The misuse of science

Print edition : August 18, 2001

The claim of researchers at Kolkata's Indian Association for the Cultivation of Science of a potential new cancer cure is scientifically dubious and based on violations of many tenets of medical ethics.

HUNDREDS of desperate patients suffering from cancer are rushing to Kolkata and Pune in search of what has been called a "miracle" cure - even as a major scandal has broken out in Kerala over clinical trials involving another "new cancer drug". The patients hope they will receive a few spoonfuls of the "miracle" drug developed and being tested by scientists in Kolkata. Hundreds of letters, fax messages and telephone calls are pouring into an unlikely address - the Indian Association for the Cultivation of Science (IACS), a Kolkata institution known for physics and chemistry rather than for the life sciences. (Indeed, medicine does not even figure in its 10 listed "major" research areas.)

Strangely, the IACS clinical trials are being conducted by a private medical practitioner and a group of non-medical scientists. A five-member team has just enlisted 100 cancer patients for the second phase of the trials. Lest it be imagined that the scientists belong or report to a medical centre, they are part of the IACS' Department of Biological Chemistry. While the treatment in Calcutta is free of cost, there are allegations that patients in Pune are being charged hefty sums of money for the experimental "drug". This itself is a violation of standard practices and norms of medical ethics. Yet, this trial has the purported backing of the Drug Controller of India, the Department of Science and Technology, and the Council of Scientific and Industrial Research.

This could be only one in a series of violations of the elementary tenets of medical ethics - possibly a gigantic fraud exploiting the gullibility and desperation of people suffering from major disease, to alleviate whose symptoms they may be prepared to try out anything. There is a distressing lesson in this for our healthcare system and for our attitudes to human life and well-being, as well as human rights. The IACS malpractices may prove far graver than the scandal at the Regional Cancer Centre (RCC) at Thiruvananthapuram. While the RCC scam involves a violation of the patient's right to be told about the likely effects of the substance used in an experiment, the IACS trial is probably based upon multiple breaches of sound ethics. Consider the following:

The "miracle" drug is a chemical derived from Methylglyoxal as the "lead ingredient", which scarcely qualifies as a medicine. Methylglyoxal is a regular chemical, not cleared for human use. It is made without conforming to sound manufacturing practices and widely respected codes of good laboratory practices followed throughout the world. Why the drug was chosen for trial two years ago remains a mystery, as does the apparent clearance of the trials by the apex authorities of science. The IACS' main supplier of Methylglyoxal is an American warehouse corporation, Sigma Medical Company, which sells it for research purposes at $1 to 2 per gramme and specifically states that none of its chemicals is meant for medical use.

The principal scientist involved is Professor Manju Ray, a biochemist, not a pharmacologist or cancer specialist. Only one of her colleagues has been identified as a medical practitioner. The "secret" of the "miracle" lies in the anti-tumour effect of Methylglyoxal - a property shared by hundreds of toxic chemicals. Methylglyoxal, it is claimed, inhibits electron flows in cancerous cells and blocks a crucial step necessary for the production of ATP, the cellular energy "currency".

This spells the theoretical possibility of using Methylglyoxal against cancer. However, the researchers have by no means established a link between Methylglyoxal treatment and retardation of growth of malignant tumours. Their findings, published in the Indian Journal of Physics (the IACS' in-house publication), do not even establish a statistically respectable relationship despite the claim of a "dramatic positive" effect. A critical ingredient, a control group with which the treated patients are compared, is absent from the study. The researchers treated 24 patients, mostly in highly advanced stages of cancer, with oral administration of Methylglyoxal, with Vitamin C, over eight to 10 weeks. They claim that after treatment, 11 were in "excellent physical condition" and five were in a condition that "can be considered stable". "The rest either opted out of treatment or died during the course of study." This is disturbing enough.

The study does not show how, through what process, the "cure" occurs. It merely defines "excellent physical condition" as one in which "the patient leads almost normal life and the disease is apparently in remission". Such descriptions are vague, and the condition can change within days. They involve highly questionable subjective criteria. The bare requirements of respectable science demand the demonstration of a causal connection between a disease and the curative properties and mode of action of a drug. For the most part, what is defined as "excellent" physical condition is no more than symptomatic relief - better appetite, general feel-good factor, with occasional increase in the haemoglobin count. (However, the critical factor even in remission, leave alone cure, is actual reduction in the cancer load.)

