Ethics on trial

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The Regional Cancer Centre in Thiruvananthapuram. Photo: THE HINDU

This article, published in the ‘Frontline @25’ special issue dated January 15, 2010, is based on a major expose of an unethical drug trial conducted on patients of the Regional Cancer Centre at Thiruvananthapuram by a researcher from Johns Hopkins University in the United States. The original reports and interviews, by R. Krishnakumar, appeared in the issues of Frontline published between August 2001 and December 2005.

THE elements of the controversial ‘Johns Hopkins-RCC drug trial’ are now well known: a U.S.-based biology professor with a potential anti-cancer “drug” discovery and links with a “start-up” pharmaceutical company; an American university holding a patent for the experimental drug; an international real-estate businessman willing to invest millions in the new company for further development of the drug through human trials; a contract research organisation that scouts worldwide for opportunities to do clinical research using the drug; and a medical institution in a Third World country eager to conduct the trials on its patients for them.

Clinical drug trials involve ethical minefields. It was in mid-2001 that a whistleblower radiotherapist at the Regional Cancer Centre (RCC) in Thiruvananthapuram startled India by claiming that the authorities of the reputed hospital had subjected unsuspecting oral cancer patients to an experiment, injecting untested, potentially unsafe chemicals into their tumours, as part of an international research project that sought to develop new cancer drugs. The chemicals, known briefly as M4N and G4N, were synthetic derivatives of a plant product that could arrest the growth of artificially induced tumours in mice, as a biology professor, Dr Ru Chih C. Huang, and her team had demonstrated earlier in her laboratory at the U.S.-based Johns Hopkins University.

The first human trials of M4N and G4N were indeed conducted between November 1999 and April 2000 at the RCC following an agreement signed “on behalf of Hopkins” by Dr Huang (the lead inventor) and the cancer centre authorities led by its then Director, Dr M. Krishnan Nair.

Among the 27 patients, some were administered the potentially more risky chemical G4N, either separately or along with M4N. Though all of them were made to sign “consent papers”, the patients thought the injections were part of their treatment, and were not properly informed of the risks involved.

A few days later, after four or five doses of M4N and/or G4N were administered to them, the tumours were surgically removed and the injected tissue samples were sent to Hopkins. The patients were sent home after the surgery and radiotherapy or chemotherapy in some cases, and there was no real follow-up on whether the injections had adversely affected them. The U.S. researchers, however, soon reported that the injected tumour samples had shown “signs of shrinking and dying”.

Barely two months after the trials ended in India, in June 2000, a Singapore-based real-estate businessman (and banker) Ang Tiong Loi visited the JHU and promised to invest millions of dollars for the development of effective anti-cancer drugs from the new compounds.

It was also announced that the investment would enable “a new company” to conduct further research, “including FDA-approved clinical trials”, using the new compounds, which had already been tested on Indian patients. Hopkins held the patent for the new compounds and claimed they would soon prove to be “wonderful cancer drugs” that would bring returns to the university and the investor.

But ethically sound research involving human participants must satisfy a number of globally accepted requirements. It must be subjected to a prior review by an ethics review committee, minimise risk to the participants, obtain voluntary and informed consent of individual participants, and ensure the risks involved are reasonable when compared with potential benefits. Moreover, the research must be non-exploitative, be essential, show equal regard for all subjects, ensure equitable distribution of the burdens and the benefits, take adequate care to compensate participants for injuries sustained directly during research and be accountable and transparent, among other things.

But the RCC’s “collaborative venture” with non-medical researchers of the Johns Hopkins University to test M4N and G4N in human cancers clearly failed to prevent the abuse of research subjects or show concern for their safety. While the RCC authorities continued to deny the allegations that came in the wake of the tests, Frontline published a series of investigative reports from November 2001 unravelling the funding, business connections and conflict of interests in the Hopkins-RCC trials, the flouting of safety and ethical norms, and the plight of the 27 patients, all of whom were discharged soon after the experiment. A number of them died within a few months or never visited the hospital again.

