Ethics on Trial

Ethics on trial

Ankur Paliwal

Date:Jun 30, 2011

Five per cent of the clinical trials conducted across the world will be in India by 2012. They are vital for confirming the efficacy of a new drug, but compromise on ethics. While doctors and organisations conducting trials make big bucks, the rights and safety of the subjects are often overlooked, says

Ankur Paliwal

This two-time participant stopped volunteering after she suffered side-effects (Photo: Sayantoni Palchoudhuri)Nine-year-old Rani is unhappy. She has to stay away from her mother Janki Patel, who is taking part in a clinical trial at a centre 10 kilometres from her house at Bapu Nagar in Ahmedabad. “I do not like these trials. They take my parents away,” says Rani.

In their late thirties, Janki and her husband Amar Patel attend trials so that they can pay Rani’s school fee and earn two square meals a day. They are subjects of non-therapeutic trials conducted on healthy individuals to confirm efficacy of drugs launched abroad on Indians. One trial fetches them between Rs 5,000 and Rs 6,000. The money kept the Patels going after they lost their jobs as diamond cutters three years ago when the market crashed.

BA Research India Limited, a contract research organisation (CRO), asked Janki if she was willing to take a cancer drug which may have side-effects like vomiting and headache. Desperate for money, she gave in. CROs recruit participant, design trials, and manage and analyse data obtained from the trials.

Within two years, Janki has taken medicines for heart ailments, chest pain and fertility. She now complains of joint pain. Amar, who has undergone three trials, suffers blackouts. They spend their savings on their treatment now. When they approached the CROs—BA Research and Lambda—they were asked to prove that their ailments were side-effects of the trials. “I know it is sheer exploitation,” says an agent who recruits subjects for CROs. “I am asked to focus on the poor because they desperately need money. A rich person rarely becomes a subject.”

“When one person is given many medicines, it can have side-effects, especially if there is no proper spacing,” says Deval A Parikh, consultant gastroenterologist at Jagmohan Hospital, Ahmedabad. Parikh conducts trials in the hospital.

Hundreds of kilometres away at Indore in Madhya Pradesh, Sooraj and Reena Yadav were clueless that their only child was subject of a clinical trial. In November 2009, four-year-old Deepak, whose growth is stunted, developed stomach problems. He was taken to Chacha Nehru Bal Chikitsalaya, a government hospital for children. Doctors there, Ashish Dube and Nirbhay Mehta, said Deepak had “shrinkage” and abscess in the intestine, and would need prolonged treatment. “I was promised a monthly compensation of Rs 250 for wage loss and transport,” says Sooraj, a vegetable seller. He was also told Deepak’s medical tests would be free.

He came to know his son was being tested for a drug when Down To Earth read out the medical report to him. Deepak was being used to test Rebeprazole, an anti-ulcer drug made by Johnson & Johnson.

“We should have been told an unknown drug was being tested on our child and given the choice to say no,” says a visibly disturbed Sooraj.

As per the law, the subject of a trial or his family must be given copies of the patient information sheet, informed consent form and clinical trial liability insurance policy, says Anand Rai, health activist and doctor. Deepak’s doctors told Sooraj the medical records would be kept in the hospital.

Hemant Jain, principal investigator of the trial, claims Sooraj was given copies of all the documents. “He may have lost them,” he says. Asked to produce the original papers, Jain said they were confidential.

Sooraj says he should have been informed his son Deepak was a trial subject (Photo: Aparna Pallavi)Governed by Schedule ‘Y’ of the Drugs and Cosmetics Act, 1940, clinical trials must be monitored by the Drugs Controller General of India (DCGI) and ethics committees. No trial can begin without the ethics committee’s consent. A body of at least seven members comprising professionals like pharmacologists, lawyers and sociologists, an ethics committee can be institutional or independent. It is this body’s responsibility to safeguard the rights, safety and well-being of a trial subject. It should also check the trial design, ensure insurance cover and review informed consent forms.

The basic ethical guidelines for performing clinical trials is the Declaration of Helsinki issued by the World Medical Association. In India, guidelines have been set by the Indian Council of Medical Research (ICMR). But there is no law that makes the guidelines binding on those involved in conducting trials (see ‘From lab to market’, p35). Trials must also adhere to Good Clinical Practice guidelines of the International Conference on Harmonisation drafted in 1996. It facilitates mutual acceptance of clinical trial data by the regulatory authorities of Japan, EU and the US—the three major drug manufacturers. The United States Food and Drug Administration, however, recently said it will not require conformation to the Declaration of Helsinki for trials done outside the US.

