Note: This article was originally published on November 17, 2016, and was republished on November 19, 2019, on the occasion of the ICMR’s announcement that clinical trials for Risug have been completed.
Everything is still the same.
Sujoy Kumar Guha, professor emeritus at IIT-Kharagpur, wakes up around 11 am, reads the paper and thinks of what science can offer as solutions to the big problems of the day. In the evenings he runs his PhD students off their feet with constant demands, yet somehow leaves them itching to do something worthy of him. Around midnight, he takes off for a jog around the handsome campus with a leather belt wrapped around his right palm to fend off the stray dogs. He is still the slight, sprightly, soft-spoken man he was. He still answers questions after a few seconds’ silence with a lateral anecdote. He still describes most persons as a “very nice man”.
Everything is much the same as in 2002, when the then health minister C.P. Thakur had announced the imminent launch of Guha’s drug molecule Risug, a reversible male contraceptive. But the clinical trials were then halted on the charge that Risug was toxic. It took five years for the professor to restart the trials. In 2016, Risug is once again almost ready for its launch at the tail end of the phase III clinical trials that have been “99% successful”, according to the ICMR. Only, he was 62 then, he is 76 now. And the past 14 years have been spent in proving what he had already proved successfully.
“We have completed testing on 282 volunteers in five centres across India, and zero side-effects and difficulties have been reported,” said Dr R.S. Sharma, head of Reproductive Biology and Maternal Health at the Indian Council of Medical Research (ICMR), in a telephone interview. “I am waiting to reach 300 volunteers and then I will submit Risug for approval to the Drug Controller General of India. It is very unusual, in fact. I have worked on Risug for 25 years and not a single problem has been reported so far.”
Phase III clinical trials are the most extensive stage of human testing and the final step before a drug is launched in the market. Stage-four trials are sometimes conducted after a drug has been marketed, to gather feedback from users. Only about a third of new drugs being tested make it to phase III. In preparation, Guha has shortlisted two spots for the production of the drug – in the Okhla and Jhilmil industrial areas.
An original drug molecule devised in India, that too by an individual, is an extremely rare thing. Like some cosmic event, it marks the alignment of science, bureaucratic approval and pharmaceutical industry interest. Only two drugs have been credited to Indian researchers so far. Dr Amiyo B. Kar’s Centchroman was the first non-steroid oral contraceptive and marketed as Saheli. Dr U.N. Brahmachari, after whom a handsome residential avenue is named in central Calcutta, developed Urea Stibamine to treat kala azar. Risug is likely to be the third. There is also Dr Subhas Mukherjee, posthumously recognised as the architect of the world’s second ‘test-tube baby’. This baby was born a mere 67 days after Louise Brown, the first ‘test-tube baby’. The two births were in fact distinct simultaneous developments and Mukherjee’s process of keeping the fertilised ova frozen, before inserting it into the womb, is currently the preferred method of medically-assisted reproduction.
Though Mukherjee’s work was marked in an issue of New Scientist in 1978 and published in the Indian Journal of Cryogenics, it had not appeared in any international journals when the birth of Louise Brown was announced. At the time, the Left Front government in West Bengal ridiculed him and later transferred him to the ophthalmology department. In 1981, he was found hanging in his Kolkata apartment. His work would receive formal acknowledgment only sixteen years later.
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Risug is likely the only reversible male contraceptive in the world. Indeed, it is the only one to have advanced this far in clinical trials and with such good scores. Its idea is simple: sperm are negatively charged and a positive charge can neutralise them. An injection to the scrotum is required of the compound styrene maleic acid anhydride with dimethyl sulfoxide (SMA+DMSO), formulated by Guha. This forms a polymer inside the vas deferens, the vein that carries sperm from the testes to the penis. The polymer film carries both negative and positive ions and defuses the sperm’s electric charge.
The effect is long term – the polymer stays for as long as you want it to – and also very localised. Only the vas deferens is affected. Most importantly, it is reversible: two injections are needed to dissolve the film inside. Hence the name Risug, an acronym for ‘reversible inhibition of sperm under guidance’.
“In 2002, when the trials were stopped, I met President Kalam. He told me, ‘Sujoy, you know this is not a scientific block. You have to solve this in other ways’,” Guha said, waving his hand in the winding movement of a snake.
