Indian Guinea Pigs for Sale: Outsourcing Clinical Trials

By Sandhya Srinivasan
India Resource Center
September 8, 2004

Mumbai: Reports that two Indian pharmaceutical companies conducted trials of genetically engineered drugs without proper approvals have renewed fears about unethical drug research in India. While the companies concerned argue that these were "minor procedural lapses", the spotlight is once more on illegal clinical trials. Bangalore-based Biocon and Hyderabad-based Shantha Biotechnic conducted Phase III trials of genetically engineered drugs (insulin for diabetes by Biocon and streptokinase for heart attacks by Shantha) without appropriate prior approval of both the Drug Controller General of India (DGCI) and the Genetic Engineering Approval Committee. Press reports indicate that they applied for and got DCGI permission but applied to the GEAC only after the trials started.

There is no effective monitoring mechanism for research, and existing regulations are to be relaxed shortly as India encourages the outsourcing of clinical trials from the West. A huge population with a diversity of diseases that are untreated - yes, that is the "India Advantage" identified by Igate Clinical Research International, (www.igatecorp.com/icri/html/aboutus/tia.htm), commenting that India represents a largely untapped resource for clinical trials. Besides the fact that the ill in India are largely "drug na´ve" (read 'untreated'), the company also lists high enrolment rates, good patient compliance/retention, "competitive costs", and an "increasingly accommodating regulatory environment" as the other benefits of conducting clinical research in India.

India has "40 million asthmatic patients, about 34 million diabetic patients, 8-10 million people HIV positive, 8 million epileptic patients, 3 million cancer patients" among other categories, says the company's website. Apparently this is Igate International's 'raw stock'.

"I believe there has been a 10-fold increase in research in the last five years," says Mumbai-based endocrinologist Shashank Joshi. "There are many more contract research organizations and trial centers." According to the website www.biospectrumindia.com, the contract research business in India doubled last year, from Rs 135 crore (about US $ 30 million) to Rs 275 crore (about US $ 60 million). Pharmabiz.com estimates that current outsourced clinical trial activity in India at around Rs 3.5 billion (about US $ 75 million), going up to Rs13.2 billion ((about US $ 281 million) by 2010 - perhaps Rs 44 billion (about US $ 950 million)if regulatory hurdles are "streamlined".

But the fact is that there are no available figures of the extent of clinical trials and other research. There is no central registry for medical research in India. We can presume that the Drug Controller General of India (DGCI) has some information on all trials for which applications are submitted but it is not available to the public.

Multinational drug companies have been conducting clinical trials in India for years, directly or through clinical/contract research organizations (CROs) which conduct the trials for a fee. In some cases, local pharmaceutical companies are setting up CROs to collaborate with the international ones. For instance, in 1999, Nicholas Piramal set up a joint venture with a UK-based health care firm in central Mumbai, site of a once-thriving textile industry. Promoted as a center for genome research, Wellquest maintains a database of over 2,000 healthy volunteers for such studies. It is reported that many of the research subjects are jobless textile workers.

Trials are apparently on-going with various CROs on drugs for diabetes, blood pressure, cancer and other diseases of interest to the international drug market. Quintiles Transnational is reported to have recruited more than 13,000 Indian patients for various clinical trials since it came to India in 1997. The Indian CRO SIRO Clinpharm claims to have done 22 studies involving more than 2,000 patients. These organizations can enroll sufficient patients for their studies in a fraction of the time it takes their counterparts to do so in the West. CROs offer to do everything for the drug company, from designing trial protocols for all stages and types of trials; getting regulatory permissions and ethics committee (EC) approval, conducting studies after obtaining written informed consent of subjects, analyzing the data, and writing up the results.

Unethical Trials Exposed

The following problem trials in India came to light because of public organizations or the press, not because a monitoring authority acted.

Bangalore-based Biocon and Hyderabad-based Shantha Biotechnic conducted Phase III trials of genetically engineered drugs (insulin for diabetes by Biocon and streptokinase for heart attacks by Shantha) without prior appropriate approval of both the Drug Controller General of India (DGCI) and the Genetic Engineering Approval Committee. Press reports indicate that they applied for and got DCGI permission but applied to the GEAC only after the trials started. Some people died in the Shantha trial, conducted on seriously ill patients. Some questions: did the patients and their families give informed consent to participate? Was the Shantha drug tested in emergency situations in which it would have been difficult to obtain informed consent? Was any compensation paid, given that the patients were in a trial? (2003).

