In 2006, London woke up to a tragedy. Six healthy men involved in a phase I clinical trial of theralizumab, a monoclonal antibody (mAb) designed to treat rheumatoid arthritis, developed multiple organ failure. The antibody triggered an intense immune reaction that the researchers didn’t observe in rhesus monkeys in preclinical tests because their immune cells responded differently from human immune cells.
The Northwick Park Tragedy, as it was called, became a textbook example of why animals can’t be used as proxies to test human drugs. Similarly, in 2022, the mAb semorinemab failed to work in 457 patients with Alzheimer’s disease during phase II trials despite demonstrating effectiveness in a preclinical mouse model.
mAbs, vaccines, and insulin all belong to a growing class of drugs called biologics — large, complex molecules produced by living cells. Their use is rising worldwide as they treat many chronic diseases.
Recognising their importance, the 2026 Union Budget of India announced the Biopharma SHAKTI strategy to boost domestic production of biologics and their generic counterparts, biosimilars.
However, animal models may not reliably predict the safety and efficacy of biologics. This has prompted a shift towards bioengineered, human-relevant systems such as organoids, organ-on-a-chip, and 3D bioprinting, which are derived from human cells and thus replicate human biology more faithfully.
Human-relevant models
These models are collected under the term non-animal methodologies (NAMs) and are used worldwide to reduce the use of experiments in animals. For example, last year, the U.K. published a roadmap to phase out animal experiments and promote the adoption of NAMs.
Thanks to the New Drugs and Clinical Trials (Amendment) Rules 2023, India is also promoting the use of NAMs in the development of novel drugs. However, their potential remains untapped in the domain of biologics and biosimilars.
“Biologics are highly specific,” University of Illinois adjunct professor Sarfaraz Niazi said. “They bind to particular receptors in the human body. But those receptors are sometimes missing or function differently in animals, which makes animal testing less predictive.”
One 2024 study in Cell reported a breast cancer-on-chip model to study the effectiveness of CAR T-cell therapy, a leading biologic therapy, against solid tumours.
While CAR T-cell therapy has proven effective against blood cancers, solid tumours like breast cancers pose additional challenges like abnormal blood vessel formation and difficulties for T-cells to find and attack the cancerous cells.
The breast cancer-on-chip model recreated this tumour environment in the lab, and the authors of the 2024 study perfused T-cells through it to observe whether they could enter the tumour and mount an immune attack, assessing both treatment benefit and potential safety risks without animals.
These models can also reduce costs and shorten development timelines, making them attractive to pharmaceutical companies. A 2019 analysis in Drug Discovery Today estimated that organ-on-chip technologies could lower overall drug development costs by 10-26%. They also found the time required for lead optimisation, when scientists identify a promising drug candidate from a pool of molecules, could drop by 19%.
Future of biologics
Even if NAMs are promising models, they are not as accessible as animal systems. More than 90 academic labs in India are working on these models. However, the innovation here is not translating into industry use.
“Translating NAMs into industry-ready assays requires a clear context of use, robust documentation, and standardised, reproducible protocols, even before qualification. While institutions support entrepreneurship, sustained commercialisation needs stronger, modern policy support,” Kasturi Mahadik, Chief Manager at the Centre for Predictive Human Model Systems (CPHMS), AIC-CCMB, said. (Note: the author works at CPHMS.)
The development of NAMs also requires sustained funding and infrastructure. With an outlay of ₹10,000 crore, Biopharma SHAKTI can provide the necessary backing.
“I think the best use of these funds would be not to develop a single product but to build systems that enable many companies to do so,” Dr. Niazi added.
“The culture of entrepreneurship is also a challenge in India,” Narendra Chirmule, CEO of SymphonyTech Biologics, said. “Although there is an increase in the number of start-ups and MSMEs in biologics (supported by DBT, ICMR, and other grants), exponentially greater investment, as well as support for the development of supply chain materials, is needed to create real impact. Additionally, investors are not well versed in the risks and potentials of the biologics industry.”
Regulatory, market challenges
Another area supported by Biopharma SHAKTI is biosimilars, generic versions of biologics that are reverse-engineered once the original product goes off patent. However, there are additional financial risks and regulatory adjustments involved, which require greater attention from the government.
One challenge is patent evergreening, which allows the exclusive rights of an original biologic to be extended. For example, although the intravenous form of the cancer drug trastuzumab was approved in 2000, the manufacturer later introduced a subcutaneous formulation with a separate patent. Because of this prolonged market exclusivity, cheaper biosimilar versions weren’t available until 2018.
Before being commercialised, biosimilars also have to receive a nod from the Central Drugs Standard Control Organisation (CDSCO), India’s apex regulatory body. These approvals are based on set guidelines; however, the updated guidelines are still in draft form.
“While India has been updating its biosimilars guidelines to accommodate NAMs, implementation has been slow, and regulatory confidence in independently validated NAM models is still evolving. If accelerated, this would expedite the adoption of NAMs in the biologics and biosimilars field, helping Biopharma SHAKTI achieve its goals,” says Mahadik.
Therefore, aligning with industry realities and securing regulatory clarity for their use will make biosimilars and biologics manufacturing in India faster, more predictive, and cost-efficient, thus realising the vision set by Biopharma SHAKTI.
Mohit Nikalje is a science communicator at the Centre for Predictive Human Model Systems, Hyderabad.
