Column: India Struggles to Meet International Biologics Standards

Editor's Note: This commentary by Paul Cornes, MD, BCH, MA, MRCP, FRCR, is in response to a research paper about copy biologics produced in India and efforts to bring them up to international standards of quality.

Reviewing papers on biosimilar medicines in India is always fraught with difficulties because there are 2 meanings of biosimilar. The first is a strict regulatory term meaning follow-on biologic approved by the multistep biosimilar regulatory pathway pioneered by the European Medicines Agency and now adopted as the World Health Organization (WHO) standard. Similarly, rigorous pathways have been applied in economically developed countries such as the United States, Canada, Japan, Australia, and New Zealand. The second use, or misuse, is a broad marketing term for any follow-on biologic brand made and approved to any standard.

Paul Cornes, BM, BCH, MA, MRCP, FRCR, is a consultant oncologist and biosimilars expert who was part of the team that developed and presented evidence to the FDA for the first successfullly approved US biosimilar.

Importantly, India itself has never approved a biosimilar. Instead, the Indian regulator, the Central Drugs Standard Control Organization (CDSCO), approves follow-on brands of biologics as Indian similar biologics, or ISBs. The distinction is important, because the regulatory standards in India still lie below the WHO benchmark. This situation led to criticism of ISB regulations by the Indian Parliamentary Standing Committee on Health and Family Welfare that oversees the CDSCO, as well as action in India’s High Court. One example might serve to illustrate the problem: the average clinical confirmatory trial for a trastuzumab biosimilar in Europe had more than 640 participants, whereas for ISBs, the numbers were often just above 100.

This doesn’t mean the resulting medicines from India are necessarily good or bad; they simply lack the assessment needed to deliver the predictability required of WHO standard biosimilars. The European regulator has called this approach scientifically unacceptable. The best term for this lesser class of follow-on biologics is more properly intended copy biologics, because the manufacturer intended to copy the reference biologic but fell short of the biosimilar standard. Other terms that have been used are biogenerics, biocopies, biomimics, or noncomparable biologics. We know little about these drugs in practice, and what little we do know is often of concern; for example, the Malaysian regulator reviewed multiple intended copy biologics from Asia and found significant issues for all the drugs assessed and listed these problems in a key paper.

This is similar to the experience of our group. We have just completed the largest-ever survey of intended copy biologics, and the resulting series of papers is at the stage of internal peer review with colleagues before submission in 2021. Importantly, we find that this situation can be unfair on Indian manufacturers who have delivered follow-on biologics to the WHO standards we require. For example, a trastuzumab biosimilar from Mylan/Biocon and filgrastim and pegfilgrastim biosimilars from Intas/Accord were developed in India and are approved as biosimilars in Europe and beyond. However, in both those situations, the biosimilar standard approval was made by regulators in Europe and the United States, not India.

Biosimilars approved by the European regulatory pathway are proven to meet the standards we require in practice. Now, with more than 70 biosimilars approved, more than 2 billion documented patient days of exposure to European biosimilars, and more than 178 studies of brand switching to biosimilars, we can be confident that the quality, safety, and efficacy of European-approved biosimilars match the reference biologics’ with no clinically significant differences.

Intended copy biologics create a problem for pharmacists and physicians in less-regulated regions of the world because selecting follow-on biologics requires an ability to differentiate originator reference biologics, biosimilars, and intended copy biologics from one another. Then, because intended copy biologics represent such a heterogenous group of products, the decision to use them places significant pressure on the prescriber to understand the development and regulation of each product through a detailed study of the drug’s development and regulatory dossier. Unlike the public assessment reports of Europe’s regulator, or the FDA Advisory Committee briefing documents on biosimilars, our experience in finding such a document for an intended copy biologic is that almost none are accessible in the public domain. The lack of differentiation also creates a problem for pharmacovigilance. In a recent publication from our group, we discovered that even the Indian Pharmacopoeia Commission was uncertain of the differences and linked unexpected adverse event reporting to the incorrect class of medicines.

It is therefore heartening to read a paper from India that begins to describe the issues involved in discriminating between these different classes of biologic medicines and why these matter. We should congratulate Ramesh Jois and colleagues for their work. They explain the problem of differentiating between original reference biologics, biosimilars, and biomimics or intended copies, when discussing biologic medicines in India.

Appreciating the Work Behind an Approval

Biosimilar regulators in Europe and the United States typically review between 60 and 100 tests of equivalence between a proposed biosimilar and its reference biologic. They also oversee the regulatory trials and inspect the production and distribution standards of the drug as well as monitor pharmacovigilance and product changes over the drug’s lifetime. This takes well-resourced regulators in Europe and the United States about 1 year for each biosimilar application, which is equivalent to the amount of time to that needed to assess a novel drug.

Those of us living and working in regions with well-equipped regulators and high standards should take a moment to appreciate our fortunate situation. Only a minority of the world’s nations are able to invest the considerable resources and educate the highly trained staff to deliver such regulatory standards. We should pay tribute to the WHO, which has been running regulatory workshops worldwide to raise attention to these problems.

The WHO has also proposed a solution, by offering to “prequalify” biosimilar versions of brands included in their list of essential medicines so that less-well-supported regulators have products with the necessary standards already listed for use. Many other nations have adopted a “trusted coregulator” approach and offer rapid assessment of follow-on biologic brands that have already gained biosimilar approval in Europe and the United States.

To their credit, the CDSCO has responded to criticism by raising its standards with guidance posted in 2012 and updated in 2016, a process that I am sure will continue until India, too, matches the WHO requirements. Until then, readers and prescribers need to be able to differentiate between biosimilars as a strict regulatory term and the marketing claims made on behalf of intended copy biologics.