Issue Date: May 21, 2007
The Indian Advantage
BIG PHARMACEUTICAL FIRMS that need to quickly get a few dozen chemists to work on a specific, well-defined research project have long known that they can turn to any of India's numerous contract research companies. But in the past two years, the country's research service providers have been undertaking far more significant drug discovery work for foreign clients—work that involves sharing sensitive data.
Eli Lilly & Co., for example, has licensed a patented drug that has yet to be launched in the U.S. or anywhere else to Mumbai-based Nicholas Piramal. GlaxoSmithKline has asked New Delhi's Ranbaxy Laboratories to work on lead compounds until the second round of clinical trials is completed. And Bangalore-based Syngene is building and will operate a 400-scientist R&D center for Bristol-Myers Squibb (BMS).
"Most large drug companies are now paying a lot of attention to external alliances as one of the strategic drivers to increase the productivity of their R&D," says Rashmi Barbhaiya, cofounder and chief executive officer of Advinus Therapeutics, a drug discovery firm that works with Merck & Co.
India's top research service providers protect their clients' intellectual property in myriad ways. Staff members are required to sign confidentiality agreements. Computer systems are set so that no one is able to upload a document, mail an attachment, or save a file to a portable device. Work on projects for different clients is done in separate labs, and employees have electronic key cards that open only certain doors.
At the end of the day, third-party research firms live and die on their reputations. A solid reputation and track record help to quell the angst that a foreign client might feel when sharing information about a drug candidate and its biological target with people working thousands of miles away.
For many years, Nicholas Piramal has cultivated the image of an Indian company that avoids infringing others' intellectual property. Unlike other large Indian drug firms, it has not tried to challenge in court the pharmaceutical patents of major drug companies. It makes and distributes generics that are off-patent or that it licenses from other firms. It also provides research and contract manufacturing services to companies from around the world. This stance is apparently paying off.
"The Eli Lilly people called us; they weren't even one of our existing customers," says Swati Piramal, the firm's director of strategic alliances and communications. "I guess we have a reputation." A medical doctor and the holder of a master's degree from the Harvard School of Public Health, Swati Piramal is married to Ajay Piramal, who is the chairman of Piramal Enterprises, a conglomerate in which Nicholas Piramal is a major component.
It's common knowledge that India has a lot to offer in terms of research capabilities. It has a huge pool of English-speaking scientists, particularly synthetic organic chemists. Many of these scientists are highly motivated and will work for a fraction of the salary of similarly trained scientists in the U.S., Europe, or Japan.
But big drugmakers have yet to figure out how best to harness this resource for the drug discovery side of the business. In China, companies such as Roche, Novartis, and AstraZeneca have opted to set up their own R&D facilities. China, though, is a bigger potential market than India, and it has honored drug patents since 2000, five years before India took that key step.
WESTERN DRUG COMPANIES have been seriously looking at India for drug discovery for a little more than two years. To date, only a handful of Western firms conduct R&D in their own Indian facilities. The process of sending a team of highly compensated scientists to the country for a few years to set up a new corporate lab has been viewed as time-consuming and expensive.
Rather, most companies outsource specific projects to established Indian contract research organizations. A growing number of drugmakers, though, have entered into innovative hybrid arrangements that take things way beyond plain task-driven outsourcing.
The deal between Lilly and Nicholas Piramal is indicative of the new, more cooperative way in which some big drug companies are working with Indian research providers. According to Swati Piramal, her company is conducting research on a patented Lilly compound that requires toxicology studies and trials on humans. While it conducts the research, Nicholas Piramal has assumed ownership of the compound through exclusive licensing from Lilly. If the compound successfully goes through its second phase of human trials, Lilly will have the option to buy it back.
The key benefit of the deal for Lilly, Swati Piramal says, is that it will shorten the time it takes to develop the drug. Because it's already patented, the clock on the compound's protection from competitors is ticking, and any effort by Nicholas Piramal to hurry its commercial launch would be of great value to Lilly.
Nicholas Piramal cannot do all the work in India, in part because the country does not allow private companies to conduct experiments on primates. But the company has substantial capabilities. In Mumbai, it operates a drug discovery center employing several hundred scientists (C&EN, April 4, 2005, page 21). Through acquisitions, it owns plants in Europe. The company has in the past managed clinical trials of new drugs on patients in North America. And, because her company is much smaller than Lilly, Swati Piramal claims, it can transfer work across national boundaries with far greater ease.
Lilly offered Nicholas Piramal the choice of several compounds to work on, she says. The company opted to license only one, but it could increase that number to four in the future.
Bangalore-based Jubilant Biosys is another company with which Lilly has set up a multiyear partnership. Whereas its parent company, Jubilant Organosys, provides drug manufacturing support, Biosys focuses on drug discovery services. Under their arrangement, Lilly brings in drug leads that Biosys works on before sending them back to Lilly for further development. Lilly covers some of Biosys' costs and will make milestone payments for successful projects.
