Print edition : December 16, 2005
R. KRISHNAKUMAR in Thiruvananthapuram

The Regional Cancer Centre in Thiruvananthapuram.-S. MAHINSHA

Frontline

"In one way the [Hopkins-RCC] controversy has helped us. It has proved to be a good lesson for all those involved in [human] research in India, that we cannot be complacent about insisting on international standards of ethical behaviour in such research... . But at the other end of the spectrum is the fact that RCC is a reputed institution offering treatment to thousands of people and we do not want to destroy it."

- Dr. C.P. Thakur (who was Union Health Minister at the time), in a telephone interview to Frontline in November 2001, explaining why the government looked the other way when allegations of serious ethical violations were raised in the conduct of the Johns Hopkins-Regional Cancer Centre drug trials.

THE identity, `EM-1421', is unlikely to ring a bell in India. It is one of the many compounds being discovered every other day in research universities of the West and are then adopted by pharmaceutical companies to be developed as money-spinning drugs through human trials.

`Erimos Pharmaceuticals', a young American company that has accepted EM-1421 as a potential cancer drug, also may not invite recognition all that easily. The start-up company has remained more or less in "stealth mode" ever since its inception.

Erimos was registered and christened initially as twin entities: `BioCure Technologies'(since described as the "holding company") and `BioCure Medicals'. Both entities came into being in Minnesota, United States, in September 2000, five months after the completion of the controversial `Hopkins-RCC clinical trials' in India, when two new compounds known briefly as `M4N' and `G4N' were tested for their anti-cancer properties on 27 cancer patients of the RCC, Thiruvananthapuram, without obtaining their informed consent.

The experimental anti-cancer compounds, tetra-O-methyl nordihydroguiaretic acid (`M4N' NDGA) and tetraglycinyl NDGA (`G4N' NDGA), were developed from nordihydroguiaretic acid isolated from a desert shurb creosote, or chaparral (Larrea tridentata), by scientists at the Johns Hopkins University (JHU), Baltimore, U.S. As Frontline had reported earlier (August17 and August 31, 2001), the first human trials of M4N and G4N were conducted between November 1999 and April 2000 at the RCC following an agreement signed "on behalf of Hopkins" by its Biology Professor (and lead inventor) Ru Chih C. Huang and the cancer centre authorities led by its then Director, Dr. M. Krishnan Nair.

Barely two months after the trials ended (initially) in India, 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 discovered by Huang and her colleagues "at her laboratory" in the JHU's Biology Department.

During Ang Tiong Loi's visit to Hopkins in June 2000, it was announced that the investment would enable "a new company" to conduct further research, "including FDA-approved clinical trials", using the new compounds, which were already tested on Indian patients. Hopkins held the patent for the new compounds and it was stated that they would soon prove to be "wonderful cancer drugs" that would bring returns to the university and the investor.

At least initially, when their discoveries were being announced, the Hopkins inventors continued to warn that crude extracts from the plant could be toxic to the liver and that people should not try to treat themselves with the unpurified material, "both because of its toxicity" and because "scientists were yet to conduct human research with the chemicals". Medicinal use of creosote is also reported to have had a history of being regulated by the U.S. government. Reports also indicate that the U.S. Food and Drug Administration (FDA) had issued a health warning in the early 1990s against the use of chaparral as a dietary supplement.

Thus, using the new chemicals in human trials in the U.S. posed its own problems for the inventors, given the strict regulations and safety requirements for conducting human research there. As it turned out, therefore, the Hopkins-RCC drug trial became a classic case of the complexities involved when researchers from developed nations undertake human trials in the developing world.

As the controversy outraged the medical community in India and abroad, it was clear that Huang and her colleagues had literally wished away the serious risks involved in human trials and drug discovery and sought to outpace the strict regulatory framework in the U.S., by managing to have the experimental compounds, with all their unknown risks, injected into the tumours of 27 human beings without their truly `informed consent', before they were adequately tested for safety on animals and before they went through regular ethical and scientific review and approval processes in the U.S. and India.

