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Biorationality: A Dr Sarfaraz Niazi Column—A New Perspective on Biosimilars' Role Within Big Pharma


Sarfaraz K. Niazi, PhD, explained why Indian manufacturers aren’t bringing biosimilars to the United States and how FDA policies and procedures discourage global companies from pursuing US market entry.

So far, the maximum price discount for biosimilars are Amgen's Avsola (infliximab-axxq), 57% lower than Remicade (reference infliximab), and Amjevita (adalimumab-atto), a 55% discount to Humira (reference adalimumab). Next in line is the biosimilar Amneal Pharmaceuticals and Kashiv Biosciences developed, Releuko (filgrastim-ayow), which offers a 50% discount to Amgen's Neupogen.

While some have predicted that an 80% to 90% discount from Humira biosimilars is prominent, the consensus is that the future competition within the biosimilar markets will be less than expected, as reported by Barclays bank.

Therefore, high discounts will likely not materialize for years, based on the average 26% discount for products launched before 2020. The reason for this shift in predictions is based on prospects for the entry of biosimilars from India and China, the 2 sources capable of disrupting the market. Here is my analysis of why these sources of biosimilars need to show success and how a shift can be made.

A significant market disrupter, the entry of Indian biosimilar companies,—except for Biocon, which had many issues—has not yet become a reality and is not expected soon. One reason why Indian companies are not likely to enter the US biosimilars market, despite having done so in the generics market, has to do with the biosimilar regulations in India, which leaves a poor impression of the quality of Indian biosimilars and requires a complete rework if Indian companies plan to introduce the 100 plus biosimilars now available in India to the US market. Indian biosimilar companies are already selling these products and generating very small revenue, which reduces the incentive to invest in the US market.

For example, the FDA and the European Medicines Agency no longer require "animal toxicology" data because animal species do not have receptors to demonstrate biological drugs' pharmacology and toxicology.

However, guidelines from the Indian Central Drugs Standard Control Organisation(CDSCO) state "the applicant should provide the scientific justification for the choice of animal model(s) based on the data available in scientific literature. However, if the relevant animal species is unavailable and has been appropriately justified, toxicity studies must be undertaken in two species, i.e., one rodent and another non-rodent species. The dose should be calculated based on the therapeutic dose of the reference biologic. A pilot dose-response study should be conducted before initiating the toxicity studies."

The Indian guidelines further state: "Information to establish comparative safety and efficacy in relevant patient population is mandatory for all similar biologics…. Also, in cases where phase 3 data on the Indian population is necessary, a single-arm study in at least 100 evaluable subjects may be carried out in the most sensitive indication ‘to address any residual uncertainty.’”

There is no scientific rationale for these suggestions. The size of a clinical trial is calculated based on the alpha value, the beta value, and the prior variability between subjects. Any meaningful comparison may require thousands of subjects. The studies proposed by the CDSCO can never fail and serve only as a token checklist.

These, and many other inconsistencies in the Indian guidance, have eroded the confidence in the biosimilars approved in India. To plan entry into the United States, the Indian marketers will have to start it all over again, including compliance assurance, a financial challenge that keeps them away; why risk when their products are already selling, albeit for pennies is the thought process.

Moreover, some who have tried, such as Intas Pharmaceuticals, have been waiting for almost 10 years to hear back from the FDA on its biosimilar filings. Recently, the FDA flagged Intas with an FDA warning letter (Form 483) for significant violations within the company’s manufacturing plant, and it is unlikely that any biosimilar product will come from Intas soon.

Acknowledging their inability, some Indian companies, such as Lupin Limited, are abandoning the US market after receiving multiple warning letters from the FDA.

It is also unlikely that Chinese companies will enter the biosimilar competition in the United States for additional reasons than those cited for the Indian products.[1] In recent years, China’s biosimilar drug industry has developed rapidly. By the end of 2019, China had the highest number of biosimilar drugs in development (n = 391 biosimilars).

The laws and regulations for biosimilar drugs in China, particularly a complete registration management system and supporting policies for supervising biosimilar drugs, have not been established yet. This has brought much confusion in the biopharmaceutical industry in China. However, China can introduce regulations that will help the sector develop globally acceptable products by not repeating the mistakes of creating guidelines for generic chemical products.[2]

While India and China are the major expected sources, the FDA has also sent a complete response letter for other biosimilar prospects, like Alvotech’s adalimumab biosimilar (AVT02), creating delays in market entry and discouragement for global developers.

Previously, I predicted that the big pharma engaging with biosimilars would leave the market as prices fall below 50% of the innovator product. However, the bold move by Amgen, with the highest discount for its biosimilar products, may change my perspective as long as the cost of development remains between $200 million and $300 million.

This prediction is only delayed; once the regulatory requirements become harmonized and more rational in the United States, such as removing the requirement for phase 3 studies, 7 companies in India and China may reconsider entry. But, that will most likely take at least a decade.

For now, the US model will hover around a 50% discount, and big pharma remains in the lead to supply biosimilars. This will hurt the possibility of over 100 biosimilars from entering the US market, which will not be of least interest to big pharma, because smaller market allow them to leave their higher prices in place.


[1] Yang J, Zhao X, Li J, et al. Creating China's biosimilar drugs regulatory system: A calculated approach. Front Pharmacol. 2022;13:815074. doi:10.3389/fphar.2022.815074

[2] Huang B, Barber SL, Xu M, Cheng S. Make up a missed lesson: New policy to ensure the interchangeability of generic drugs in China. Pharma Res. 2017;5(3): e00318. doi:10.1002/prp2.318

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