Ethics on trial

The Regional Cancer Centre in Thiruvananthapuram stands accused of experimenting with untested chemicals on patients without their knowledge and consent and without the sanction of the Central authorities concerned, as part of a drug research project which also involves the Johns Hopkins University.

R. KRISHNAKUMAR in Thiruvananthapuram

CLINICAL drug trials involve ethical minefields, as physicians at the Regional Cancer Centre (RCC) in Thiruvananthapuram have just discovered the hard way.

The RCC's "collaborative venture" with the U.S.-based Johns Hopkins University (JHU) to test the effectiveness of certain chemicals as anti-cancer drugs seemed to have the ubiquitous flaw, right from the beginning: it failed to address the primary duty of preventing the abuse of research subjects with or without their knowledge.

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, be accountable and transparent, and so on.

The first-ever human trials of the chemicals conducted at the RCC from late 1999 to early 2000 appear to be a re-run of the classic case of the conflict of interests involved in recruiting patients for clinical trials sponsored by international drug researchers, and of how principles may be compromised to achieve ever-quicker results.

Frontline has reliable information (see box) that the human trials at the RCC and the studies that followed were carried out without the authorisation of the JHU. Although the RCC issued a statement in March 2001 declaring that it had developed an experimental drug (wrongly stated then as "NDGA") jointly with JHU and that it was found to be effective against cancer, the study was not approved by any of the university's institutional (ethics) review boards.

In its efforts to justify itself the RCC seemed to be tying itself in knots with contradictory statements, denials and postponed press conferences. The Johns Hopkins University, meanwhile, has asked its researchers to suspend all activities relating to the study.

A preliminary inquiry ordered by the JHU has found "credible evidence" of violation of the university's policies regarding research involving human participants. A panel of experts has been constituted to conduct a formal investigation and the university has asked its faculty member associated with the project to cease "all activities" relating to the study. (RCC director Dr. M. Krishnan Nair had said that Ru Chih C. Huang, a Professor in JHU's Department of Biology, was the principal investigator at the university associated with the project.) Johns Hopkins has also informed the U.S. Food and Drug Administration (FDA) and the Office of Human Research Protection of its investigation.

BETWEEN November 12, 1999 and April 8, 2000, 25 oral cancer patients awaiting surgery at the RCC were given a series of injections of the chemicals tetra-O-methyl nor-dihydro-guaiaretic acid (M4N) or tetraglycinyl nor-dihydro-guaiaretic acid (G4N). The injections, administered at intervals a few days before the patients underwent surgery, were not part of their treatment but an experiment to see whether M4N and G4N could be effective cancer drugs in the long run. The chemical was administered into designated, small portions of the tumour. Dr. Krishnan Nair said that after surgery, when the tumour was removed, the effectiveness of the chemical, especially at the injected portions, was studied with the specimens being sent to the JHU laboratory.

The intention was honourable. An ambitious cancer research institution like the RCC, ever ready to leap out of the general bind of scientific conservatism, could not let go of the opportunities offered by such an international academic collaboration in a frontier area of scientific research. Researchers of the JHU had successfully tested the chemicals over a period of time in mice. The next stage involved studies in humans. Success meant an effective new treatment for certain types of cancers.

However, such chemicals may work well in the laboratory or in animals but not in people. Researchers from the JHU wanted to find out whether M4N and G4N were safe and effective in human beings. The RCC needed the funds and the expertise in a promising new area of drug research. The RCC, the largest cancer centre in India, with over 10,000 new registrations and over 1,50,000 people seeking treatment every year, had no dearth of patients.

Perhaps, it was such a rewarding common ground that made the rights and needs of the 25 patients a subordinate concern. The patients - almost all of them poor and semi-literate - had come to the RCC only for treatment and not to participate in any drug research programme. All of them were asked to sign consent papers. Copies of a few of the signed statements were given to the State government and some were distributed to the media. At least three of the patient "participants" (identity and addresses are confidential, according to the RCC) said in media interviews that although they signed the papers presented to them, they had no inkling of what the injections were all about. None of them seemed to have known that the chemical that they were injected with was being tested in human beings for the first time, or that it was not at all necessary for their treatment (surgery, and/or radiotherapy, or chemotherapy) as such.

The story is a typical example of the conflict of interests that arises when hospitals become research centres too. The case of a 65-year-old "participant patient", who spoke to Frontline is illustrative. In 1999, encouraged by the excellent care and treatment that his wife had received earlier at the RCC, he did not hesitate when doctors at his home town Tirupur in Tamil Nadu diagnosed his disease as oral cancer and referred him to the RCC. He was soon admitted as a patient. A few days before his scheduled surgery, he was asked to go to "another room" and sign on a "piece of paper". Although he did not understand a word of what was written in the paper in Malayalam, he signed it. He thought that the signing was a "standard procedure before surgery".

