Clinical trials: Human lab rats feed biz growth

Clinical trials: Human lab rats feed biz growth
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First Published: Wed, May 30 2007. 09 39 AM IST
Updated: Tue, Jun 05 2007. 06 21 PM IST
One recent May morning, Sonu Sarkar stood among 60 candidates at a Mumbai drug testing facility that planned to recruit 10 healthy volunteers for a new drug test for a multinational client.
An unemployed 24-year-old from Ahmedabad, Sarkar got to know of the test through an agent, who, working on behalf of the lab, was offering free food and Rs3,000 for a four-day study.
The cash was compelling for Sarkar, who had been introduced to the agent a couple of months ago at another testing laboratory in Ahmedabad.
“I get money and food besides medical care. We swallow the pills they give and just relax while they draw some 10-15 blood samples,” says Sarkar, who has had on-and-off jobs in the last five years since finishing senior school.
The extra Rs18,000-25,000 he will earn if he enrolls for six such drug studies a year, he hopes, will add to his meagre income. The sole breadwinner in his four-member family, Sarkar says he is desperate to make a living, any which way.
Sarkar is just one of the hundreds of human “guinea pigs” in the country who have chosen this route to make a living even as the loosely regulated drug trials business explodes in India.
“Being a drug trial subject is a new ‘secret profession’ that has emerged out of the burgeoning pharmaceutical development services business in India,” complains Sanjai Shobhan, director of Mumbai-based PeopleCare, a consumer awareness forum.
During a recent visit to India, Dennis Gillings, chairman of the world’s largest ‘contract research’ firm, Quintiles Transnational Corp., said his company prefers to do more trials here. “In India, we found volunteer recruitment is much faster than anywhere else, which helps us save time as well as keep costs low,” he told Mint in an April interview.
The market for such drug tests, called clinical trials, is expected to grow at 25-30% annually to touch over $600 million (Rs2,400 crore) by 2010, says Arun Bhatt, president of Clininvent Research Pvt. Ltd, a contract research organization (CRO). It is today worth $210 million, more than 10 times the $20 million in 2002, according to a recent report by audit firm KPMG.
Meanwhile, India’s diverse genetic pool—from Caucasoids to Australoids, from Mongoloids to Negroidal—and a wide variety in terms of lifestyle, food habits and biological constitution make it a unique destination for drug research companies. Also, a fast-growing domestic market for medicines—Rs33,000 crore per annum—makes it essential for drug makers to be ready with Indian test data for each of their new drugs.
Not surprisingly, then, global majors, including Pfizer Inc., Glaxosmithkline Plc., Novartis AG, Bayer Corp., Sanofi Aventis SA and Merck & Co., are among those conducting extensive trials in India for drugs to treat diabetes, cardiovascular conditions, cancer and for conditions afflicting the central nervous system through local partners as well as their clinical research units.
“We receive 25 to 30 applications a month seeking approvals for new drug trials,” about double what it was a few years ago, says M. Venkateshwarlu, drug controller general of India (DCGI).
Clinical trials involve the testing of a new drug on humans after successfully proving that the chemical or ‘bio-pharmaceutical’ has the potential to cure a disease or control a disorder, and that tests on animals show no adverse reactions.
Human trials are conducted in three stages. In the first phase, a drug is tested on a handful of healthy human volunteers to prove the safety of the drug being tested and measure the maximum tolerable dose that can be administered to healthy volunteers; the second stage involves trials of the drug in a limited number of patients suffering from the disease or disorder the medicine is meant to address; and the third and final phase is the extended trial of the drug in patients in multiple locations.
Important as it is to bring a new drug to patients, first phase studies using healthy volunteers often involves major risk as the drug is being tested on a human for the first time and the sponsor (drug firms sponsor the trials), CRO and the regulator, which approves the trial, have no prior data of how the drug behaves in a human body.
In India, when trials are outsourced to a CRO, there is an agreement entered into between the sponsor and the investigator to keep every bit of data pertaining to the trial confidential even as human subjects in the trial are supposed to be fully informed about the nature of tests and its side effects.
