Onmanorama Explains | Is it ethically right for Kerala to use a cheaper generic drug to treat Spinal Muscular Atrophy?

On July 5 this year, the Kerala Health and Family Welfare Department decided to procure a considerably cheaper generic formulation of the drug Risdiplam used to treat Spinal Muscular Atrophy (SMA), a progressive neuromuscular disorder.

Under the KARE (Kerala United Against Rare Disease) programme, the Kerala government has been procuring Risdiplam from Roche, a Swiss healthcare giant, under the brand name Evrysdi. Roche holds the patent for the Risdiplam formulation. The patented drug is called the 'innovator formulation'.

The state requires 2133 bottles of Risdiplam annually for the treatment of the existing 109 beneficiaries under the KARE Programme. Each Evrysdi bottle costs ₹5.2 lakh. However, as part of a deal cut with the Kerala government, Roche provides 11 bottles free for every four bottles procured. Meaning, Kerala has to pay only for 568 bottles. Therefore, instead of ₹110.92 crore, Kerala has to shell out only ₹29.54 crore annually.

The government purchases the bottles and administers it free of cost to beneficiaries, children up to 12 years, free. Kerala is the only state to provide costly Risdiplam free.

In October 2025, the Indian pharmaceutical company Natco Pharma came up with a generic formulation of Risdiplam under the brand name Natsmart. A Natsmart bottle is priced at ₹15,900 per bottle, just 3 per cent of Roche's cost. At this price, 2133 Risdiplam bottles can be purchased for just ₹3.39 crore. The price has now been negotiated down to ₹8500 a bottle.

Roche went to court saying that Natco had violated its Indian patent. Though Roche's patent is valid till 2035, the Delhi High Court on October 9 sanctioned the manufacture of Natsmart, and nearly a fortnight ago, on September 30, the Kerala High Court allowed Kerala to proceed with the tender process to procure Risdiplam.

Why is Natco's generic drug feared?
The underlying fear among parents of SMA-afflicted children is that there is no scientific evidence to show that Natco's generic formulation is efficient and safe. A bioequivalence study, for instance, has not been conducted.

A bioequivalence study is done, according to the World Health Organisation (WHO), "to establish the absence of a statistically significant difference in the rate and extent of absorption of an active pharmaceutical ingredient from a pharmaceutical product in comparison with the reference product when administered under similar conditions in an appropriately designed study".

In other words, the study is done to check whether the generic drug (Natsmart) has the same effect as the innovator drug (Evrydsi).

What is Natco's defence?
Natco says a bioequivalence study is not required for Natsmart under WHO guidelines—Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability.

Clause 4 speaks of instances where equivalence studies are not necessary. Clause 4(b) says that equivalence studies are not required when pharmaceutically equivalent products (Evrydsi and Natsmart) are solutions for oral use (e.g. syrups, elixirs and tinctures), contain the API (active pharmaceutical ingredient) in the same molar concentration as the comparator product (Roche's Evrysdi). Risdiplam is administered in oral dosage form, and both Evrysdi and Natsmart have the same molecule; thus, Natsmart is exempt from equivalence study.

Further, Natco has been granted the requisite regulatory approval by the Central Drugs Standard Control Organisation (CDSCO) for the manufacture and marketing of Natsmart as a generic formulation of Risdiplam.

Natco also argues that there exists no literature reporting a failure of Natsmart in any patient anywhere nor is there any complaint from any patient, caregiver or treating physician. There is no notice, recall, suspension or adverse finding of the CDSCO either.

What prompted Kerala to procure Natsmart?
The National Health Mission director, first during the LDF rule and later when the UDF came to power, had proposed that the CDSCO-approved generic formulation be procured under the KARE Programme to ensure uninterrupted treatment to beneficiaries in a financially sustainable manner. The director also informed the government that there was shortage of Evrysdi.

What appeared to be even more persuasive were the observations of the Technical Committee constituted by the LDF government to study the issue.

Here are some salient findings of the Technical Committee: One, there is no need for safety and efficacy studies as Natsmart was a generic drug; two, the Drug Controller General of India (DGCI) has approved the molecule to be marketed in India; three, the substantially lower cost of the generic formulation would contribute to the sustainability of the KARE Programme; four, other treatment centers, including Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, were using the generic formulation successfully; five, doctors in Kerala, particularly in private hospitals, were already prescribing Natsmart in certain cases.

Nonetheless, the Committee also said that bioequivalence study could be conducted.

Why was Roche's patent claims rejected?
In international patent law, it will not be infringement of patent rights if the structure of the innovator formulation (in this case Evrydsi) was already 'disclosed' in the genus patent (the entire range of molecular arrangements that share a functional property), or was already 'obvious' in the genus patent. It is an innovation in one molecular arrangement within the genus patent that creates species patents like Evrydsi.

The Delhi High Court, while rejecting Roche's objections, noted that in several of the chemical structures in the genus patent, Nitrogen figured at different positions. Nitrogen looked important. Roche's species patent was created by substituting Nitrogen in the place of a carbon-hydrogen (CH) group. In other words, a less potent chemical (CH) within the group is replaced by a more potent one. "The substitution of Nitrogen in CH would, therefore, be obvious to a person skilled in the art," the High Court noted.

The replacement did not seem a random one either. N and CH figure in the same column of Grimm's Hydride Displacement Law. Meaning they are bioisosteres, or atoms having the same number of electrons and the same biological activities.

The High Court noted that "a person in the know", who is aware of the intricacies of medicinal chemistry, would be readily motivated to substitute carbon-hydrogen with nitrogen, a restructuring that resulted in Risdiplam.

In effect, Roche's Evrydsi is not as innovative as claimed because the supposedly hidden treasure was too obvious to be missed.

What caused 'clinical trials' fear?
Some Natsmart bottles arrived with the label 'Physician's Sample/Clinical Trials Only'. This had understandably triggered fears in caregivers, particularly parents. It gave the impression that SMA-afflicted children were being used as guinea pigs.

Official sources said that only those packets provided under the 'patient assistance programme' carried such a label. For every three bottles supplied, one was offered free. Such a labelling was necessary to account for these free bottles.