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In India, oversight lacking in outsourced drug trials

GUJARAT, India – Rambha Gajre was desperate. She and her family faced eviction from their cramped, tin-roof hut if she didn’t soon repay loans she used to cover life-saving medical treatment for her son.

David Lom/NBC News

When Rambha Gajre and her family faced eviction from their cramped hut in Gujarat, India, she signed up to be a human guinea pig in drug trials for foreign pharmaceutical companies.

Hauling bags of concrete mix for $1 a day wasn’t nearly enough to pay back the money she borrowed to pay a doctor to repair a hole in her son’s heart, let alone feed her family of five more than one meal a day.

“Many people commit suicide,” she told “Dateline NBC,” “and I didn’t want to become one of those and I didn’t want people to think I did it to avoid repaying. I have two young kids, 10 and 12 years old. What would become of them?”

So Rambha did what thousands of other desperate women and men from India’s slums, and across the world, now do to survive -- she signed up to be a human guinea pig in drug trials for foreign pharmaceutical companies.

“I am helpless, I have to do this,” she said. “They don’t really force us, but I don’t have a choice.”
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Now, with the money she earns from drug studies -- up to $250 per trial -- Rambha is slowly repaying her loans.

Drug trial outsourcing to foreign countries is rapidly becoming an attractive alternative for pharmaceutical companies that are looking to save millions of dollars, avoid regulatory scrutiny and tap into a seemingly endless supply of drug study participants. 

Americans fill four billion prescriptions each year. But some medical experts question how strong the safety net is that keeps unsafe drugs off the market.  Dateline NBC's Chris Hansen reports.

But a year-long Dateline investigation into one of the preferred destinations for overseas drug trials, India, raises questions about lax regulatory oversight in these studies, the integrity of some of the companies contracted to run them and the reliability of the data they produce. 

Foreign drug trials have become crucial to pharmaceutical companies looking for approval from the U.S. Food and Drug Administration to sell their products to Americans. Eighty percent of the drugs that the FDA reviews for approval now rely on some tests done on foreign soil, according to a 2010 report issued by the U.S. Health and Human Service’s Office of Inspector General. 

The same report included another startling figure: The FDA inspects fewer than 1 percent of foreign drug trial sites, a number slightly higher than the percentage of sites inspected in the U.S. 

“We have no idea what's going on in these clinical trials,” said Dr. Carl Elliott, a professor at the Center for Bioethics at the University of Minnesota and author of “White Coat, Black Hat: Adventures on the Dark Side of Medicine.”

Elliot worries that the lack of oversight in foreign drug studies leaves poor, and often illiterate, people vulnerable to exploitation when companies consider test subjects part of a profit-making equation. 

Tim Sandler/NBC News

"Dateline NBC" correspondent Chris Hansen interviews "Rekha," another drug trial participant, in her home in Gujarat, India, which she shares with her husband and six children.

“The faster you can get the subjects, the faster that you can do the trials,” he said. “The faster you do the trials, the faster you get the drug approved.  The faster you get the drug approved, the sooner it goes on the market and the more money it makes.”

Testing the Testers

With each drug trial costing an estimated $180 million in the U.S., many pharmaceutical companies are turning to places like India, where they can often pay less than half as much for their human experiments. 

Some pharmaceutical companies, including Pfizer and Bristol Myers Squibb, have their own research operations in India. But other companies rely on foreign middlemen -- contract research organizations, or CROs -- to recruit patients, conduct tests, and analyze data that will be submitted to the FDA.

The proliferation of CROs in India worries Dr. Chandra Gulhati, editor of the “Monthly Index of Medical Specialties,” an Indian medical journal. Indian CROs, he cautioned, are entirely unregulated and unmonitored by the government. 

“They've just come, opened the shop and nobody is asking them any questions,” he said. “To my knowledge, not even one trial has been monitored from A to Z. … They have no legal status in this country.  Who are they?”

To test the integrity of those unregulated companies, Dateline set up a fictitious pharmaceutical company called Malum Kinetics. The company was little more than a $13-a-month homemade website, a post office box address in New York, business cards, cell phones and an answering machine. 

Using publicly available information, Dateline put together a plan to test a drug identical to Vioxx, a pain reliever withdrawn from the market in 2004 and linked by studies to thousands of strokes, heart attacks and deaths.  The plan was virtually the same one that Vioxx’s manufacturer, Merck, used to test whether Vioxx could shrink colon polyps. The test was halted after Merck discovered an increased risk of heart attacks and strokes.

Dateline producers removed Vioxx’s brand and generic names from the plan, but left in other red flags that clearly identified the drug, including the drug maker’s original abbreviation for Vioxx: MK-0966. A simple Google search shows MK-0966 is Vioxx. The plan also included other simple clues, such as Vioxx’s chemical name and its approval history as a pain reliever.

The test: Would the CROs have the basic scientific knowledge to question proposed experiments on humans with a drug already withdrawn from the worldwide market? And how thoroughly would a foreign CRO check the legitimacy of an unknown drug company offering a potentially lucrative business opportunity?