As alleged by Dr. V.N. Bhattathiri, the whistleblower at the RCC, and a patient, M. Gopalan, before the Kerala Human Rights Commission (and from what another physician Dr. V.P. Gangadharan and a handful of other patients told the media), the unsuspecting patients awaiting regular treatment signed "consent forms" (just a piece of paper) that committed them to the trial, without knowing the risks involved or realising that the injections were not a part of their treatment.

The world came to know of these trials only from Dr. Bhattathiri's complaint to the Human Rights Commission in March 2001, nearly a year or more after the tumours with the injected drug were surgically removed and (as was stated by RCC authorities) sent to Huang and her colleagues to aid in their search for a lucrative drug for cancer through "FDA-approved trials".

Dr. Parvesh Parikh, the one-man commission which was appointed reluctantly by the State government, announced after a controversial inquiry that "all patients were fine". However, he later told Frontline in response to a query that he had examined only "10 or 11" of the 27 patients involved in the trial. Dr. Bhattathiri refused to be part of a "sham inquiry".

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 collaborators were left to pretend that "except perhaps for some procedural irregularities" no harm was done and the trials were conducted in an above-board clinical setting (Frontline, December 7, 2001).

In contrast, in November 2001, after a high-profile internal inquiry that refused to name Huang as the scientist involved, Hopkins sought to take the moral high ground and said that "it was barring the scientist from serving as principal investigator on any future research involving human subjects" and that any future participation of the scientist in human studies, led by other principal investigators, had to be supervised by a senior Hopkins faculty member with expertise in clinical research. Since then the university has maintained that neither Hopkins nor Huang is involved in any way, any longer, with additional human subjects research involving M4N and G4N. "Far from absolving itself, the university has acted in accordance with its responsibilities," says Dennis O'Shea, spokesperson for the JHU.

But it was never explained what Huang or her colleagues did with the biopsies. Were further studies to understand the unknown effects of the new compounds in live human tumours carried out? How, if at all, did the RCC results contribute to ensuring the safety of patients in further trials in the U.S.? Says O'Shea: "Johns Hopkins has no institutional position on the scientific usefulness of the 1999-2000 results."

From reports in the U.S. media and inquires conducted by Frontline, it appears that while the controversy raged and the JHU went public with the inquiry and barred Huang from further research involving humans, and continued to deny her involvement in any further clinical research using M4N or G4N, the post-trial company, BioCure Medicals (with which Huang is closely associated), armed as it was surely with (unregulated, unmonitored) human trial data from the RCC, went on organising "FDA-approved" trials using M4N in the U.S., under licence from Hopkins.

"The results from the biopsies have directly led to further and more extensive evaluation of M4N as a drug [EM-1421]," says Huang.

Dr. M. Krishnan Nair, the retired Director of the RCC.-S. GOPAKUMAR

But as the controversy threatened to engulf further research, perhaps, BioCure Medicals also carried out a total image makeover and reinvented and registered itself with a new name `Erimos Pharmaceuticals' at Houston in Texas. Erimos also established a research facility, not in Texas but up north at Raleigh in North Carolina, at the campus of North Carolina State University. From then on Erimos began to describe its "lead candidate" for new drugs, the chemical M4N NDGA, as "EM-1421". The born-again company did not wear its close association with Huang and Hopkins or its blemished association with the RCC trials on its sleeve. Some reports suggest that `BioCure Technologies' was in existence from 1982 and had been synthesising NDGA or M4N NDGA at Chihuahua in Mexico from 1982 and at El Paso in Texas from 1989. But a company representative, clinical trials manager Jennifer C. Stern, told Frontline that "none of the original founders of BioCure Medical or BioCure Technologies are now on the staff of Erimos Pharmaceuticals" and that "the longest standing member of Erimos joined only in 2002".

The distancing of Erimos and its staff from the controversial clinical trial was thus more or less complete.