Multinational drug makers outsourcing testing to India are also putting in place systems to ensure quality of data. Companies such as Sanofi Aventis’ local unit, for example, maintain an independent drug development monitoring cell that is separate from its clinical research operations, to oversee its clinical trials for compliance with international trial protocols, ethical practices and patient and trial subject safety. “Large companies insist CROs too follow the standards strictly as these companies are taking a higher risk of failing a trial by mishandling it. (The standards) help avoiding risks of subjects,” says Dhananjai Bhakle, senior director, medical and regulatory affairs, Aventis Pharma Ltd.
But the scenario on the ground is different as public awareness about drug trials is low and even those taking to this “profession” are not an exception. While the payments appear good—anywhere between Rs3,000 and Rs10,000, depending on the study—it does come with risks that may not be fully understood by the volunteer. The medical director of the Indian unit of a Swiss multinational company says, on condition of anonymity, that the rules and processes large global companies follow are often much more stringent that at local CROs.
“Unless the CROs are equipped with an emergency medical care facility within the lab to handle critical adverse reactions, which is always expected in a Phase I study, the organization as well as the volunteers are taking a big risk,” says Bhatt.
Most CROs in India do not have a dedicated medical emergency cell attached to their facilities; some have tie-ups with nearby hospitals. However, since time is very crucial in the case of an adverse event, many such unequipped centres are incapable of handling situations that may ending up costing lives.
In 2000, Dharmesh Vasava, a 22-year-old volunteer from Bharuch in Gujarat died while participating in tests on Citalopram, an antidepressant drug. The study was sponsored by Sun Pharmaceuticals Industries Ltd, one of India’s biggest drug makers, which denied the death was caused by the trials. A case is pending in the Gujarat high court.
Three years later, three deaths were reported in Hyderabad during a clinical trial to test the drug recombinant streptokinase, an effective and cheap clot-dissolver. The trial was sponsored by Shantha Biotechnics Ltd, whose MD insists there was no wrongdoing. “Those who died during the trials were patients of myocardial infarction or heart attack. Their death was not because of the product,” says K.I. Varaprasad Reddy. “The regulatory authorities have realized that the product was safe and accordingly, approved manufacturing of the product.”
Still, say industry experts, many volunteers only broadly know the risks associated with drug tests and aren’t necessarily fully informed. “In India, monetary compensation may be the only subject that is discussed with the volunteers,” says C.M. Gulati, editor, MIMS, a monthly trade publication devoted to drug launches. “There are lots of issues concerned with conducting Phase I trials, right from patient recruitment to consent to compensation,” adds Gulati.
No one exemplifies such “issues” better than Shanmukh Shetty, a middleman who brings in study volunteers for CROs in Mumbai for a commission. The availability of test candidates is the least of his worries; he is more concerned about the fitness of his “volunteers” as he gets his fees only when the people qualify for participating in the studies.
Shetty explained his methods to Mint. When the CRO needs to recruit volunteers for a trial, it just spreads the word among its agents. Once details such as tenure of tests, number of trial subjects needed, location, payment and other factors are understood, the agent sets about roping in volunteers—either from his own diary of such “professionals” or fresh recruits. “The usual places we go first to find new volunteers are the blood banks of large hospitals where people in need of money come to donate blood,” said Shetty said in a recent interview at Mumbai's KEM Hospital.
“Koi hai kya kaam pe laganeko? Koi hai tho bol dena; acha paisa milega,” Shetty told this reporter. (Do you have anyone to put on the job? Tell me if you have someone; one can make good money.)
Another agent from Ahmedabad, who did not want to be identified because he may lose business from regular customers, said he relies on what is already a long list of ‘volunteers’ in his diary. When he gets an assignment from a CRO, he just dials his men and ensure their availability—even if it means that the test subject has not completed the mandatory two months from the last round of tests. The two-month period is de riguer in this industry so that the effects of the drug used in the previous test do not remain when the next round of tests are done.
“One needs to ensure that the ‘professional test subjects’ keep a minimum gap of two to three months between assignments,” says Clininvent’s Bhatt. “A major concern is that many of the CROs do not have effective system to ensure that the volunteers are not participating in cross-trials during the intervals of a study.”
Some CROs, such as Lotus Labs Pvt. Ltd, work directly with volunteers on its own database, which it claims has over 4,000 subjects, to keep out volunteers who enrol for tests in rapid succession.