Mumbai-based Sun Pharmaceutical Industries Limited bypassed the DCGI altogether and got private doctors to prescribe the anti-cancer drug Letrozole to more than 400 women for ovulation induction. They used the results to promote this drug through medical representatives for this unapproved usage. While there are debates about doctors' legal and ethical right to prescribe a drug off-label, off-label research done without following proper procedure is outright illegal. Letrozole is patented by Novartis. There is nothing to indicate that Novartis was involved in the illegal trial. (2003).

Between November 1999 and April 2000, 25 oral cancer patients at the Regional Cancer Centre, Thiruvananthapuram (a government institution) had their tumors injected with tetra-O-methyl nor-dihydro-guaiaretic acid (M4N) or tetraglycinyl nor-dihydro-guaiaretic acid (G4N), an experimental chemical in order to evaluate its anti-tumor properties. They were not told that it was an experiment, that a trial had not been approved by the Drugs Controller (approval was obtained retroactively), that they were being denied the established treatment for their condition, and that the sponsor institution, the Johns Hopkins University in the US, had not cleared the trial Interestingly, JHU released the money for the research before its own ethics review committee gave ethical clearance. (1999-2000).

Dharmesh Vasava was one of a number of daily wage earners administered a psychiatric drug in Vadodara as part of a bioequivalence study sponsored by the Mumbai-based Sun Pharmaceuticals. He developed pneumonia and died and others were reportedly injured. Bioequivalence studies - to establish that the drug is as effective as the approved branded version -- are not done for Indian regulatory purposes but to satisfy international regulations and the trial was done for an importer, whose name is not known. The People's Union of Civil Liberties, Vadodara, asks if the trial subjects could possibly have given their voluntary informed consent to participate, and whether their health was checked properly before entering the trial, and monitored closely during it. (2002).

Multi-center Phase III clinical trials of the diabetes drug ragaglitazar by the MNC Novo Nordisk were suspended when animal studies reported urinary bladder tumors in rats. The results of these studies should have been available before the human trials started. The drug was developed by Dr Reddy's Laboratories, Hyderabad, and licensed to Novo Nordisk which conducted the trials. 130 people in eight centers from India were part of the trial, of which half would have received the experimental drug. Novo Nordisk refused to give further details on the centers. A total of 650 from North America, 200 from Latin America, 100 from Australia / New Zealand, 800 from the European Union, 200 from non EU Europe, 550 from Asia. (2002).

For years since the early 1980s, a pair of US-based 'barefoot researchers' Dr Elton Kessel and Dr Stephen Mumford, led a massive, illegal multi-country trial of the potentially hazardous anti-malarial drug quinacrine as a terminal contraceptive without legal approval. Trials had been halted in the West. They smuggled the drug into India and distributed it directly to practitioners in West Bengal and elsewhere. They went underground after a petition was filed in the Supreme Court in 1997. Another illegal 'contraceptive trial', this time with the antibiotic erythromycin came to light in 2004.

Use of Public Services

Significantly, many trials are conducted in government hospitals which are largely the last resort of poor patients. Resource-starved public hospitals see trials as a source of funds and equipment. Dr Joshi has done a number of trials in the ESIS hospital in Mumbai, though these days most of his trial subjects come from poor, needy patients in the private sector. It is argued that such trials can benefit patients since they get close medical supervision for the duration of the trial. "For example in a diabetes trial poor patients will get blood sugar monitoring machines that they could not otherwise afford," says Dr Joshi.

It is worth noting a parallel phenomenon as public health services deteriorate without funds and the private health sector is being developed to meet other needs. The combination of low costs, trained personnel, medical and communications infrastructures also make India a competitive source of high quality health services internationally. Associations of medical professionals have lobbied with the UK National Health Service to send their patients to India for treatment at a fraction of the cost. Private hospitals there are already testing the service and SRL Ranbaxy has approached the UK government for its business. The Indian government's National Health Policy (NHP) 2002 explicitly commits to promoting health tourism. "To capitalize on the comparative cost advantage enjoyed by domestic health facilities in the secondary and tertiary sectors, NHP-2002 strongly encourages the providing of such health services on payment basis to service seekers from overseas. The providers of such services to patients from overseas will be encouraged by extending to their earnings in foreign exchange, all fiscal incentives, including the status as 'deemed exports', which are available to other exporters of goods and services." (Section 4.25.1 http://mohfw.nic.in/np2002.htm)

Difficulties in Conducting Clinical Research

"When getting a subject's informed consent, some research is complex and it is difficult to convey the relevant issues," notes US-based bioethicist Ruth Macklin who has participated in the development of various international ethical guidelines for collaborative research in developing countries. Equally worrisome is the fact that "people may not distinguish between treatment and research. There is a false belief that sometimes research may have a direct benefit. Research does not provide individualized medical treatment, titrating doses according to the patient's need, for example."