The argument advanced by the IACS team that there is "widespread hope" amongst cancer patients because this drug is "cheaper and has fewer side-effects" is beside the point. Such considerations only become relevant once the therapeutic effectiveness of a medicine is established.

It is truly amazing that such a "scientific" paper was published in the Indian Journal of Physics, without peer review by biological or medical professionals. Its editor says he rushed the article through although it was submitted one day before the issue was to go to press, because its "findings were important". The study is so shabby that it should have been summarily rejected. What is equally astonishing is that the drug should be used in clinical trials on human beings in the first place. Such trials are permissible only after the pharmaco-kinetics (the way and the speed with which the body will handle the drug) is properly understood, and trials on experimental animals have been carried out.

In this case, the first criterion was not fulfilled. And there is no mention of animal trials. According to the Indian Council of Medical Research's (ICMR) "Ethical Guidelines for Biomedical Research on Human Subjects", any trials on humans should be conducted "only after the approval of the Drugs Controller of India". There is no evidence that this was ever obtained.

Yet, the IACS has apparently granted its approval to Phase II trials, which is part of a three-phase process by which a medicine under evaluation is judged to be effective and (relatively) safe enough to be marketed. (Phase I trials are conducted on healthy volunteers to determine toxicity, safety, adverse effects, and so on. Phase II involves controlled studies on 20 to 25 patients of both sexes to determine therapeutic uses and effective doses and so on. And Phase III trials are meant to obtain adequate data on the safety and efficacy of a drug in a large number of patients, in comparison to a standard drug/placebo). Going by all appearances, the IACS researchers violated the requirement that each phase of the trials be given prior approval by a qualified Ethics Committee.

IF the IACS is guilty of a serious malpractice, so are the media, which breathlessly reported the "miracle" without critically examining the claims made by its conjurors. The Kolkata papers went rapturous on this "great achievement". Even worse, some "national dailies" too celebrated it as a "breakthrough" by a "brave breed", and a triumph of Indian science - one more landmark in India's "arrival" as a technology "superpower". Some of the pathological breathlessness may be explained by the fact that the IACS is a very old institution, established in 1876 and the Indian Journal of Physics was set up by C.V. Raman, India's only winner of the Nobel Prize for physics. But the Prize was awarded in 1930 - not for medicine or oncology (the science of tumours) 80 years later. The IACS got embroiled in an area totally outside its competence - in violation of good scientific practice.

While slightly less scandalous, the RCC scam is equally violative of human rights. The experiment was carried out in association with a reputed U.S. institution, Johns Hopkins University (JHU), Baltimore. It came to light because the head of radiobiology Dr. V.N. Bhattathiri, and Dr. V.P. Gangadharan, blew the whistle and disclosed that RCC Director Dr. M. Krishnan Nair had sanctioned drug trials without informing the patients that they would be administered a new medicine. This violates medical ethics: no trial must be conducted without the patient's full prior, informed, consent.

Going by the media debate over the trials, it would appear that even "obtaining" prior sanction from an institutional Ethics Committee is not a scrupulously followed practice. As a former member of the RCC Ethics Committee confesses, sometimes there is a gap of four to six weeks after the trial commences, which, she says, is considered "okay". However, this is not okay. Medical ethics are based on the principle that human life is sacred and that each person must have full information on what she or he is subjected to and at what risk and potential benefit. Trials must have the prior approval of Ethics Committees.

Bhattathiri has since alleged that "NDGA M4N (the substance being tested) is not a drug but a chemical that has been excluded from the U.S. Food and Drug Administration's list of drugs generally considered as safe". The JHU has instituted an inquiry into the drug trials and said that faculty member Ru Chi Huang "has been directed to cease all activities related to the study in question". It has categorically said the experiment had "not been approved". (This university does seem to have a supervision problem, despite its acceptance of the importance of ethical norms. It was recently involved in a controversy in the U.S. where a 24-year-old woman died in a drug trial.)