The JHU applies a somewhat similar logic to disconnect itself from the controversy or any responsibility for the RCC trials. Even as early as November 2001, soon after its 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 did not mean it authorised the trials and that no patients were, after all, harmed. It has consistently tried not to own any responsibility for the experiments while its own inquiry found they were done without adequate safety testing on animals and without proper Institutional Review Board (IRB) review with chemicals developed at its Biology Department. "Erimos supports laboratory research by Professor Huang and lists her as a scientific adviser," says O'Shea, explaining the university's position on Huang's relationship with the new company.

Asked whether the trials sponsored by Erimos were not a follow-up of the trials conducted by Huang, Jennifer Stern told Frontline 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).

She claims, "As such the RCC institution, conducting ethical medical research, broke ground for what may be the next major advance in chemotherapy for cancer."

Breaking his silence on the issue after nearly four years, Dr. Krishnan Nair, told Frontline: "We were on the verge of a major cancer drug discovery then. The RCC would have had the first original drug discovered in India. In fact, we had launched work on a new division at the RCC for Molecular Biology and Drug Discovery and had already planned for the development of six or seven drugs when the controversy broke out. The commotion that followed has pulled back drug development not only at the RCC but also in the whole of India by at least 20 years."

Krishnan Nair also said that there were some lapses in the trials because they were done "at a time when no concrete guidelines existed in India for doing clinical trials. Even the Indian Council of Medical Research's [ICMR's] guidelines, which the government asked everyone to follow, were published only in 2000, after the trial ended". But he asserts that the conduct of the trial was proper and that the RCC and India as a whole lost a great opportunity because of the controversy surrounding it.

Two points are emphasised through these arguments: all those involved are now ready to acknowledge the invaluable role of the (then risky) experiments on 27 patients at the RCC to the continuing M4N/G4N research in the U.S.; but all of them are unwilling to acknowledge responsibility for the unethical way in which the trials were conducted.

EM-1421 is now Erimos Pharmaceuticals' lead candidate for new drugs for two types of afflictions: head-and-neck cancer, a morbid variety of tumour that develops in the mouth, throat, sinuses, nasal cavity, voice box and salivary glands (as in the case of the RCC patients); and Cervical Intraepithelial Neoplasia (CIN), a pre-cancerous abnormality - not a cancer - in women, affecting the lower part of the womb, which is caused by a sexually transmitted virus, the Human Pappiloma Virus (HPV). Hopkins, Huang and her colleagues and co-inventors at the university (some of whom are in Erimos now), however, stand to gain if Erimos succeeds in developing a lucrative drug out of those controversial chemicals.

Yet, according to information provided by Jennifer Stern in response to questions, it appears that Erimos has so far been able to undertake only a single Phase I study of M4N being injected directly into head-and-neck tumours at three different centres in the U.S.

That Phase I study (to test the safety of the drug, its side effects and the best way to administer it) was conducted only on "a total of nine patients" at the Medical University of South Carolina (MUSC), Duke Comprehensive Cancer Centre, Durham, North Carolina, and an undisclosed "private clinic in Colorado" using "clinical research support", and ended in December 2003, she said.

The Phase I clinical trial reports from the MUSC and the Duke Centre were presented by the principal investigators, Dr. Terry A. Day and Dr. F.R. Dunphy respectively, at separate international medical conferences in 2004, with Erimos describing at least one of them as "positive data from Phase I trial of EM-1421 in refractory [advanced, otherwise untreatable forms of] cancer".

However, a January 2005 newsletter update (by the U.S.-based human rights organisation CIRCARE) on the Hopkins trial, quoting the results from the Duke Centre study as cited in the Journal of Clinical Oncology (Vol 22, No 148 July 15 Supplement 2004:5614), says: "The results described by Dr. Dunphy directly contradicts the earlier assessment of Dr. Huang, to whom the statement that it is a wonderful drug, and it's not toxic in humans was attributed in Science, 2001:1024. Far from being not toxic in humans, of a total of three subjects enrolled in Dunphy's trial, one subject was removed from the study after developing a tracheal-cutaneous 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 intra-tumoral injection of the same investigational drug. Such statements strain credulity in the light of Dunphy's recent data."