Professor Macklin strongly believes that there is a need for international research in developing countries - but on drugs that are relevant to the host country, and for which plans for post-trial availability are drawn up before the trial starts. Second, research must ensure informed voluntary consent, proper data control, experimental drugs must be tested against the best proven treatment (not on placebos when effective treatment exists), and care must be ensured for those who develop conditions in the course of the trial - whether or not they are related to the drug tested.

Informed Consent

Dr Urmila Thatte, professor of clinical pharmacology at the Mumbai municipality-run BYL Nair Hospital , conducts a number of Phase I and Phase II trials, many for herbal drugs for Indian companies. She finds that in her work, "Patients are more aware, they understand that they are in a trial. People opt out if they see no benefit." The fact that some opt out indicates that they are able to make independent decisions and refuse to participate, for whatever reasons. She also notes that the process has improved with the introduction in India of Good Clinical Practice (GCP) norms for pharmaceutical research. "Research is getting more structured," she says.

The GCP guidelines drawn up by India are required by the ICMR and are based on those formulated by the WHO and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (revised 2000).

A medical director notes that GCP guidelines will make a marked improvement in the quality of informed consent expected in a trial. "But how effectively informed consent is actually administered is for you to guess. It will depend on individual investigators, and the type of study." For example, a trial for chronic hepatitis has a limited number of potential subjects so there is more pressure to get consent from patients eligible for the study. Since there are a limited number of drugs currently available and they are expensive, it is always possible for the investigator to persuade the patient that the trial is the only or best option. "In other cases, such as a trial for antibiotics or drugs for diabetes, patient refusal is fine," because there are plenty of people to choose from who need antibiotics or diabetes drugs. "The population base is an advantage."

"The quality of voluntary informed consent obtained in clinical trials is very poor," says Dr Joshi. "If they were informed that they were in a trial, 90% would not participate. For non-affording patients the doctor is God. They will sign on the dotted line. They will assume the drug is for their benefit, that it is not experimental. It takes time to inform patients properly." The ICMR guidelines represent an enormous improvement on previous available ethical guidelines for research in India, since they implicitly recognize that the investigator-subject relationship can be unequal and therefore potentially coercive. The category of 'vulnerable groups' includes the economically or socially disadvantaged who should not be used to benefit the better-off. However, while such inequalities - and the potential for their exploitation- are recognized, the language of the guidelines is open-ended. It is up to ethics committee members to note that, for example, patients of public hospitals are an especially vulnerable population in giving their consent. EC members must also carefully scrutinize patient information sheets and informed consent forms in English and the other languages to be used, to ensure that they are truthful, complete and comprehensible. Finally, in the absence of independent monitoring, it is not possible to say whether the process of getting informed consent is done ethically.

Control Over Trial Design and Data

Dr Joshi is quick to state that MNCs (through their CROs) determine every stage of the research. "All we do is provide them with the material," he says. "They dictate every detail of the trial protocol, they deal with IEC review, they control the data analysis and publication. The contract will stipulate that the CRO controls the data, we must sign a confidentiality agreement. We only supply patients. The investigator is part of a master slave relationship." The local investigator who actually does the research has no control at all, to for example question a trial design. If the drug is found ineffective or even dangerous, the company can bury the findings without publishing them. If the researcher tries to publish, s/he can end up with a court case.

There are certain benefits to the researcher. Trials run according to GCP guidelines will mean that the company provides certain equipment, pays staff, and so on. The investigator also gets some money per patient recruited, ranging from Rs 500 (US$ 10) to Rs 5,000 (US$ 100) per patient. For some members of the research team, the money may be less important than the opportunity to participate in an international trial, or the career benefits. For trial subjects, the incentives projected are less tangible but relevant for poor people - close medical monitoring for the duration of the trial, instruments such a blood sugar monitor for a diabetic drug.