Later, he said, two doctors, "not the ones who used to treat him regularly", examined the lump on his tongue. They "squeezed it" and then they gave the injection, which was "more painful". "They gave a few such injections," he said. He went home cured, but 13 months later he was back again at the RCC with a second malignancy. On July 27, when Frontline met him a day before he was to return home after a course of radiotherapy, he was still not sure why the doctors gave him those injections. "When my doctor asked me why I allowed the others to administer the injections and did not inform him about it, I asked him, 'Didn't I give you my trust? I thought it was part of the treatment'," the patient said.

Would he have become a willing volunteer had he known that the injections were part of an experiment? Did he know that it involved risks and it was not part of his treatment? Was he aware that he had a choice to say no or that the RCC benefited financially and academically from the trial? Did the doctors explain to him that it would help researchers from an international university possibly to develop a drug and possibly sell it to a big pharmaceutical company? Was he aware that an eventual share of the royalties might also come to the RCC (as Krishnan Nair announced belatedly at a press conference)? Gopalan said: "Do you think anybody would take that risk? Who would have thought they would do such a thing to me?"

Almost a year after the trial was conducted, and soon after the RCC issued a press statement that it was jointly developing "NDGA" as a drug since its anti-cancer properties had been demonstrated effectively, a physician in the RCC decided to blow the whistle, so to say. On March 18, Dr. V.N. Bhattathiri, Associate Professor of Radiotherapy, registered a complaint at the Kerala Human Rights Commission stating that there were "irregularities" in the conduct of some clinical trials at the RCC which "violated human rights and medical ethics" and that their continuation would involve "further violation by promoting unethical research". The complaint sought a detailed inquiry, appropriate action for the violations and preventive steps, and said Dr. Krishnan Nair, who was named as the 'principal investigator', should be held responsible for the drug trials.

The complaint alleged that the aim of the clinical trial was not the well-being of the patients but collection of specimens for the study; that the patients were not properly informed about the risk involved; and that it exposed the patient to the toxic effects of NDGA. The complaint also alleged that in the studies conducted in the U.S., NDGA was found to be active only against culture cells and was in fact found to stimulate most of the cancers when tried on patients; that NDGA was not the RCC's research product; and that the Drugs Controller-General (India) sanction for the study was obtained only in February 2001, after the experiment had concluded.

Despite delayed efforts by the RCC to distribute samples of "information statements" that it insists were read out to all the 25 patients and witnesses, there was no real evidence in them to prove that the patients understood the implications, especially that they were going to be subjected to the first experiment in humans of chemicals which were said to be derived from NDGA, widely reported to be unsafe. Early studies had belied hopes of it being an anti-cancer drug after it created lesions on the kidneys and lymph nodes of animals. However, studies at the Biology Department in the JHU were stated to be "promising"; it was stated that they showed that NDGA derivatives could be synthesised chemically and were good for "blocking viral replication" and as an effective anti-tumour agent. According to the JHU website, the university's biology laboratory was "currently pursuing the development of M4N as a clinically tested chemotherapeutic agent".

There is no mention of the RCC as a collaborator in the JHU website where the study is mentioned. However, RCC authorities said that Prof. Ru Chih C. Huang had approached them as early as June 1998 and a protocol was prepared by October 1998 for human trials in RCC patients. Dr. Manoj Pandey and Dr. Radhakrishna Pillai were appointed as co-researchers.

At a press conference held on July 28, Dr. Krishnan Nair said that there was no harm done to the patients as M4N was not "water soluble" and hence the injected chemical would stay put within the tumour and would not dissolve into the bloodstream. However, Dr. Bhattathiri told Frontline that these were only assumptions, and he pointed out that there was no study to prove that that was indeed the case.

When questions were raised at the press conference about a patient on whom "water soluble" G4N was injected as shown in the case sheet, the Director said that "he was not aware of it and will look into it".

Dr. Bhattathiri said there were some other participants who became unfit for surgery for other reasons such as asthma. However, this was probably discovered only after they received the injections. They were later sent for radiotherapy with the injected drug inside their tumours. He said that the effect of radiotherapy on drug-injected tumours was not ascertained.

Dr. Krishnan Nair denied all the allegations and claimed that the trial was perfectly safe and that perhaps there were only a few procedural lapses. However, he was not immediately available for an interview. There was also no response to an e-mail sent to Dr. Ru Chih C. Huang seeking his comments.