Dateline sent the plan to two prominent Indian contract research companies, Lambda Therapeutic Research and Synchron Research Services. Both firms claim to do business with large pharmaceutical companies. 

Along with reviewing the Dateline study plan, they were asked to develop their own plan to recruit patients, get necessary approvals, and run the actual tests. 

Both companies put together plans, and meetings in India were arranged. 

‘Doctor is God’ 

In the sprawling central city of Hyderabad, Synchron’s director of clinical operations, Narasimha Murthy, warmly greeted Dateline correspondent Chris Hansen, the purported CEO of Malum Kinetics, and his team (all of whom were outfitted with hidden cameras). They were escorted to a bare-bones conference room in a building prone to power outages.

During a laptop PowerPoint presentation, Murthy said that Synchron was well equipped to manage a drug company’s testing from start to finish. 

“It’s one-stop shopping,” he said.

Murthy never indicated that he knew the drug he was bidding on to test was identical to Vioxx.

In fact, he told Hansen that he showed part of the plan to private doctors who would be conducting the clinical trials and they did not spot any safety issues.

“They have not come up with any queries as such,” he said. “They have no issues.”

Murthy also noted that those same doctors would not have a problem finding patients to test the drug. Poor patients getting free treatment obediently follow their doctors’ orders, he assured Hansen. 

“Doctor is god,” Murthy said. “So if I go to him, I will blindly follow what he says.” 

Related story: How poor Indians are recruited for clinical drug trials

Synchron, he said, was ready to move ahead with the plan to test Malum Kinetics’ drug on humans, though he raised the prospect that an Indian ethics panel might have concerns -- not due to safety risks, but because some patients in the study would be receiving a placebo and would not benefit from the drug. 

“Personally, I don’t see any issues,” he said. “We can do it. I am confident that we can do it.” 

The price tag: just over $1 million.

Hansen was invited to meet Murthy a month later at a huge expo in Chicago, where drug companies and hundreds of potential contractors from around the world were to gather to promote their products and services. 

Dateline's Chris Hansen confronts Narasimha Murthy, director of clinical operations for Synchron Research Services, an Indian company that claims to do business with major pharmaceutical companies, at a trade show in Chicago.

When the two met, Hansen disclosed to Murthy that he was in fact a journalist, not Malum Kinetic’s CEO. He asked how it was possible that Synchron did not pick up that the drug they were to test on humans was identical to Vioxx, a drug so potentially dangerous that it was withdrawn from the market worldwide. 

At first Murthy said Synchron would have detected it after more research. But minutes later, he claimed the company knew what the drug was all along. 

“We did pick up, we did pick up,” Murthy said. “But the only thing is we didn’t share it with you at that point of time. We didn’t bring it to your notice.” 

Synchron, he added, would never have agreed to take on the test. 

“We definitely wouldn’t have taken it up,” Murthy insisted.  And, he added, an Indian ethics committee would have found problems with the study too, contradicting his optimism about getting approval during the meeting in India. 

“The ethics committee would definitely halt it,” he said before turning away and walking back to Synchron’s promotion booth. 

‘This is a very risky trial’

Dateline’s meeting with executives at the other CRO, Lambda Therapeutic Research, in India ended more contentiously. 

In the fast-growing western Indian city of Ahmedabad, Lambda’s immaculate headquarters and test facilities rise above desolate slums that supply an endless stream of drug study volunteers. 

Armed guards met Dateline’s team at the gate and directed them to an expansive reception area. A sign greeted them: “Lambda welcomes Mr. Hansen & Malum Kinetics team." 

Dr. Philip Mathew, a Lambda vice president who ran clinical trials for a contract research company in the U.S. before joining the firm, led a tour of the vast facility, pointing out  offices, labs and scores of human test subjects. 

“These are our volunteers,” Mathew said, walking past test recruits watching a wide-screen television in a waiting area.  The test subjects earn an average of $150 per study, he said, noting it was a fraction of what researchers in the U.S. would pay their volunteers. 

“That’s for the entire study, as opposed to, say $150 a day, which is what the U.S. rates are,” he said. 

In a plush boardroom, Lambda’s presentation was projected onto a large screen. One company executive said four specialists, all physicians, had reviewed the Malum Kinetics plan.

“They came to the conclusion it’s practical,” he said. 

Lambda’s price tag for the project: $775,000. 

Well into the discussion, Mathew raised a concern that suggested he knew that the proposed study was fictitious. After months of correspondence with Malum Kinetics, he said his team had just realized the test drug was the same as Vioxx. 

“It’s withdrawn currently worldwide, right?” he said. “It’s not sold …This is a very risky trial.” 

But rather than turn down the business because of the drug’s potential deadly side effects, Mathew said Lambda was still interested in getting the trial started. 

“We are willing to give it a fair trial,” he said. “We are in the business of doing research regardless of how challenging the project is, but we have to be also realistic.” 

Mathew and his team said they would need to take precautions to protect patients, such as monitoring those with cardiac risks and lowering doses if necessary. 

But the major challenge, he explained, would be persuading an Indian regulatory board to approve human testing. 