“While volunteers come from a varied background, our internal policy does not allow them to participate in more than one study per quarter,” says a senior official of the Bangalore firm, who asked not to be named as he is not authorized to talk to the media.
Yet, there is no foolproof biological method to test that a volunteer is keeping the two-month gap or, worse, is not participating in another trial at the same time, despite most CROs having specialized staff to keep such “offenders” out. Screening processes at CROs include general physical fitness test, blood tests to ensure that the volunteer is free of any kind of infections, HIV and hepatitis besides other routine health checks to ensure the people are not drug addicts.
According to industry estimates, currently more than 200 Phase I studies are being conducted in India. Each study typically requires about 25 healthy volunteers, taking the total number to 5,000. Depending on the nature of drugs, the period of study varies from four to eight days and often there are two stages of studies for a 20-day trial with a gap of two weeks.
The manner in which some of these drug tests occurs in India galls some. Says Rashmi Bharbhaiya, chief executive of Advinus Therapeutics, a Tata group-backed drug discovery company in Bangalore, “Unlike in the developed countries, many illiterates in India seem to be used for drug trials, which is quite unethical and should not be tolerated,” he says, noting he himself has been a trial volunteer while doing his doctorate in the UK.
But, it is also lax laws in India, which are supposed to govern such testing and loopholes, that encourage some CROs to take short cuts. ‘Good clinical practices’ guidelines, which are codified ethics that govern clinical trials in India and framed by Indian Council for Medical Research (ICMR), specify that payments to trial subjects should not be so large as to induce volunteers into such trials with little regard for the risks of such testing. But the guidelines stop short of prescribing a ceiling. It also suggests that all payments, reimbursements and medical services to be provided to the volunteers should be approved by independent ethical committees consisting of members from different walks of life including lawyers, consumer activists, medical professionals and social workers.
The catch: none of these guidelines are mandatory on CROs or drug companies. And in the absence of self-regulation among new-found CROs chasing business, volunteer safety has the potential to become a casualty, say some. For instance, ethical committees are often far from independent and several CROs have formed their own advisory teams to the ethics that govern such testing.
C.J. Shishoo, a pharmacologist and chairman of Ahmedabad-based Suraksha, one of the half-dozen independent ethical committees in India, calls the government’s ability to crack down on unethical practices “still weak”. “The government monitoring has to be strengthened by implementing practices of regular inspections, and also change the laws to make CROs and study sponsors more responsible for risks of the subject,” says Shishoo.
The payment to trial subjects also needs to be regulated, says Urmila Thatte, head of the department of clinical pharmacology at BYL Nair Hospital in Mumbai. Some CROs, she says, “are paying very high sums of money to volunteers in Phase I studies”.
CROs get paid anything from Rs5 lakh to Rs40 lakh for their services for each trial.
Still, some changes are being ushered in. Recently, the government altered the rules under Schedule Y of the Drugs and Cosmetics Act, 1940, making the subject consent forms in vernacular languages to enable volunteers to understand the implications of participating in clinical trials. This became important, say drug policy makers, after India allowed last year Phase II and III trials to be conducted simultaneously with tests in developed countries, overturning a long-standing rule that such trials would be allowed only after they were done in the West. However, simultaneous first phase studies of foreign molecules are still not allowed here even unless it is for molecules discovered in India.
DCGI Venkateswarlu says he believes in even more periodic revisions in testing regulations. “Facilitating smooth transition for scientific advancements and R&D progresses are essential for a developing country. If developed countries have achieved it, why can’t we?” he asks.
The rule changes will only aid the growth of an industry that the pharmaceuticals world will increasingly look towards for testing new drugs. Says Aventis Pharma’s Bhakle: “India just entered into the space as there weren’t many new drug studies in the pre-patent regime. As long as the sector grows, it will certainly help evolving better legal framework to avoid the risks involved.” For Sonu Sarkar and hundreds of ‘treatment naive’ Indian drug trial subjects, that will be the protective shroud the pharmaceutical world promises.
(ch.unni@livemint.com)
(Y.V. Phani Raj in Hyderabad contributed to this story.)
This is the first of a two-part series.
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First Published: Wed, May 30 2007. 09 39 AM IST
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