Quality of Review

The last few years have seen a number of efforts worldwide, to provide systematic ethical review to researchers, whether through institutional review boards or unaffiliated ethics committees that support their work by charging for each protocol they review. One reason for this trend is that ethical review is part of international GCP norms and India will have to provide ethical review as part of the competitive research package.

Ethical review of research is a critical step in protecting trial subjects from harm. Dr Thatte welcomes the rise in the number of ethics committees. "We need to improve their quality, provide administrative and financial support. I have seen ECs who insist on stringent criteria, who stop the trial if they see it necessary."

"Trial protocols must be gone through carefully," notes Dr C M Gulhati, editor of the Monthly Index of Medical Specialties (MIMS), India. "Some of the many issues to be covered are: Is there adequate protection for patients? Will proper informed consent be taken? Is there insurance in the case of an adverse event? Does the investigator have a conflict of interest or does s/he have shares in the drug company?"

However, even well-intentioned and independent ECs can find it tough to do a thorough review of research protocols. In the absence of a systematic study of EC functioning, informal reports provide an insight into their problems. Many have inadequate administrative and financial support. EC members are not usually formally trained in ethical review, nor do they necessarily follow specific guidelines for the review process. They must often review a number of trials in a short period. The quality of discussion within the EC depends on the composition of the EC, the level of training in review, the time available for discussion and the administrative support. And there is always the possibility that politically supported trials (such as contraceptives, given the "national imperative" of population control) will face less stringent ethical review.

Monitoring and Compensation

There are plans to enact legislation on the basis of the ICMR ethical guidelines for biomedical research. Further, the WHO's GCP guidelines require that papers submitted to the EC describe the mechanism to monitor the conduct of a trial. However, no such system exists in India. Even in the case of "serious adverse events", the government apparatus is unable to even accept such reports, according to Dr Joshi.

"ICMR guidelines specifically require each project to incorporate a compensation mechanism for all eventualities," notes Dr Gulhati. However, he adds, "Clinical trials in India can be conducted without organizing compensation in case of study-related injury, disability or death." Even if insurance is provided, compensation requires that a causal connection is proved between the clinical trial and the injury, and this is difficult. In contrast, when Jesse Gelsinger died in a gene therapy trial in the US (1999) his family sued the University of Pennsylvania which conducted the study and received a settlement.

Legal action for compensation is possible in the US even if the trial does not incorporate it. Further, there are greater chances of government action and a public inquiry into unethical research. For example, when Ellen Roche died in an asthma study run by Johns Hopkins University (2001), the government shut down all research at JHU pending an inquiry. Roche was a laboratory technician and a healthy volunteer. She was given a chemical (hexamethonium) to see how the lungs of healthy people protect against asthma attacks. The chemical led to the progressive failure of her lungs and kidneys. The chemical, which was unapproved for human use, had already reports of side effects but she was not informed. Following this, an inquiry into gene therapy trials revealed a number of wrong-doings including at the level of the investigators' commercial ties and the level of informed consent.

Examples of Questionable Trials in Other Countries

In 1996, the US-based company Pfizer parachuted into Nigeria during an epidemic of meningococcal meningitis to test a new antibiotic (trovafloxacin) on 200 affected Nigerian children, giving half of them the standard and best available treatment and the other half their experimental drug. 11 children in the 'trial' died. A letter of ethics committee approval was forged later on, when submitting to the USFDA for a license. Patients' families had no idea that the drug was experimental - or that the best available treatment was being given free by an NGO nearby. The drug was later withdrawn in Europe because it was toxic to the liver and some patients had died.

In 1999, US-based Maxim Pharmaceuticals Inc (California) needed to check out a new liver drug urgently as it was about to raise stock on the basis of the drug's potential. The US FDA wanted more animal tests before it could be tried on Americans so the company went to Russia. 149 patients were screened and Russian doctors were not told about the FDA's concerns. The company didn't break rules, US or Russian.

In 1997 US-based Triangle Pharmaceuticals (North Carolina) wanted to test mozenavir dimosylate, an AIDS drug, but animal trials found problems so they could not test in the US. So they established the drug's safety by testing it in Europe and Mexico first.