Business of clinical trial

The global clinical trial industry is worth Rs 1,56,870 crore. Clinical trials conducted in India in 2008 were worth Rs 1,345 crore, shows data collected by Ziven Consulting, a Gurgaon-based clinical trial consulting firm. The figure may seem small but is growing at a staggering 65 per cent every year.

From lab to market
When a new drug is discovered, the office of the Drugs Controller General of India (DCGI), the regulatory authority, grants permission to conduct clinical trials in India. An ethics committee, formed by the institution conducting the trial, gives its stamp. The Clinical Trial Registry of India (CTRI) registers it as a drug being tested in India. The trial is conducted by investigation agencies, which could be CROs or non-profits. Data from trial sites is submitted to DCGI after which marketing licence is issued.

The trial business is likely to reach Rs 8,951 crores by 2012. In the next five years, India may conduct about five per cent of the global clinical trials, the firm’s data shows.

Of the total cost of research and development (R&D) almost 70 per cent is spent on conducting trials. In 2010, US biopharmaceutical research companies invested Rs 3,02,086 crore on R&D, up from Rs 2,95,364 crore in 2009, states the report ‘Putting CROs on the radar’ of the Centre for Research on Multinational Corporations (SOMO), a Dutch non-profit.

Clinical trials are conducted in four phases (see ‘Phases of clinical trials’,). It is the third phase which is most expensive. Conducted on 1,000-3,000 patients, it confirms the therapeutic benefits of a new drug. PhRMA, an association of drug companies in the US spent Rs 2,12,446 crore on R&D in 2008. In the third phase the drug companies spent a whopping Rs 69,022 crore. This calculates to 32.5 per cent of the total amount, the SOMO report states.

Multinational drug companies, therefore, outsource the third phase of trials to non-traditional research areas where cost is much less. Countries of Latin America and Eastern Europe, besides India, China and Russia, have become the clinical trial hotspots. About 50 per cent of the new drug applications submitted in the EU and the US say trials are being done in these countries, the SOMO report states.

“Compared to Western Europe and North America, these countries are less regulated. They have a less developed healthcare system and a relatively vulnerable population,” says SOMO researcher Irene Schipper. Indian industry is the winner as it gets huge amounts when the currency is converted to rupee.

Boom time for CROs

Most pharmaceutical companies conduct trials through CROs, which have mushroomed to take advantage of this booming business opportunity. Its market in India has grown from Rs 423 crore in 2005 to Rs 1,611 crore in 201 0 (see ‘Charting progress’). It is expected to cross Rs 2,721 crore by 2012, says SOMO.

According to CROs, payments cover expenses like recruitment fee, staff salary, equipment and communication. “The principal investigator—the doctor conducting the trials—gets Rs 25,000-Rs 30,000 per patient,” says Sudip Sinha, vice-president and country manager, CliniRx, a Gurgaon-based CRO. The amount may increase to Rs 80,000-Rs 90,000 if trials are for complex diseases like cancer which take a long time to complete. The investigator gets 50 per cent of the amount budgeted for the trial because he is responsible for ethics approval, consent, recruitment and safety management, says Arun Bhatt, president of Clininvent Research, a Mumbai-based CRO.

Investigators in private hospitals are paid much more. Money ranges from Rs 70,000 to Rs 1 lakh per patient.

Regulatory authorities have no control over CROs. They are not mentioned in Drugs and Cosmetics Act and are not required to get registered. “They have mushroomed on their own to make money. If questioned, they can easily shut shop and disappear,” says C M Gulhati, editor of Monthly Index of Medical Specialities. Anyone who is trained in clinical research and has good contacts in hospital and laboratories can set up a CRO, says Amit Sengupta, member of All India People’s Science Network, a non-profit.

Taking advantage of poor regulations, many CROs compromise on ethics. They are called data producing shops. At times they do not report adverse events as it delays completion of the trial, says Divya Bhagianadh, researcher with the Centre for Studies in Ethics and Research (CSER) in Mumbai. They complete trials at least 30 per cent faster than pharmaceutical companies, states a SOMO report.