One of them, 65-year-old M. Gopalan from Tirupur in Tamil Nadu, (who later approached the State Human Rights Commission and had his complaint rejected on technical grounds) told Frontline in an interview in 2001, a few months before he died: “Nearly a fortnight before the scheduled surgery in January 2000, I was asked to ‘go to another room’ in the hospital and ‘sign on a piece of paper’. I did not understand a word of what was written on the paper as it was in Malayalam, the local language. Anyway, I signed it, thinking that it was a routine procedure before surgery. Then, two doctors, not the ones who were treating me regularly, examined the burning lump on my tongue. They squeezed it, and then they gave me a painful injection. More injections followed, almost at the same place, the same unbearable way. Then the injected lump was removed. The doctors said I was cured and then they sent me home. “But I was not cured. When I came back with another lump on my tongue, my doctor asked me one day why I had allowed them to give me those injections and why I had failed to inform him about it. I asked him, ‘Didn’t I give you my trust?’ I thought it was part of my treatment.”

Would he have volunteered had they told him that it was an experiment? Did he know that it involved risks unknown even to the researchers? Was he aware it was the first time the chemicals were being injected on human beings to try and find a cure for his type of cancer? Did he know he could refuse to be part of the experiment? He replied: “Do you think anybody would take such a risk? Who would have thought they would do such a thing to me?”

The treatment data were never revealed, and subsequently the RCC authorities also began to fudge the figures. The partial data from the case-sheets of patients released by the RCC in 2001 at the beginning of the controversy too give room for uneasy conclusions (‘Trial and Errors’, Dec. 16, 2005). Data on only 23 patients were released, though the RCC itself had acknowledged earlier that 27 patients were involved. Later, the doctors began to discuss results of just 18 patients. There was no evidence to show that all the 27 patients had been monitored after the injections, specifically to understand the effect of the injected drugs on them.

Thereafter, in what was alleged to be “a sham government inquiry” a one-man commission (Dr. Parvesh Parikh of Tata Memorial Hospital in Mumbai) concluded “all patients were fine”. But later, in a telephone conversation, Parikh disclosed to Frontline that he had examined only “10 or 11” of the 27 patients involved in the trial. As the then Union Health Minister explained to Frontline, the government had the duty to protect “the reputation of an institution offering treatment to thousands of people”.

Thus, even though the patients were exposed to unknown risks without their voluntary or informed consent, because of the overriding, and perhaps convenient, concern of the State and Central governments “to save the reputation of the RCC”, the drug trial collaborators were left to pretend that “except perhaps for some procedural irregularities” no harm was done to the patients and the trials were conducted in an above-board clinical setting.

Subsequently, in 2005, when the controversy seemed to have died down with no action being taken against the erring doctors, an audacious attempt was made by some of the RCC physicians involved to whitewash their deeds and claim credit for concocted claims about the trial. Some of them began to publish papers at international medical conferences stating that the trials at the RCC had been a grand success and that the patients had shown “relapse-free survival even at five years”.

The report of Frontline’s inquiry into this claim was published in December 2005, proving their lies and with exclusive new disclosures about the unsuccessful bid that had continued in the U.S. to develop a cancer drug out of M4N, with help from the biopsy results of the RCC trials and brushing aside the ethical, moral and legal questions that were being raised in India.

A spokesperson of Erimos Pharmaceuticals, the start-up company that was conducting further human trials of M4N in the U.S., Jennifer C. Stern, told Frontline in an interview that the Erimos clinical programme “would not have occurred” without the safety and effectiveness clinical information provided by the Huang-Krishnan Nair study at the RCC. She also said that the early development work conducted in India, “prior to Erimos taking over the development programme, provided invaluable support information on the potential clinical usefulness of EM-1421, as well as its lack of systemic effects” (those that involve many organs or the whole body).