“We have to have a huge, huge scientific argument to make the case for doing a study with Vioxx,” he said, noting that Malum Kinetics would have to help Lambda prepare a scientific case. 

To help build the scientific argument, Mathew proposed a strategy: hire a well-connected medical opinion leader as a consultant to persuade Indian regulators to allow the drug be tested on humans. 

“Nothing works like consultants from within India who are in this field who can speak for the drug,” Mathew said. 

By paying a $5,000-to-$10,000 consultant fee, he added, “We can take whoever we want who is a big heavyweight in India.” 

Asked how confident he was that a consultant could help make a winning case for a drug like Vioxx, Mathew replied, “Very confident. Very confident.” 

He estimated the odds for approval were “fifty-fifty.” 

 “From our perspective,” he added, “we’d love to take on the challenge.” 

“Lockdown now!” 

The meeting ended with Lambda ready to take the study to the next level. With most of the executives gone from the room, Hansen pulled Dr. Mathew aside, and, with two open cameras now trained on him, informed the Lambda executive that he was a news reporter. Malum Kinetics, he told him, did not exist. 

“I knew that,” Mathew said, laughing nervously. “You must be out of your mind to come here with a withdrawn drug.” 

Unaware that hidden cameras had recorded the entire tour and meeting, Mathew backpedaled. 

“We are fully aware of the risks of Vioxx and we never agreed to do your study,” he said. “We want to discuss with you what this is all about.” 

Hansen reminded Mathew, “Even after we talked about this being Vioxx, you said that we could go ahead and very likely do a study.” 

“No. Fifty-fifty it will get rejected,” he replied. 

“Fifty-fifty we could go ahead,” Hansen said. 

Mathew said he took offense that Lambda’s integrity was being questioned. 

“We stand for ethics,” he said. “We work for sound scientific principles.” 

Another Lambda executive, Mrinal Kammili, stepped in and angrily declared the interview over. With the tension in the room rising, Hansen told the executives, “If you want us to leave, we’ll respectfully leave.” 

But Kammili blocked the door. Raising his voice, he told the NBC crew, “Please have a seat! Please have a seat!” 

“You can’t hold us against our will,” Hansen said, moving toward the doorway. 

Kammili responded that they were calling the police, and once again insisted that the crew be seated. 

Security guards at Lambda Therapeutic Research, a contract research company in Ahmedabad, India.

Mathew yelled to other staff in the room. “Call security! Lock the doors! Lock down now!” 

A security detail quickly arrived to guard the door, detaining Hansen and the rest of the Dateline team for nearly five hours. 

Local police arrived and logged complaints from Lambda and the Dateline crew, who were eventually escorted out of the building and brought to a small police station. 

After reviewing the allegations, the top police inspector informed Lambda’s executives that the Dateline crew had not violated any laws.  The crew was free to leave, he said, on the condition that copies of footage taken openly at Lambda be provided to police and Lambda executives. Neither group was aware of Dateline’s hidden camera footage. 

Assessing the risks 

Dateline took its findings to former FDA Commissioner Dr. David Kessler. 

“No contract research organization should undertake any clinical trial without being sure that the risks are acceptable in light of the benefits,” he said.  “And in light of what was known, that conduct is just totally unacceptable.” 

Kessler said questions about the integrity of foreign drug trials, and those who run them, will only increase until a universal system is in place that roots out unqualified researchers. 

“Any doctor who runs a clinical trial should be certified, should be trained, should have specific qualifications to do those trials,” he said. 

Doug Peddicord, the director of the Association of Clinical Research Organizations, defended the industry's track record. 

“Concerns notwithstanding, on the whole the clinical research enterprise is amazingly safe and amazingly productive,” he said. 

Peddicord, whose organization does not include Lambda or Synchron as members, says there is too much at stake for the industry to tolerate unethical behavior. 

“In the instances where we have seen bad actors,” he said, “we’ve often seen that those bad actors go out of business rather promptly.” 

The pharmaceutical industry's lead trade group, Pharmaceutical Research and Manufacturers of America, declined comment. 

U.S. Sen. Charles Grassley, R-Iowa, an outspoken critic of the FDA’s oversight of pharmaceutical companies, faulted the agency for not taking a more active role in policing clinical trials from the very beginning. 

“They don't oversee those clinical trials until most of them are completed. Then they see the results,” he said. “To what extent can they trust the results?” 

The FDA declined requests for an interview, but said in a statement that the agency is already "strongly engaged in the clinical research process" -- from inspecting drug makers and their contractors to monitoring drugs after they are approved for sale. 

The agency also said it is establishing international offices to "improve its ability to oversee" the growing number of foreign drug trials. 

Kessler believes the situation will not improve until Congress provides the FDA with the resources it needs to more fully monitor and regulate the clinical trial system. 

In the meantime, Kessler worries about the ongoing risks -- risks for volunteers testing the drugs and for the people to whom they are ultimately prescribed. 

“What's going to happen, and I can predict this … it’s been the history over the last 100 years.  We don't act until there's a problem.”  

“Until people die?” Hansen asked. 

“Regrettably.”