However, unlike Johns Hopkins, the RCC has not even admitted that it committed any ethical violation. Now, embarrassed by adverse publicity, however, the Kerala government has appointed a one-man panel to investigate the scandal. Even this has got mired in controversy because the investigator is a junior doctor; and his terms of reference are extremely limited.

As the sordid drama is played out at the expense of cancer patients, the ICMR and the Drug Controller respond with thundering silence. The ICMR did publish "Ethical Guidelines" last year. But it has to do a lot about implementing them, ensuring compliance, and punishing their breach in an exemplary fashion. It speaks poorly of the apex institution that it has to wait for a scandal to break out and fester for months before it responds - always, in an apologetic, defensive, fashion.

Had the ICMR behaved more responsibly in enforcing its own norms, it might have prevented some of the worst abuses we are witnessing today. For instance, had it punished in an exemplary manner those guilty of gross malpractice in the Delhi "cervical cancer" scandal which came to light in 1997, it might have created a deterrent. This involved failure to treat 62 "control group" patients with anti-cancer drugs, from among a sample of 1,100 illiterate women. The women were not properly informed of their condition (cancer), or about the trial and its risks.

The ICMR, to its credit, accepted blame for the scandal, involving its own Institute for Cytology and Preventive Oncology. There was a strong case for prosecuting the researchers under Section 300 of the Indian Penal Code: "to do an act with the knowledge that is likely to cause death, is culpable homicide". Similarly, had it penalised the perpetrators of the Quinacrine fraud - one of the worst instances anywhere of Nazi-style abuse of poor, illiterate women through a highly corrosive chemical, involving dedicated neo-Malthusians and population control fascists, besides Bharatiya Janata Party MP J.K. Jain - we might have had a greater semblance of respect for human rights in drug trials.

Today, several cases cry out for the ICMR's intervention. One is a neo-Malthusian experiment on men, with a dubious polymer - conducted at the instance of yet another non-medical researcher (Sujoy K. Guha) at the Indian Institute of Technology, Delhi. This involves the injection of the polymer, styrene maleic anhydride (SMA,) into the vas deferens in a vehicle of dimethyl sulphoxide (DMSO).

Put simply, the polymer swells and forms a block or barrier and prevents the ejection of sperm - and hence conception. However, there are serious problems here. DMSO is a moisture-absorbing industrial solvent used in antifreeze and hydraulic fluids, and as paint/varnish remover. It is toxic to humans and produces primary irritation with redness, itching and sometimes scaling and weals. Corneal opacities have been produced in experimental animals. Besides, there are nagging questions about the use of SMA and its reversible effects. Will the swelling it produces lead to other harmful effects? What is the acceptability of such a method over competing alternatives like straightforward vasectomy? And yet, the trial is now going into Phase III. This clearly calls for ICMR intervention.

There have been numerous cases of abusive drug trials in India, Quinacrine being just one. The country has a huge patient pool and is severely under-regulated. High illiteracy rates and extremely unequal relations between rich upper-caste doctors and poor low-caste patients are conducive to abuse. The ICMR itself has come across several instances of dubious trials: in 1995, of a bovine virus "vaccine" against HIV/AIDS (Mumbai and Kolkata); in 1997, a dubious eye surgery procedure (Hyderabad); and most recently, treatment of coronary artery disease with vascular endothilial growth factor (at Metro Hospital, Noida). Its "Guidelines" forbid trials without proper authorisation and require that a drug that has gone through a certain phase of trials abroad be put through the previous phase in India.

The case for direct intervention does not arise from a narrow, professional, "expert" consideration, but a simple human one. Decent science cannot tolerate lack of transparency, abuse of human rights, and disrespect for safety. To condone such abuses in the name of science is to degrade and berate it, and to vulgarise a rational pursuit - thereby demeaning rationality itself as something whimsical and indifferent to human dignity. It is also to legitimise hierarchy, the rule of the powerful, and the tyranny of "experts". Nothing could be worse for democracy.

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