Apart from the concerns about safety, the RCC study faces allegations of lack of transparency in its dealings concerning Johns Hopkins, of flouting several ethical and legal norms, of going ahead with the experiments even though sanction for them, both from the RCC's own ethics committee and from the DCGI, came months after the experiments were conducted. Moreover, the actual study varied in several respects from the sanctions obtained from the ethics committee and the DCGI. For instance, the Drugs Controller's letter sanctioned "Clinical Trial Phase II M4N and G4N Nor-dihydro-guaiaretic acid derivatives". Clinical trials include research in three different phases: Phase I is the first step in testing a new treatment in human beings and it tests the safety of the drug, its side effects and the best way to administer it. Phase II tries to learn about the effectiveness of the new treatment. Phase III compares the results of the new treatment with those of other standard treatment. That sanction was obtained for "Phase II" M4N and G4N studies is significant. Although what occurred was the first-ever human trials, it created the feeling that the drug had already been tested in human beings for safety.

Moreover, because of the risks involved, Phases I and II were done only in a limited number of patients while Phase III involved hundreds of patients. It is significant that the researchers from the JHU did not conduct the clinical trial in the U.S. where legal and ethical formalities left little leeway in research involving human participants. But, Dr. Krishnan Nair said, the RCC had agreed to be the coordinator for the trials in India - scheduled also to take place in three other hospitals in Kanpur, Varanasi and Jaipur - for Rs.25 lakhs a year and other benefits.

The decision of the JHU to suspend "all activities related to the study" came soon after a big blow the university had suffered. On July 19, the U.S. government suspended all federally funded research on human subjects at the university, following the death of a "healthy volunteer" during a study on asthma. According to agency reports, 24-year-old Ellen Roche, a laboratory technician at the Johns Hopkins Asthma and Allergy Centre who died, was one of the three volunteers who inhaled hexamethonium as part of a study to learn how the body fights asthma by inducing asthmatic symptoms in healthy individuals. The drug, earlier used to treat hypertension, was later withdrawn by the U.S. Food and Drug Administration.

Of special interest in India in the context of the M4N and G4N trials conducted at the RCC are the comments from the federal agencies in the context of the asthma study. As reported in the U.S. media, the agencies highlighted, among other things, the failure of those involved in the study to obtain effective, informed consent from subjects, to inform participants that the drug was experimental or to describe the risks and discomfort associated with the research; to report the symptoms of discomfort experienced by the first of the three volunteers in the study; to ensure that the risks were minimised and reasonable; to follow protocol in that it stated that the drug would be administered by inhalation, when it was actually "administered" to the second and third volunteers; and to stick to the approved protocol.

The JHU receives more federal funds than any other medical school in the U.S. (it received $301 million in 2000). It has taken full responsibility for the death of the volunteer but strongly challenged the action of the federal government in suspending funds. The JHU described the action as "unwarranted, unnecessary, paralysing and precipitous action". A press statement issued by the JHU's Office of Communications and Public Affairs said that the action was taken in utter disregard of patients' health and potentially of life because even a temporary interruption of therapeutic clinical trial, such as those involved in cancer patients, could be devastating. In the wake of the incident, the university had also said it was imposing additional supervision on the hundreds of studies it conducted every year.

For the RCC, the controversy and the action taken by the JHU has come as a rude shock that threatens its hard-earned reputation. The RCC is acknowledged as a centre of excellence by the Government of India and as a collaborating centre for cancer control programmes by the World Health Organisation (WHO). It has also made pioneering efforts in paediatric oncology and preventive oncology. It is its efforts that have put Kerala much ahead of other States in cancer prevention and early detection efforts and in providing pain relief to patients. But the professional and ethical conventions on which it had built itself up from a small facility about two decades ago to its present status was sorely tested all through its involvement with the study.

Significantly, Dr. Krishnan Nair, who played an important role in the RCC's development, had also said that it was the dearth of patients in the U.S., in comparison with the wide variety of cancer conditions available in India, and the RCC's eagerness to achieve the capability for drug development in Kerala that had prompted his institution to join hands with the JHU in the M4N, G4N study. He insisted that the drug, when developed, would get a joint patent and that the profits would be shared equally. If it is given to a drug company, as is usually done, the RCC would get 50 per cent of the royalty. "We expect a very good monetary benefit," he said.

The controversy epitomises the familiar story of researchers from developed nations exploiting in developing countries the limited capabilities for scientific, technical and ethical research and review and the lack of ability of individual patients to provide informed consent.

In the context of multinational drug companies flocking to India to sponsor drug trials, the RCC story proves that provisions for the protection of patients' rights in such trials need a major overhaul. Meanwhile, the question whether such sponsors of research should adhere to international standards of ethics instead of trying to seek loopholes in the inadequate legal and ethical standards in developing countries would hopefully be answered once again by the investigation of the JHU.