Asked to explain what the study implied with regard to the safety of using M4N in human beings, Jennifer Stern wrote: "In five out of six patients receiving three doses, clear tumour necrosis was seen without damage to surrounding healthy tissue and without systemic side effects. The drug injection was associated with transient pain [not unusually for drug directly injected into the tumour]. Tumour necrosis in some of the larger tumours was associated with fistula [a hole appearing where the dead tumour tissue occurred]." She also said that in all the support toxicology studies, no evidence of drug-related toxicity was seen to date and that there was also no evidence of local or systemic toxicity in the ongoing CIN study.

Frontline's efforts to seek clarifications from Dr. Dunphy and Dr. Day were not successful. Dr. Dunphy did not respond to messages and Dr. Day wrote back to say that he was not permitted to discuss the results under an agreement with BioCure Medicals.

However, from what the Erimos representative told Frontline, it appears that no further trials were undertaken in the U.S. with M4N since December 2003, nor was a Phase II study of `intra-tumoral injections' planned, adding credence to reports by CIRCARE that the Phase I data may not be all that positive as claimed by Erimos and that Erimos may be finding it difficult to get volunteers for its head-and-neck cancer trials (even though it has proceeded into Phase II trials with M4N for CIN).While it was so easy for Huang and her collaborators to ensure easy enrolment of human subjects for the experiments at the RCC, from the CIRCARE report and other indications it appears that the researchers are indeed finding it difficult to get the expected number of volunteers. Both Jennifer Stern and Huang evaded a direct answer to a question about possible dearth of volunteers. Though Jennifer said "we have approximately 200 patients planned/participating in Phase I and II clinical studies with EM-1421", in her other replies, there was nothing to suggest that except the nine patients involved in the M4N intra-tumoral study that ended in 2003, 25 participants in the Phase I and the ongoing Phase II CIN studies and an undisclosed few in a study on oral dosing of M4N going on in Nottingham, England, Erimos has not managed to get volunteers.

Several other elements of the ongoing human trials in the U.S. with the controversial chemicals are significant from the perspective of a developing country such as India with its genetically diverse population having a varied disease profile, as it starts to throw its doors open to international human research aspirants at relatively very low costs, through half a million practising doctors, a large majority of them uninitiated in the science and ethics of biomedical research on human beings.

For example, despite what is described by Erimos now as "the invaluable patient data from India that helped the company understand the mechanism of action of the drug, its effectiveness and likelihood of safe administration", Huang and her co-researchers, now in Erimos, were forced to undertake further tests on animals to obtain the sanction of the FDA for conducting a similar "Phase I M4N" study on human beings in the U.S. "Erimos abides by Good Clinical Practice guidelines and the Code of Federal Regulations. As such, mandatory IRB approval is needed. The FDA requires certain animal testing to be conducted as part of the IND [Investigational New Drug] process," says Jennifer Stern.

Moreover, all the nine patients in the Erimos study were those who were "refractory [resistant] to surgery, radiotherapy and chemotherapy" and had no other treatment option left. In contrast, all the 27 participants in the 1999-2000 Indian trial did not need the injections at all, even as an experimental drug, because they had other treatment options such as surgery, radiotherapy and chemotherapy.

An important aspect of Dr. Krishnan Nair's defence in 2001, when questions were raised about the safety of patients whose treatment was delayed and had to wait for up to 24 days with the injected chemicals in their body, was that M4N was "not water soluble" and hence would stay within the tumours and not reach other parts of the body by entering the blood stream. As Frontline had reported then, when asked about the effect of the "water-soluble G4N" which was also administered to the patients, Krishnan Nair merely said that "he was not aware of it and would look into it".

Significantly, in her response, Jennifer Stern said the Erimos trial demonstrated that M4N (too) "was absorbed into the bloodstream after intra-tumoral injection". This finding, she said, had now encouraged the company to "progress to an intra-venous formulation" to be tried in patients in a study scheduled for December 2005.

