May 28, 2023

Beyond the Brand: Biosimilars for Affordable Health Care


SERENDIPITY and experimentation with what was available often showed us humans that plant products could help treat or prevent certain diseases. But the first modern drug was by Friedrich Sertürner in 1804, who extracted the main active chemical from opium in the laboratory and called it morphine. Till the beginning of the 20th century, only small molecule drugs (SMDs), typically defined as organic compounds with a molecular weight of less than 900 Daltons, were in use. Dalton (Da) is atomic mass and is a measure of the complexity of the molecule. In contrast, biologics or macromolecules, like proteins, are larger in size and can range from several thousand to millions of Daltons. 

Biologics are more complex than small molecule drugs, which are generally manufactured using chemical synthesis processes. Though biologics have and can be manufactured without using genetic engineering, e.g., antibiotics, most biological drugs developed today are through genetically engineered technologies.

In 1922 insulin purified from cattle was used to treat successfully a 14-year-old boy dying of Type 1 Diabetes. This was the first biotherapeutic or biologic to be used. On January 23, 1923, US patents on Insulin and the method used to make it were awarded to Banting, Collip and Best. These patents were sold by them for one USD each to the University of Toronto. Banting wanted everyone who needed it to have access to it and said, “Insulin does not belong to me; it belongs to the world.” Today, nearly 100 years later, biological Insulin is inaccessible to many people due to its exorbitant cost, as the system puts profits before people. The quote from Amit Sengupta in “Political Journeys in Health – Essay for and by Amit Sengupta” (Leftword books ) says it all, “...if care is linked to profit, more ill health means more profit!”. This is the consequence of the ever-greening of patents, minor tweaks being awarded new patents under the US Patent law and what the Indian Patent Act does not allow. The 3(d) clause was included in the Patent Act in 2004 due to the Left’s fight in parliament.  

Macromolecules, such as the protein insulin, monoclonal antibodies, growth factors, hormones, enzymes, oligonucleotides and other large molecule therapeutics, are made from living cells or organisms and are called biologics. Biologics have helped many patients by either halting the disease progression or alleviating symptoms for inflammatory bowels, rheumatological or dermatological conditions, connective tissue disorders and cancers/malignant growths. 

This is the fastest growing class of medicines today and forms a major part of current health care costs. The price of some of the biological therapies like oncology monoclonal antibodies currently range from Rs 2 Lakhs to Rs 4 Lakhs per cycle of treatment, while the price for biologics that are gene therapies—modify or manipulate the expression of a gene or alter the properties of living cells—are enormously higher. Access to biologics for disease treatment or gene therapies, therefore, gets severely limited due to their very high costs. 

The introduction of generic drugs, which have the same active component as the equivalent small molecule drugs (SMDs), led to competition and a huge drop in prices, significantly enhancing access. HIV/AIDS drugs are the classic example. In the early 2000s, after the introduction of generics by Indian companies, prices dropped by 97.5 per cent. 

Unlike small molecules, no two biologics, even two batches of biologics, are identical. That is why the equivalence of generics for biologics is called biosimilars. Though the original biologic drug and the new one may have similar structures and actions, they are not identical. The US Food and Drug Administration (FDA) defines a biosimilar as “a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product” in terms of safety, purity, and potency. Biosimilars are equivalent to the biologics they are developed to imitate. Biosimilars are not identical to the reference biologics because of their complex structure. Usually, the data submitted during the approval process of a biosimilar is meant to show the clinical equivalence between it and the reference biologic. As all drugs undergo rigorous testing prior to regulatory approval, biosimilars are as safe and effective as their reference biologic products.

Small molecules are protected by patents as the patented drug is clearly identified by its chemical structure and components. This is not a workable form of protection from large molecules as it is not chemical equivalence but clinical equivalence that determines a biosimilar drug. Instead of patents, it is regulatory barriers that protect the original biologic developers. It is based on what constitutes clinical equivalence and satisfying other regulatory requirements. 

As the pipeline for novel small-molecule drugs has dried up, a range of large-molecule biologics has become the battleground for new drugs and how to provide them at reasonable prices to those who need them. The entry and cost of biosimilars can therefore bring down the cost and availability of biologics and gene therapies significantly. 

In the US, the Association for Accessible Medicines (AAM) Biosimilar reports that the FDA has approved 39 biosimilars across 11 molecules. Biosimilars have provided savings of USD 7 billion in 2021 alone, with a total of USD 13 billion since 2015. Patients spend about 50 per cent less than their reference brand biologic. There are also over 95 biosimilar development programmes ongoing, showing about a 50 per cent increase over the previous four years. Market competition has brought down costs by pushing down prices for both the reference product and its biosimilars. 

In India, the biosimilar market was around USD 300 million in 2015. In 2000, India approved and marketed the first biosimilar for hepatitis B at a time when no specific guideline was available. Now there are around 127 approved biosimilars in India. Presently, there are more than 100 Indian biopharmaceutical companies which are engaged in the manufacturing and marketing of biosimilars. Biosimilars are called “similar biologics” by Indian regulatory agencies. In 2012, the “Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorisation in India” was brought out by Central Drugs Standard Control Organisation (CDSCO) in collaboration with the Department of Biotechnology (DBT). This was revised in 2016. 

In 2021, the UK waived both animal studies and comparative efficacy trials for the approval of biosimilars. In 2022, the WHO replaced its existing Similar Biological Products Guidelines with revised Biosimilar Guidelines, considerably reducing the need for in-vivo (inside the live body) animal studies and allowing the animal studies to be based on animal tissues in the laboratory (in vitro). In December 2022 US president signed legislation which removed the animal studies requirements for biosimilar marketing approval. Similarly, Health Canada also does not require animal studies for biosimilar approval. 

The waiving of comparative efficacy studies and in-vivo animal toxicity studies will drive down the huge regulatory costs involved in such studies. With significant reduction of costs due to the new, streamlined biosimilar development, the cost of biosimilars can be reduced significantly, while maintaining its safety and efficacy. India urgently needs to revise its Biosimilar Guideline of 2016 along these lines, as it will bring down the costs of biosimilars, making them more accessible.

Though patents are supposed to protect patent holders’ right to profit from their inventions for a reasonable time, drug companies have made patent weapons to block competition. The article “How a Drug Company Made $114 Billion by Gaming the US Patent System”, which came in the New York Times (January 28, 2023), relates how AbbVie delayed competition for its blockbuster drug Humira which treats conditions like arthritis at the expense of taxpayers and patients. The key patent on the best-selling anti-inflammatory medication was expiring at the end of 2016, but AbbVie, blocked competitors using a strategy called “patent thickets”: instead of just one patent file, a whole series of patents are filed on various parts of the process and intermediate products. AbbVie not only blocked biosimilars but also kept on increasing the price of Humira. It also filed suits against its competitors like Amgen and nine other manufacturers, who were likely to get regulatory approval, and finally settled with them on the condition that their product launches be delayed until 2023! 

The patent-prolonging strategies are not AbbVie’s creation. Companies like Bristol Myers Squibb and AstraZeneca have used similar tactics to increase profits. Even in an industry known to use the US intellectual-property regime for its greed, AbbVie’s handling of Humira is still striking. As Amit Sengupta said in 2018, during the Fourth People’s Health Assembly held at Savar, Dhaka, “Finally, the hunger of capital has crossed borders into the belly of the beast—it haunts Europe, haunts North America as well”.