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In 1979, the professor published his first scientific paper on Risug in the journal Contraception with five coauthors. He was 40, a professor at both IIT Delhi and AIIMS with the reputation of a maverick. But he did not have a medical qualification; the ‘Dr’ in his title was earned from his PhD studies in the University of St Louis. Before this, he had a B. Tech and M. Tech from IIT Kharagpur. The ICMR said it could not allow a drug developed by a non-medically trained individual to be submitted for clinical trials. So he studied for the medical entrance test and secured admission to an MBBS degree programme at Delhi University.
Trials on rats and rabbits (smaller animals) and monkeys (larger animals) proved successful. Phase I of the human clinical trials on 17 volunteers was completed in 1993. It went perfectly. Those who were injected Risug above a certain dosage were seen to possess no “viable sperm”; no side-effects were reported.
And then, someone photocopied sections from a book called Hazardous Chemicals: Desk Reference and sent them to the ICMR. The sections in question listed styrene and maleic anhydride, both part of Guha’s Risug formulation, as carcinogens. In response. Guha argued that substances can be individually toxic in nature but harmless as compounds. He gave the example of pure chlorine, which can melt human flesh on its own but, when combined with sodium, it becomes sodium chloride – the basic salt that we consume in our diets. But it wasn’t enough to persuade them.
When trials did not resume by 1996, the professor petitioned the Supreme Court and hired Siddharth Shankar Ray to argue for him. Ray was the former chief minister of West Bengal, admired for his cold-blooded witch-hunt of Naxals in the 1970s. The Supreme Court dismissed Guha’s petition in five minutes, saying they were not the competent authority to rule on it. But it seemed to have sent a message to the government. Phase II resumed.
By 2002, Risug was well into phase III and 139 volunteers were being tested. Thakur, the health minister, declared it would be available as a drug in six months’ time. And suddenly, a question was raised by a section in the ICMR about traces of albumin found in the urine of volunteers. The doubts suggested Risug was toxic.
ICMR’s Sharma remembered the time differently. “The rules of clinical trials changed. International norms insisted on [good manufacturing practices] and [good laboratory practices],” he said. “We had to put those in place before we restarted phase III in 2007.”
It has been nearly a decade since then. In these years, the professor retired from Delhi and came to IIT Kharagpur, a campus with which he goes back a way. His maternal uncle was jailed by the British administration at the infamous Hijli detention centre here for eight years. The professor joined the seventh batch of the institution in 1957. With a new batch of students and researchers, he established the Risug Centre at Kharagpur, including a laboratory where they produce the drug and syringes required for the clinical trials held in six centres across India. A number of international outfits have approached Guha to collaborate on the production of Risug. The US-based Parsemus Foundation acquired rights to produce Risug in 2010 under the name of Vasalgel. In 2011, the World Academy of Biomedical Technologies sought permission to make the drug in France, Germany, Hungary, Italy, the UK and, likely, Greece and Ukraine.
The average time taken for a drug to go from idea to the shelf is 10-15 years, presumably in the developed world. It has been 37 years since Guha published a paper on Risug, in 1979, and the official approval, though close, is still not here. It takes not just the mind but a certain kind of temperament to be a scientist in the Third World. To not be worn out by the waiting and form-filling and counter-questions and inevitable jealousies. Guha knows this. He makes sure to get some sleep. He runs every night because it makes him feel like himself. He tucks his shirt in and combs his silver hair carefully.
The antagonist in Risug’s story is not the government, according to Guha, but the international pharma lobby. “The government has in fact put in a lot of time and money for the clinical trials,” he said. “In the first place, there would be no trials without them.” The questions raised about Risug and the resultant delays have come from the National Institutes of Health in the US. For several years, they wanted to promote a new drug that involved regular ingestion like the female pill, Guha said. “In fact, even in the WHO, there are people who don’t want the drug to come through,” A.R. Nanda, the union health secretary in 1999-2002, had told me some years ago. A hormone-based drug would offer prospects for continual demand and long-term profit.
A number of Indian and international companies had been enthused by Risug, including Dr Reddy’s Labs. But nothing has worked out finally. So the professor has decided to sell his flat in Delhi. He has asked his sons – both American residents – for some capital. “I guess Risug is a bad business proposition: inexpensive, single-use and it does not require major surgery,” he said.