Expressing the sentiments of many research executives in India, V. N. Balaji, Jubilant Biosys' director and chief technology officer, maintains that "we're not taking away anyone's job in the U.S." He notes that major drug companies that don't tap into the R&D capabilities of India and China face tremendous competition from companies that do. "We're expanding the range of what's feasible," Balaji says.
Balaji set up Jubilant Biosys in 2001 as a provider of informatics services to drug companies abroad. The firm's chief executive officer, Sri Mosur, took Balaji's place not long after visiting the company while employed by a U.S. firm exploring research partnership opportunities in India. It was Mosur, Balaji recalls, who pressed Biosys to add wet labwork to its informatics capabilities.
Jubilant Biosys already employs about 500 people, including 70 medicinal chemists, 20 computational chemists, 30 people in structural biology, and about 200 people developing custom software applications.
Despite what one might think, Balaji claims that Lilly does not actually reduce its research expenses by outsourcing to Jubilant. He explains that the travel costs of the great number of research executives that Lilly has sent to Bangalore to meet with Jubilant scientists over the past year-and-a-half has added up to a significant expense.
THE VALUE Jubilant Biosys brings to a big company like Lilly, Balaji says, is greater efficiency and speed in completing projects outside the bureaucratic structure. And time is money for major drug firms-bringing a drug to market early generates substantial additional profits.
Most of Jubilant Biosys' senior managers have extensive international experience. They have returned to India for various reasons, the one most often cited being the desire to be close to relatives.
During her 17 years in the U.S., Veena R. Agarwal, the firm's vice president of drug discovery, held R&D positions at Bayer's research center in West Haven, Conn., at Ligand Pharmaceuticals in San Diego, and at the National Institutes of Health in Bethesda, Md. Walking through Jubilant Biosys labs that she helped design, Agarwal observes that the facilities are similar to what one would find at a top U.S. company. "Our managers come from different organizations, so we have incorporated principles of the Bayer way, the Pfizer way, and so on," she says.
She contends that outsourcing to India could enable major drug companies to launch new treatments that doctors will prescribe only to certain patients according to their biomarkers. So far, Agarwal says, the enormous cost of developing new drugs has stopped pharmaceutical companies from researching treatments that work only for certain groups of patients. She says this field, known as personalized medicine, has become a hot topic among drug researchers.
Rashmi Barbhaiya, of Advinus, has his own take on how working with partners in India enables major drug companies to ratchet up their R&D productivity.
Unlike the managers at Jubilant, Barbhaiya argues that doing drug research in India costs a lot less than it costs in the U.S. Big companies, he observes, spend most of their money studying compounds that aren't launched commercially because researchers run into safety or effectiveness hurdles. "When you do research in a place where the cost of failure is less, it is bound to have a beneficial impact," he says.
Two-year-old Advinus operates in two locations. Aiming to become a pharmaceutical innovator, it pursues its own drug discovery efforts in Pune, a city about 80 miles east of Mumbai, where it has a lab staffed with 70 scientists. In Bangalore, Advinus has established a drug development lab dedicated to serving international pharmaceutical companies.
Advinus' biggest foreign partner so far is Merck. Under a multiyear agreement, the two firms are looking at codeveloping drugs for metabolic disorders and are focusing on two targets. Advinus will get as much as $75 million in milestone payments for work on each target, as well as royalties if new drugs are launched.
Bharbaiya says Merck executives were in touch with him even before Advinus was launched, at a time when he was still thinking about starting his own drug discovery firm in India. "This is a true drug discovery alliance," he notes. "Whatever we discover under the alliance, the patents will belong to us, but the worldwide rights will be assigned to Merck."
Barbhaiya is a well-known figure in the U.S. pharmaceutical industry. The holder of a Ph.D. in clinical pharmacology from the St. Bartholomew's Hospital Medical College of the University of London, he is a 21-year veteran of BMS, where his last position was vice president of the company's Pharmaceutical Research Institute in Princeton, N.J. He returned to India five years ago to head the R&D operations of Ranbaxy Laboratories, but he left after two-and-a-half years to form Advinus.
Advinus' Bangalore lab features some capabilities that are unique in India. "This lab is the Rolls-Royce of drug development labs in India," comments K. S. Rao, the company's senior director of toxicology and safety pharmacology, while leading a tour of the site. Large enough to accommodate 400 scientists, the lab is the only one in India to have all the capabilities necessary to file an Investigational New Drug Application with the U.S. Food & Drug Administration, Rao says.
The Bangalore unit, Rao adds, includes the largest animal research facility in India that is allowed to perform work for other companies. Its operational practices are certified by the Association for Assessment & Accreditation of Laboratory Animal Care International, which, he says, is the highest qualification a lab can get for ethical handling of lab animals. Advinus is authorized to host rodents and dogs.
As is the case with Jubilant, Advinus is managed by people with substantial international expertise. Rao returned to India after 38 years abroad. He worked at Dow Chemical for 21 years, including three in Sydney, Australia, where he managed the regulatory registrations of agrochemicals and other products in 14 Asian countries.
