The truth of the 'drug' trials

The Johns Hopkins University admits the illegal nature of the cancer 'drug' trials its staff conducted at the Regional Cancer Centre in Thiruvananthapuram. However, the governments in Kerala and at the Centre are yet to disclose the findings of their own investigations.

R. KRISHNAKUMAR in Thiruvananthapuram

AFTER a four-month-long inquiry, the U.S.-based Johns Hopkins University (JHU) has stated what was already quite obvious: that the controversial experiments at the Regional Cancer Centre (RCC) in Thiruvananthapuram were indeed the first human trials of the potentially anti-cancer chemicals developed at the Hopkins Biology Laboratory; that those chemicals had not been properly tested in animals before they were tried out on patients at the RCC; that the Biology Professor who conducted the experiments was not qualified or authorised to do experiments involving human subjects; that she did not have the mandatory approvals from the university's institutional review boards authorised to make ethical clearances; that she did not have the U.S. government's approval to export the chemicals used in the trial to India; that the clinical trial conducted at the RCC did not meet the standards for research with human subjects; and that adequate and proper consent was not obtained from the patients before they were made part of the experiments.

On November 12, JHU announced the much-awaited findings of the inquiry by its faculty investigative committee into the "drug" trial conducted on 26 cancer patients at the RCC between November 1999 and February 2000.

A statement issued by the JHU Office of News and Information said (significantly, without naming the Biology Professor concerned, Dr. Ru Chih Huang) that "one of its scientists" tested experimental cancer drugs on patients in India "without required federal or university approvals and without adequate preliminary tests in animals".

This statement of the true nature of the experiment conducted at the RCC by the Hopkins scientists is however yet to be acknowledged by the authorities in India, including the Central government and the government of Kerala. The Kerala government's inquiry has in fact concluded that except for certain procedural irregularities, there was nothing wrong in the experiments at the RCC. Dr. Parvesh Parikh of the Tata Memorial Hospital, Mumbai, who conducted the State government inquiry said: "The inquiry has found that all the patients are fine. I verified the consent forms, the signatures, the statements of witnesses and medically examined the patients... None of them seemed to be affected by the drug trial. There wasn't anything wrong with the conduct of the experiments. It had the necessary approvals." However, he told Frontline that he had examined "only 10 or 11" out of the total 26 patients involved in the trial because the rest had not responded to the commission's summons.

Even a month after both the governments received the inquiry reports, the results have not been made public. The Central government did order suspension of all further research on human subjects at the RCC for six months, pending inquiry, but the Kerala government initially went to the extent of severely criticising all those who were demanding action against the RCC authorities and the media. Chief Minister A.K. Antony even said the allegations that were raised (first, by an RCC doctor) were a "blatant attempt to destroy the carefully nurtured reputation of a great institution in the State." A self-appointed inquiry by the Kerala branch of the Indian Medical Association (IMA) had also virtually absolved the RCC of the allegations.

According to the November 12 press statement issued by JHU, its faculty committee, appointed after a preliminary inquiry in mid-July (see Frontline, August 17, 2001), had found that:

"The scientist was negligent for failing to submit a proposal for the clinical trial to a Johns Hopkins University institutional review board. Under university policy and federally mandated procedures, faculty experiments involving human subjects must have prior IRB approval, whether conducted in the United States or abroad.

"The trial did not meet Johns Hopkins standards for research with human subjects. For example, there was inadequate safety testing of the drugs in animals before they were injected into human beings... Consent forms used to recruit patients for the study were inadequate.

"The scientist carried drugs used in the study to India without either an 'investigative new drug' approval from the Food and Drug Administration (FDA) or explicit FDA export permission.

"The scientist, without authority, signed several versions of a document committing the university to collaboration with the RCC.

"There was no evidence that any patient had been harmed or that any patient's conventional treatment was delayed by the clinical trial."

The statement also said that on the basis of the committee's findings, the Dean of the university's Krieger School of Arts and Sciences (of which the Biology Department is a part), Richard E. McCarty, has "barred the scientist from serving as principal investigator on any future research involving human subjects". Any future participation by the scientist in human studies, led by other principal investigators, must now be supervised by a senior faculty member "with expertise in clinical research from either its School of Medicine or its Bloomberg School of Public Health".

The committee also said that the "inquiry should have begun in March 2001, when the university - which had earlier been aware of the 1999-2000 trial - first learned that the scientist had run it without university IRB approval," the statement said.

The chemicals (M4N or tetra-O-methyl nor-dihydro-guaiaretic acid or G4N or tetraglycinyl nor-dihydro-guaiaretic acid) were isolated from a North American desert bush at the Hopkins Biology Department by Prof. Ru Chih C. Huang and her colleagues. Their effectiveness as anti-cancer agents were sought to be tested on the 26 cancer patients awaiting surgery at the RCC under a controversial "collaborative agreement" (see Frontline Cover Story, August 31) between the two institutions, signed by Ru Chih Huang and the RCC authorities.