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A long-term use male contraceptive is itself an unusual thing. In any case, birth control focuses overwhelmingly on the female body. There is The Pill, considered so seminal that it is among the select common nouns that are capitalised. In December 1999, The Economist called it the most significant advance of the 20th century. Then there are the intrauterine devices (IUD), diaphragms, vaginal rings, birth-control patches, contraceptive implants, the morning-after pill, the intrauterine system (a T-shaped device inserted into the vagina), the contraceptive injection, the female condom and the irreversible method of sterilisation. The UK’s National Health Service website sums up this state of affairs well: out of 16 choices listed for ‘methods of contraception’, 13 are female.
The best-known male contraceptive is the condom. Its effects however are very limited-term. Aside from this, there is the vasectomy and it is irreversible. Dr Sharma estimated that approximately 1% of all Indian men undergo vasectomies. “The contraceptive methods which are available to men today are essentially the same as they were 400 years ago: the condom, the withdrawal method and temporary abstinence,” Miriam Klemm, a Berlin-based researcher whose PhD thesis is on long-acting reversible contraceptives (LARCs) for men, told The Wire. “Vasectomy is the newest form of male contraception, having first been developed in the 1890s.” Klemm visited India in October to meet Guha because Risug is one of the handful of LARCs in development. Interestingly, it also non-hormonal in approach.
In late October, there was news of a male hormonal contraceptive whose trials were stopped because volunteers reported side-effects like headache and depression. Nearly all news reports on this took the position that men complain too much while women have put up with side effects for decades. This may well be true – but all hormone-centred solutions are likely to have side-effects. Hormones, Guha explained, affect the whole body. And when a certain substance’s level is lowered or raised across the body, there is naturally the likelihood of a discernible impact.
In the 1970s, when he was working out the idea of Risug, Guha expressly wanted a solution that was not hormonal. Studies of The Pill, introduced in the 1960s, mentioned side-effects and he wanted to avoid this. In the end he came up with something that sounded too good to be true, almost like an advertisement. Risug is localised, has no discernible side effects, is long-term, inexpensive, easily reversible and, on top of this, it is feminist.
Risug holds the potential of drawing in men in a more meaningful way into family planning programmes. At the moment, family-planning is almost entirely the responsibility of women. More worryingly, the pressure of meeting government-set targets are borne by women. It was arguably this kind of pressure that led to the deaths of 13 women in a sterilisation camp in Chhattisgarh in 2014. Already, the phase II trials offer promising possibilities: Dr Sharma said a significant number of the volunteers are Muslim men.
Guha’s feminism, however, is accidental. He was in search of the most elegant scientific solution and, to him, it is simply more logical to address the male body for contraception because the genitalia are external. The vagina, on the other hand, is harder to access. Nevertheless, he has adapted a version of Risug for the female body that enters the vagina (via a minimally invasive procedure) to administer the drug into the fallopian tubes. In an ordinary tubectomy, the tubes are cut and tied. Here, the injected drug forms a film inside, just like in the vas deferens.
For this, he received a Bill and Melinda Gates Foundation grant in 2012, but the drug delivery process is still at an early stage of development. Another ongoing project is the thirteen-chamber artificial heart modelled on the cockroach. (“Have you ever wondered why the cockroach features in every apocalypse story, in so much science fiction?” Guha posited. “It’s truly resilient because of its heart.”) A third project is a transportation model to lower air pollution prompted by stories about Delhi. There are also his PhD students whom he hustles around like a demanding boss.
It’s hard to guess that his decades-long struggle for Risug is on the brink of culmination (at 76, he has spent exactly half his life waiting for the drug to come through). When I visited him some years ago, Risug was deep in phase III, the ICMR was reluctant to speak, the end was nowhere in sight. But Guha was the same man: working on multiple projects, walking briskly ahead of us all, rushing home at midnight to prepare for his run. A man in a hurry to get things done.
I came away taken by his energy and optimism and stylish reticence. I expected to see a different man this time. More anxious, perhaps, that things might slip up again. Or relaxed, that everything had finally worked out. Perhaps even smug that he had been proved right. But everything was just the same.
Sohini C. is a freelance journalist.