Advinus stands for Advantage-India-U.S., Barbhaiya says. He and other senior managers own some equity in the firm, but its main shareholder is Tata, India's largest business group. In Tata, Barbhaiya says, he found a partner that could back his dream of launching a drug discovery company. For example, the Bangalore facility makes use of a toxicology lab where Tata had been testing agrochemicals. The lab has been substantially upgraded, but about 110 Tata employees who were already at the site now work for Advinus.
Like Tata, AstraZeneca has operated facilities in the Bangalore area for decades. It operates a drug formulation plant in the city employing nearly 300 people.
The firm conducts two types of research in Bangalore at a site on eight well-landscaped acres. Since 2003, it has run a drug discovery center targeting tuberculosis, a disease that affects about 16 million Indians, the company says. The center employs 90 scientists and is part of AstraZeneca's efforts to address neglected diseases. The firm claims it has been four decades since a major drug company seriously looked at tuberculosis. During that time, the disease has become resistant to many drugs.
The company is also ramping up operations at a new process R&D center, its fourth worldwide and the first outside Europe. This facility taps into the traditional strengths of India's synthetic organic chemists in developing efficient ways to produce commercial drugs. Sudhir Nambiar, the director of the facility, says 40 scientists are already at work and that number will reach 80 by next year. While the site gets into gear, it maintains close contact with the other AstraZeneca process development centers. Staff from the other centers regularly visit Bangalore.
"We're the only major drug company to do both drug discovery and process development for new drugs in India," he says. Other AstraZeneca process development centers around the world typically employ about 200 scientists. The Indian center has a lower headcount, he says, because it's new and has yet to prove itself.
Nambiar claims the center has delivered "marvelous" results so far, albeit mostly as a supporter of AstraZeneca's other process development centers. But by the end of this year, the center will start managing its own projects. It will have to discover efficient methods for large-scale delivery of compounds that have been produced only in research labs.
With its largest production facilities consisting of four kilogram-scale labs, the center cannot currently produce enough material to support drug clinical trials. But depending on the Bangalore's team performance during the coming year, Nambiar says, the center may get a pilot plant with enough capacity to support human trials.
Although AstraZeneca conducts its own research in India, scientists at corporate headquarters and at other locations abroad also outsource work to third-party Indian firms. One recipient is Syngene, a company that at 13 years of age is the granddaddy of India's contract research sector. Syngene employs 600 scientists and is a wholly owned subsidiary of Biocon, India's largest biotech firm.
For research managers at big pharmaceutical firms who contemplate ways to do work in India, there is a middle ground between setting up a company-run lab and assigning projects to a third party. Syngene, in a deal that represents that middle way, is building a dedicated lab that it will operate on behalf of BMS. The lab will employ 400 scientists.
BMS's deal with Syngene is similar to one set up last year by Wyeth and GVK Bio, a contract research firm in Hyderabad, a major drug production center 300 miles north of Bangalore (C&EN, May 16, 2006, page 34). The lab that GVK is building on behalf of Wyeth will employ as many as 150 scientists.
The Syngene-BMS deal is the natural evolution of 12 years of collaboration, says Goutam Das, president of Syngene. "They know us as much as we know ourselves," he points out, because BMS was one of Syngene's first customers.
Das says the BMS facility is scheduled to be fully staffed in 2010. Syngene will operate the center until at least 2013, at which time the companies will review their arrangement. The BMS center is located on land owned by Biocon, he says, but it would not be impossible for BMS to fence it out and take full control of it.
C. G. Sethuram, an executive at the industrial group Archean in Chennai who previously developed the contract research business of Sanmar Group, predicts that BMS will choose to buy the facility. Big drug companies such BMS and Wyeth, he says, ultimately will prefer to run their own facilities rather than go through a third party.
"I think that eventually, all the major drug companies will have their own corporate research laboratories in India," he says. He adds that drugmakers should look at General Electric for inspiration on how to do things in India. In 2000, the U.S. giant set up a large research lab in Bangalore employing more than 2,000 scientists.
BMS could just as well have decided to build its own Indian lab, Das acknowledges. "But it's a question of taking full advantage of the costs here," he says. He notes that BMS does not have the experience of undertaking a large project in India, certainly not something that entails employing 400 researchers.
Das further explains that the deal between the two companies is structured in a predictable manner. It's basically a long-term fee-for-service agreement that does not provide Syngene with any royalties for work done on drugs that are commercially launched. The deal's most interesting feature, he says, is that it includes a substantial amount of biology, a scientific component that is relatively new for contract research companies in India.
Das has been in the partnership business longer than most Indian executives. In the early days, he had to endure the skeptical attitude of foreigners and Indians living abroad concerning the idea of conducting research in India. Later, he heard stories about how Indian scientists were supposedly taking jobs away from Americans while providing inferior services.
He says it's absurd to think that Indians are stealing jobs. Big drug companies need Indian scientists, he says, simply because there aren't enough researchers in the U.S. and other developed countries to take on all the projects that drug companies have under way.
As to the performance of Indian scientists, it's clearly providing value, or the major drug companies would not be so keen to get more and more entangled with India. The key question for these firms is not whether India provides value but rather how best to tap into it.
- Chemical & Engineering News
- ISSN 0009-2347
- Copyright © American Chemical Society