Destination India

Pharmaceutical companies prefer India because of low cost—almost 60 per cent less than the US or Europe. India has a large number of patients with acute and chronic diseases and lifestyle disorders. The country’s genetic diversity also helps in achieving accurate results. “There are many ethnic groups in India. Testing drugs on people with different ethnicities helps get diverse data,” says Sengupta.

Besides, India has a large “treatment naïve” population—people who have not been diagnosed or treated for specific diseases. This minimises interference of the effect of other drugs. “The US population is therapeutically saturated with most people taking six to seven drugs a day,” says Mohan Rao, professor at the Centre for Social Medicine and Community Health, Jawaharlal Nehru University, New Delhi.

Maharashtra accounts for maximum number of trials conducted in India, shows data maintained by the CSER. Of the 882 trials registered till June last year, 239 were conducted in Maharashtra. A large number of trials are also being done in Delhi, Bengaluru and Ahmedabad.

Source: US National Institute of HealthIn India, the earliest big trials were conducted in 1995 by Eli Lilly and Pfizer. Sanofi-Aventis, Bayer, Novartis, Johnson & Johnson, GlaxoSmithKline and Merck followed in mid-2000. Conducting trials in India became easy after the 2005 amendment to Drugs and Cosmetics Act, which permits concurrent trials. According to this, second and third phase trials of drugs discovered abroad can be conducted in India in the same phase and at the same time as in other parts of the world. Earlier, companies had to repeat the first phase in India (see ‘Trials in India’,). “The amendment, which came due to industry pressure, opened the floodgates for companies to conduct trials here,” says Sandhya Srinivasan, executive editor of Indian Journal of Medical Ethics (IJME). “But government is promoting trials without setting up proper regulatory and monitoring structures,” she adds.

Malpractices exist because very few professionals are trained to conduct trials ethically, says Sengupta.

Loopholes in law

Over the years, ICMR has revised guidelines to check malpractices. “But it seems the government has made them just to show that it is working. Ethics are being compromised at every level,” says Amar Jesani, founder member of IJME, who has been part of several ethics committees. “The industry takes advantage of this.” There is no check on the functioning of ethics committees. This has led to mushrooming of independent committees. “Ethics committee shopping has become a norm,” says Sengupta. When the mandatory approval for trials is refused by one, pharmaceutical companies go to another. Ethics committees are not legally bound to make their decision public.

It seems the government has made guidelines just to show it is working. Ethics are compromised at every level
— AMAR JESANI Founder member, Indian Journal of Medical Ethics

The ethics committee of Public Health Foundation of India (PHFI) refused PATH, a US-based non-profit working in collaboration with the Indian government, the permission to conduct a clinical trial for HPV vaccine for cervical cancer in Andhra Pradesh and Gujarat. PATH then approached an independent committee in Vadodara which gave its approval, says N B Sarojini, coordinator at Sama, a Delhi-based non-profit for women and health. Seven girls died during the trial.

PHFI president K Srinath Reddy says the proposal was based on the assumption that HPV vaccine is safe and effective. “But no data was provided to substantiate it. Ethical aspects of the project were also not stated. We, therefore, rejected the proposal,” he adds.

ICMR director-general V M Katoch admits loopholes in the system. “We will put in place a system where decisions of ethics committees are made public,” he says.

Source: US National Institute of HealthLack of monitoring of ethics committees has resulted in exploitation of the vulnerable section, says Sengupta. Patients with incurable diseases (see ‘Diseases targeted,’), unemployed, poor, those under detention, refugees, and minors incapable of giving consent constitute the vulnerable section. This should be avoided, states the ICMR guidelines. The vulnerable become subjects as that is the only way they can get treatment. Studies show in most cases subjects are referred by their personal physician. Health activists say many subjects are taken for a ride as trials are often promoted as treatments. “They are actually experiments with possibilities of risk,” says Sengupta.

Victims of Bhopal gas tragedy were made subjects of clinical trials without their informed consent. The trials were conducted in 2004 at the government-funded Bhopal Memorial Hospital and Research Centre (BMHRC) set up to treat them. They were tested to study the effects of the antibiotic televancin; tigecycline, which minimises antibiotic resistance; prasugrel, a drug for cardiovascular disorders; fondaparinux, which prevents blood clots; and a combination of the antibiotic cefoperazone and sulbactum, a chemical salt. Cefoperazone is no longer marketed anywhere. Fixed dose combination of cefoperazone with sulbactum was never approved in the US, home base of Pfizer which manufactured it, says Gulhati.