Despite denials by RCC Director Dr. M. Krishnan Nair, the statements made by a few patients and Dr. V. N. Bhattathiri (the RCC doctor who first brought the issue to public attention) showed that most of the patients who signed the consent forms thought the painful injections they received were part of their treatment. The RCC later claimed that the injections had substantially reduced the extent of the tumours. From all available indications, the experimental chemicals were injected into the tumours of the oral cancer patients awaiting surgery and a few days later the tumours were surgically removed, the patients sent home, and the samples sent to Dr. Huang and her colleagues at Hopkins. They reported that the tumours had shown signs of shrinking and dying. However, once surgery was over, no further monitoring was done to see if the chemicals had harmed the patients.

In reply to a question Dr. Parikh told Frontline that the issue of risk to which the patients were subjected to, if at all, was the responsibility of the sponsor, JHU and Dr. Huang. "The university cannot absolve itself of all responsibility, because it was its scientist and officials who signed the agreement and the cheques," he said.

The RCC's role was merely the supply of live samples for the experiments, for which, it received two cheques signed by JHU treasurer William E. Snow, worth $19,400, and was awaiting the third, according to project leader Dr. Manoj Pandey, when the controversy erupted.

"The Hopkins inquiry has vindicated the allegations made by those who blew the whistle," Dr. C. R Soman, chairman of the activist organisation Health Action by People, which was on the forefront of the protests, said.

Dr. Bhattathiri told Frontline: "The Hopkins report says I was right. But there is so much animosity towards me within the RCC for doing what I did. The IMA representatives have criticised me for going public. The refrain is, I should have found a solution to 'the problem' within the organisation. I have in effect tried to destroy the RCC is the allegation raised against me by the 'RCC Protection Forum'."

From the beginning the controversial collaborative venture had failed to address the most important duty of any research involving human participants - of preventing the abuse of research subjects.

The critical issue involved was the serious risk to which unsuspecting patients were subjected when the experimental chemicals were injected into their tumours. Asked whether his enquiry has found the injected "drugs" safe, Dr. Parikh said: "A chemical becomes a drug only when you add knowledge to it. A drug can never be produced unless you test it in human beings. Animal tests are never sufficient to prove the efficacy of a drug in human beings."

The Hopkins inquiry failed to address this problem, according to Dr. Soman. "All that the researchers were interested in was biopsy, before and after. In every case, the morbid curiosity of the scientist alone worked. There was no concern for the poor patients," he said.

Dr. Soman said that however "it is a credit to the American system that truth could not be hidden for long. Despite their best efforts to protect their colleagues - the university did not even name the scientist involved - they could not put a lid on truth for long. The Hopkins inquiry should have gone deeper into the question of ethical violations."

There has been no reaction from the RCC authorities. Nearly six weeks after its one-man inquiry commission submitted its report, the Kerala government refuses to divulge its details. The State Principal Secretary for Health and Family Welfare, N. Chandrasekharan Nair, had no comment on the Hopkins inquiry. "The Dr. Parikh Committee report is still under the consideration of the Council of Ministers" was all that he would say. Dr. Parikh, however said: "I stand by my conclusions. I have no idea why the government is taking so long to take action on it."

The government of Kerala and the Central government face a dilemma - whether to tell the truth and be forced to take action against well-known medical professionals, some of whom played a key role in building up the RCC, or not to tell the truth in order to "save the reputation of a good institution". Union Minister for Health and Family Welfare Dr. C. P. Thakur explained to Frontline in a telephone interview: "In one way, the controversy has helped us. It has proved to be a good lesson for all those involved in research in India, that we cannot be complacent about insisting on international standards of ethical behaviour in such research. Soon after the issue came to light, the government of India issued directions that the Indian Council of Medical Research's (ICMRs) guidelines should be followed in all institutions conducting such research. We also ordered the suspension of all research with human subjects at the RCC for six months. But at the other end of the spectrum is the fact that the RCC is a reputed institution offering treatment to thousands of people and we do not want to destroy it."

Dr. Thakur said that the Central government had received the Hopkins inquiry report and would take that also into consideration before making a final decision. The State government's inquiry report, however, is yet to arrive, he said.

Meanwhile, Dr. Huang has said that Hopkins did not tell her that she had to seek approval from the university's internal review board for a trial at a foreign medical centre, The Baltimore Sun reported on November 13. Huang is quoted in the newspaper as saying that she and her husband donated money to the university for the project because they thought it was important in the fight against cancer and that the university wired it to the RCC. The biologist is also quoted as saying that despite the setback she and her colleagues plan to conduct a series of experiments with the drug.

The Hopkins trial at the RCC is also significant in that it is one in a recent series of human subject research violations reported from the university. The most important one led to the temporary suspension by the U.S. federal agencies of all human research at the university, following the death in July of a healthy volunteer in an asthma study. At least three such incidents have been reported since then.

Says Dr. Bhattathiri: "If they continue to happen, the reputations of such great institutions will continue to be tarnished. The solution certainly is not putting a lid on truth, whatever it may be."