Significantly, the G4N human trials were not held in the U.S. and, despite the trial data from the RCC, the researchers were allowed to launch human trials using M4N in the U.S. only after further trials with the chemical were con- ducted in animals there. What was becoming clear in 2005 was that drug development from the two controversial chemicals was not going smoothly in the U.S. too, with the principal investigator of a Phase I study conducted at one of the three centres too reporting extreme adverse (M4N) drug reactions in the trial participants.

A January 2005 newsletter of the U.S.-based human rights organisation CIRCARE quoted the results from this adverse study as cited in the Journal of Clinical Oncology (Vol 22, No 148 July 15 Supplement 2004:5614) and said: “Far from being not toxic in humans, of a total of three subjects enrolled in Dunphy’s (Dr F.R. Dunphy of a North Carolina cancer centre) trial, one subject was removed from the study after developing a trachealcutaneous fistula [essentially a hole extending from the windpipe through the skin of the neck], a second patient required hospitalisation twice upon developing heart-block – both of which were presumably adverse drug reactions – and all patients experienced pain, severe enough to require intravenous morphine relief. According to public statements given out by the RCC in Kerala, India, however, none of the research subjects contacted suffered any adverse events, complications, or harm upon receiving intratumoral injection of the same investigational drug. Such statements strain credulity in the light of Dunphy’s recent data.”

Interestingly, between July 27, 2001, when the Hopkins authorities first announced through Frontline that the trials at RCC “had not been authorised by any department of the university”, and 2005, when Frontline’s re-investigation took place, Dr Huang and her university had clearly tried to distance themselves from the controversy and any responsibility for the RCC trials.

Even as early as November 2001, soon after an internal inquiry, the university had tried to build a legal wall between itself and the RCC clinical trials by saying that Huang had no authority to sign the agreement on its behalf. It maintained that merely because the university cut a cheque it did not mean it had authorised the trials. Hopkins consistently disowned the trials at the RCC even though its own inquiry had found they were done by a Hopkins professor without adequate safety testing on animals, without a proper Institutional Review Board (IRB) review and with chemicals developed at its own Biology Department.

Dr Huang got away with a mild punishment barring her from being the “principal investigator on any future research project involving human subjects”. Asked how she could claim that there was no harm done to the patients in India when indeed there was no evidence of continuous monitoring of the patients at the RCC, she told Frontline: “I am not clinically involved with the follow-up of these patients. You would need to direct that question to the appropriate [RCC] physician”.

She and the Hopkins spokesperson Dennis O’Shea also explained to Frontline that there was no basis for the claims made by the RCC authorities that the drug when developed would get a “joint patent”, “profits would be shared equally” and “if it is given to a drug company, as is usually done, the RCC would get 50 per cent of the royalty”.

“The gains from the RCC trial were, from the very beginning, meant to be shared by Johns Hopkins University, its scientists, the company they floated and the Singapore millionaire who is sponsoring it. For them, it was merely a question of finding a gold mine and being very quick about it. It is a fairly accepted principle that you should not do research on people who would not benefit from the product of that research. The people of India, at whose expense they got the preliminary encouraging results, would not benefit at all,” Dr C.R. Soman, former chairman of the activist organisation ‘Health Action by People’, commented in Frontline in 2005.

Over 35 interviews were conducted as part of Frontline’s investigation into the Hopkins-RCC drug trial controversy from 2001 to 2005, with doctors, researchers and authorities of the RCC and Hopkins, administrators, professors, historians, experts in medical ethics, representatives of non-governmental organisations (NGOs), hospital staff, inquiry and ethics committee members, media correspondents, government officials, regulatory authorities, pharmaceutical company representatives, Ministers and politicians in India and the U.S.

Their disclosures eventually turned out to be the incremental elements in a classic jigsaw case of conflict of interests involved in clinical trials sponsored by international drug researchers in developing countries.

The most significant outcome of the controversy and the disclosures that followed was an increase in public awareness in India about clinical trials and the effect of unseen, market-driven forces that threaten the safety of the patients involved and taunt the objectivity of investigators and the scientific integrity of clinical trials.

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