Source: The Body Hunters. Washington Post December 18, 2000

Short-Cuts to Approvals

While corruption is widespread in India, malpractice and corruption in the office of the Drug Controller General of India is more worrisome because decisions here deal with the safety of trial participants as well as users of the approved drug. A senior medical officer in a multinational pharmaceutical firm illustrates how papers are pushed to meet the strict deadlines of international drug companies: "The timelines for each section of the process are very short. But the lead time in the application is long. For example, the clinical trial application dossier with detailed pre-clinical data, earlier phase trial data, etc, will take five months to put together. It will spend five weeks at the DCGI's office but will become 'active' only in the last week. To shorten the lead time we file the application with the fees and whatever data we do have. Then just before it becomes 'active', it is supplemented with the relevant information. This is an innovation based on how the Indian government operates. People may have divergent views on this. The DCGI takes an inordinate time to clear projects, but he has also been very cooperative. Things don't move without money. This is not related to the technicalities of the product but what must be done to jump the queue."

Overcoming Regulatory "Hurdles"

Industry bodies in India such as the Confederation of Indian Industry (CII) have argued that money from outsourced clinical trials go up by 10 times "if regulatory hurdles are streamlined". What are these hurdles?

Phase I trials test a drug's safety on healthy volunteers. Phase II and III trials test larger numbers for the drug's efficacy while also collecting information on its safety and effective doses. Phase IV trials are conducted once it is marketed to monitor for its safety in larger populations.

According to Schedule Y of the Drugs and Cosmetics Act, permission is given for international clinical trials in India one phase behind the rest of the world. Thus, if a drug was in Phase III trials elsewhere, it could be tried only in Phase II trials in India.

"The present Schedule Y allows Phase I trials of new drug substances discovered in other countries to be conducted in India if data of the Phase I trials in other countries are already available," says Dr Amit Sen Gupta of the Delhi Science Forum. "However, the DCI retains a right to waive this requirement if the drug tested was of special relevance to the health problems in India.

This is due to change shortly and trials may soon be conducted at the same phase as they are abroad. According to the interim report of the expert government committee "Comprehensive revision of Schedule Y, that prescribes requirements of clinical trials, has been undertaken in order to harness (the) country's potential to participate in global multi-centric clinical trials."

Concurrent phase trials will open up the scope for multi-centric trials at all phases, currently not possible here. They will also expose Indians to greater risks since Phase I trials will be permitted.

At the same time, neither industry bodies nor the government mention that foreign drugs tested in India should/will be made available and affordable here. So there is a real danger of drugs being tested here for information to meet US regulatory requirements, without even assuring that the drug will be available in India.

While the amended rules have not yet been publicly notified, a senior official in a multinational corporation states that the DCGI is "progressive" and considers concurrent phase trials even while waiting for the notification. What are the implications?

The official is admitting that the company is breaking existing rules, with the support of the government. The government's argument is apparently that since the rules are soon coming into play anyway, why harass MNCs whose profits are calculated according to their research-to-marketing schedule?

The interim report also states that the government had already laid down a schedule for processing clinical trial applications. The Confederation of Indian Industries is reportedly pushing for "automatic approvals" of all applications with the DCGI if not cleared within a stipulated timeframe.

In The New Research Environment

According to Dr Gulhati, the amendment to Schedule Y will only mean that Indian patients and volunteers will be put to greater risk. "What does India get out of these clinical trials? Some middleman, the CRO, will collect $ 2 million, spend $ 20,000 and make a huge profit. The Helsinki Declaration (World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects adopted in June 1964 and amended several times, and with a note of clarification added in 2002) requires that the community where the drug is tested should get some benefit from the trial results. Where is the evidence of such benefits? What will happen is that you will do the initial testing in India. If initial testing finds it safe, then you do the rest of the tests abroad." Dr Joshi, who has been involved in dozens of trials for multinationals as well as Indian companies, admits: "Rarely do you see the drug available after the trial period is over. For this an agreement must be negotiated by investigators; I insist that the drug must be made available to my patients after the trial is over. I also demand some assurance that the drug will be made available in the future, but these are only verbal assurances."

A senior medical officer in an MNC conducting clinical trials here says: "Availability of a drug post-trial is a gray area today. I can't gauge the commercial potential of the drug. Only after the costing is worked out will a decision be taken about marketing in India. Also there is a cost and generic threat here. You are expecting too much of multinationals. We hope that once the patent regime is put in place a lot of the menace will go down. It (requiring post-trial availability) goes against the principles of free trade."

With outsourcing poised to increase once the new patent regime instituted by the WTO takes effect in January 2005, one dreads to imagine the fate of thousands of trial subjects in India.

Sandhya Srinivasan is a Mumbai-based journalist.

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