It is striking that Erimos does not have a G4N trial in its list of concluded/planned human trials. Huang avoided answering the question why G4N was never used again in trials in the U.S. but said it was undergoing further "basic research" in her laboratory as part of a drug discovery programme to "more effectively" treat tumours and viral diseases.

The partial data from the case-sheets of patients released by the RCC in 2001 when the controversy began themselves give room for uneasy conclusions. Data on only 23 patients were released, though the RCC itself had acknowledged that 27 patients were involved. Of the 23, at least two patients were recorded as "expired due to unrelated cause" and another is recorded as "lost in follow-up" within a month; another developed a second cancer within four months very near the site of the removed tumour; five were stated to have had "progressive disease" within two to six months of the "last follow-up"; three were declared "disease free" within four months of surgery, at last follow-up; nine were stated as having "no evidence of disease" after surgery, radiotherapy or chemotherapy after the last follow-up (between four and 11 months); two were stated as having "leukoplakia", a skin disorder, not a cancer.

There was no evidence to show that all the 27 patients were monitored after the injections, specifically to understand the effect of the injected drugs on them. Significantly, Huang now says she was "not clinically involved" with the follow-up of the patients at the RCC.

Yet another important factor is that Huang's claim that Erimos has progressed to Phase II studies of EM-1421 is only partly true. From Jennifer Stern's reply to Frontline, it is clear that the only Phase II study Erimos has progressed to is for CIN, being conducted at the University of Maryland and at "a private clinic" in Delaware. All other studies by Erimos are only in "various stages of planning". In short, Erimos has, at least until mid-November, not undertaken any more cancer studies using M4N and seems to have dropped its plan altogether for any more experiments involving the injection of M4N directly into the tumours. It now claims it is "progressing" into intra-venous formulations for solid tumours, studies that are yet to start at undisclosed locations in Arizona, New York and Tennessee. Erimos claims it will start in December.

Erimos is conducting only one study outside the U.S., according Jennifer Stern, "at a private clinical pharmacology unit" at Nottingham. And "preliminary discussions" are on for an M4N study on treatment-resistant brain tumours at seven centres "including the Johns Hopkins Medical School".

What is clear from all this is that drug development from the two controversial chemicals is still a long way off.

"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, chairman of the activist organisation `Health Action by People', said.

There is indeed another perspective to the Hopkins-RCC trials as they unfolded in India. In her reply to e-mailed questions, Jennifer Stern asked: "From your perspective, are we right in our belief that local ethics, rules and regulations, were followed at RCC in the conduct of the study?" On being told about what Frontline's enquiries seemed to suggest, she replied: "Your comments certainly dissuade me from initiating any future research programme in India, which is really a great shame for the sick and critically ill population of your country. I truly believe that EM-1421 has the potential to be a great oncology drug. But more importantly, I would be concerned that other pharmaceutical companies will be dissuaded from bringing new treatments to India for fear of being blamed for the unethical conduct that you believe is so rampant in your country's clinical research system - especially after your next article."

She also said: "I do hope that the aim of your article will be to expose the problems with the Indian clinical research system so that they can be fixed and not simply to search abroad for causes of what seem to be issues with India's own processes... it seems unlikely that the study conducted on M4N is the sole instance of questioned research conduct in India."

The unconvincing conclusions of the `confidential' inquiries ordered by the State and Central government notwithstanding, the trials surely highlighted the vulnerability of a number of globally accepted requirements for ethical research involving human participants in a country like India - that they must: be subjected to prior review by a clearly independent and effective ethics review committee; obtain truly voluntary and informed consent of individual participants; minimise risks to participants and ensure the risks involved are reasonable when compared with potential benefits; not be exploitative; be essential; show equal regard for all subjects; ensure equitable distribution of burdens and benefits; take adequate care to compensate participants for injuries sustained directly during research; be accountable; be transparent and so on.

The continuing Hopkins-RCC drug trial saga is, therefore, a lesson for India as it gets ready to welcome the onslaught of multinational drug companies and other private players eager to conduct clinical trials on its patients. Its weak regulatory system and inadequate safeguards and the free-for-all setting that revolts against the rights of patients only encourages their exploitation.

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