similarity to that of the reference product. There were also some products that would not have been registered if they’d been reviewed using current Thai FDA biologics/ biosimilar guidelines.”

It’s important to note that both biosimilars and stand-alone products are now covered under the current Thai FDA biosimilar and biologics guidelines respectively, Deechongkit clarified.

The Thai FDA found it necessary to draft biosimilar-specific guidelines after a surge of follow-on erythropoietin (EPO) products began causing adverse events. As a well-written and thorough 2016 article by Tilleke & Gibbins discusses, the influx of substandard EPOs brought about eight times as many cases of pure red cell aplasia than was observed in other countries.

In many cases, these follow-ons lacked the necessary data to demonstrate their similarity to the originator. For instance, Tilleke & Gibbins explains that biosimilarity in Thailand was previously determined based solely on bioequivalence with a reference biological product — in alignment with the country’s small molecule generics pathway. As such, biosimilar applications did not include the preclinical or clinical studies required today by the U.S. FDA and the European Medicines Agency (EMA).

After observing these lapses in safety, the Thai FDA determined bioequivalence was not sufficient for determining safety and efficacy of potential biosimilars. Ergo, new requirements were launched in 2013. (The Thai FDA is also in the process of reevaluating all Marketing Authorization (MA) licenses for “follow-on” EPOs released prior to these official biosimilar guidelines.)

These guidelines specified the need for information on the molecule, its manufacturing process, and comparative physiochemical characterization between the biosimilar and biologic. In addition, the agency called for non-clinical and comparative clinical trial data, as well as a risk management plan. For those of you in the U.S. and EU, these expectations should sound familiar.

Comparing Thai FDA, EMA, and FDA Biologics & Biosimilar Regulations

For Siam Bioscience, which is striving to bring biosimilars onto the market both in Thailand and elsewhere, the new Thai FDA guidelines were quite welcome. But there are a few interesting distinctions between other nation’s guidelines.  

For instance, one difference between the U.S. FDA’s and the Thai FDA’s guidelines has to do with how biologics/biosimilars are categorized. In the U.S., the FDA makes a distinction between polypeptides (simply referred to as peptides) and proteins. In the U.S. a peptide is a chain of 40 amino acids or less, while a protein is a chain of amino acids higher than 40. The FDA does not consider anything under 40 amino acids to be a biologic; therefore, an amino acid chain under 40 would be regulated as a drug. The same can be said for an amino acid chain created through chemical means (known as a chemically synthesized polypeptide), which the FDA will also regulate as a drug if it is made entirely by chemical synthesis and is less than 100 amino acids in size. Similarly, in Europe, a chemically synthesized peptide is not considered a biologic or a biosimilar.

For Thailand, such small synthetic peptides are considered biologics. Therefore, the follow-on version of those synthetic peptides has to be evaluated under the biosimilar pathway by default. This is different than U.S. and EU regulations, which would not consider these follow-on synthetic peptide products to be biosimilars.  

When it comes to developing biosimilars in Thailand, one key guidance-related challenge for Siam Bioscience has been the interpretation of the Thai FDA’s guidelines. It can be particularly challenging to apply the guidelines to the actual development process. In order to ensure the company’s process is in line with the regulations, Siam Bioscience and Thai FDA have engaged in scientific advice consultations to share information and opinions in order to find the appropriate solutions.  

The company has also found that the Thai FDA and EMA approach GMP issues somewhat differently. One of the biggest differences between the two regulators’ approaches is the EMA’s emphasis on process efficiency and product quality in parallel. In the company’s experience, Thai regulators are more likely to home in on product quality control.

Recent gap analyses of Siam Bioscience’s facilities by a former EU regulator (now a consultant) revealed the EMA’s desire to see a more streamlined, efficient process in place. In the eyes of an EU regulator, the process in place has to ensure the creation of a quality product without relying on redundant procedures. 

Deechongkit admitted Thailand is not quite as “Ferrari-like” as that of the U.S. and EU in terms of the R&D engine’s “horse power”. However, the company recognizes there is still room to grow when it comes to balancing risk management and process efficiency. Not only will this be important for helping Siam Bioscience attain EU certification for its facilities, but it could also enable the company, as well as the Thai industry, to take advantage of a more streamlined and cost-effective approach to biosimilar development, while achieving the product quality standard.