DRUG TRIALS AND ETHICS

A Frontline investigation comes up with new revelations on funding, business connections and conflicts of interest in the Johns Hopkins-linked drug trials at Kerala's Regional Cancer Centre.

R. KRISHNAKUMAR in Thiruvananthapuram

A NON-MEDICAL scientist with a potential anti-cancer "drug" discovery, and links with a "start-up" company. A university holding a patent for the experimental drug. A businessman willing to invest a couple of million dollars in the new company for further development of the drug through trials in human beings. An international contract research organisation that scouts worldwide for opportunities to do clinical research using the drug. An institution in a Third World country willing to conduct trials on its patients for them. These are among the ingredients of what has now come to be known as the "Johns Hopkins-RCC drug trial controversy" in Kerala.

It was on July 30 that the Baltimore-based Johns Hopkins University (JHU) revealed to the media in the United States that the clinical trial of the "experimental anti-cancer drug" developed by one of its faculty members, conducted at the Regional Cancer Centre (RCC) in Thiruvananthapuram, did not have its authorisation. The JHU went on to say that the trial did not have the approval of any of its Institutional Review Boards (IRBs) that ought to have considered whether it would be safe to conduct human trials of the drug.

In an interview to a U.S. newspaper on July 31, the faculty member, Dr. Ru Chih C. Huang, a Biology Professor at the JHU since 1965, said that she was unaware that the university had a requirement to seek internal approval of experiments conducted abroad. She added that she had gone ahead with the clinical trial because it already had the approval of a "similar panel" in the RCC.

"I will never do this again this way. But certainly I did not hurt the people in that country in any way, and I think this will prove to be an effective anti-cancer drug," Huang, who did not respond to an e-mail message sent by Frontline, is quoted as saying in The Baltimore Sun.

But perhaps the most significant statements reported in the newspaper as having been made by Huang are that her "study was funded by $2 million from 'Biocure Medical of Minnesota"' and that "Hopkins holds a patent on the drug and could profit if the company can bring it to market as a cancer treatment".

On a request for confirmation, one of the correspondents of The Baltimore Sun wrote to Frontline that the information about the source of funding (Biocure Medical of Minnesota) and the patent (held by the JHU) was obtained by him from Ru Chih Huang in the course of a telephonic interview. The correspondent said that Huang had described the company as a "start-up" and that she had expressed the hope that "Hopkins could make a profit if the drug is brought to the market in four or five years".

Responding to a request for clarification, a spokesperson for the JHU and its Executive Director, Communications and Public Affairs, Dennis O'Shea, wrote to Frontline: "Yes, Hopkins does hold a patent on the M4N drug that was used in the study. This patent was assigned to the university by the researcher in routine compliance with the university's technology transfer policy. Such patent assignments are standard operating procedure with any discovery or invention made at Johns Hopkins. The assignment of the patent to the university had nothing to do with the clinical trial in India and it did not in any way alter the researcher's obligation under university rules to submit the proposed trial to an institutional review board."

O'Shea also said that while the patent application had been filed on October 15, 1999, before the trials, the patent had not been granted until April 10, 2001, well after the trial was completed. Replying to a question on the source of funding for the study, he said that "the source of the funding of the trial remains a focus of the investigation" ordered by the university in the wake of the controversy in India. O'Shea added that the JHU investigation "is being conducted as expeditiously as possible, given the complexity of the facts involved" and that there was no deadline for its conclusion.

However, a report published last year in the JHU newspaper, The Gazette Online, gives a clear indication of the funding that Huang's study would have received. On July 3, 2000, the online newspaper (Volume 29, Number 40) reported that a Singapore-based businessman planned to make "a multi-million-dollar investment in a groundbreaking new start-up company that will further develop basic cancer treatment research conducted at Johns Hopkins".

THE BALTIMORE

The report said that real estate businessman Ang Tiong Loi had signed a letter of intent on June 27, 2000 "to invest in a new company dedicated to developing a group of naturally occurring compounds isolated from creosote bushes that have shown some early signs of promise as cancer treatments" in the experiments conducted by Huang and some other members of her laboratory.

THE first-ever human trials of two chemicals, tetra-O-methyl nor-dihydro-guaiaretic acid (M4N) and tetraglycinyl nor-dihydro-guaiaretic acid (G4N) - originally isolated from the creosote bush Larrea tridentata at the JHU laboratory by Huang and her co-workers - were conducted between November 12, 1999 and April 8, 2000 on oral cancer patients awaiting surgical treatment at the RCC (Frontline, August 17). From available indications, including statements made by a few patients and Dr. V.N. Bhattathiri of the RCC who first brought the issue to public attention, the majority of the 25 patients on whom the trial was conducted had not realised that the injections they received were not part of their treatment but belonged to an experiment to understand the effectiveness of the chemicals in treating some forms of human cancer. Although the RCC claimed that there was no harm done to the patients and that the injections had substantially reduced the extent of the tumours, there was no evidence of continuous monitoring of the patients, most of whom were sent home after the drug-injected tumours were surgically removed.

The Gazette Online report indicates that the letter of intent was signed in June 27, 2000, about two months after the trials at the RCC were completed. It quotes the university's Director of the Office of Technology Transfer, Nina Siegler, as saying that "one of the first objectives of the new company will be to design and conduct FDA (Food and Drug Administration)-approved clinical trials of these substances." This puts a question mark on the approval status of the RCC trials, which had already been completed.

George Lee, a U.S.-based representative of Ang Tiong Lee, is also reported in The Gazette Online as saying that although the new company is a business venture, it intends to keep the price of the drug "as low as possible". According to Siegler, the expectation was that the drug could be manufactured "fairly inexpensively" since it was a modification of a natural product. She says: "That still has to be confirmed, as does the product's potential as a cancer treatment, but we are hopeful that if this works out, we might be able to price any resulting drugs in a way that makes them available to all the people of the world and still makes returns for the university and the investor."

The July 2000 report in the JHU's online newspaper also said that the university, which holds the patent rights, will grant an exclusive licence to the new company to use those inventions and that "there will be contracts between the university and the company for Hopkins to continue work on new drug analogs and clinical development".

Siegler also said that "most of the money will go into clinical trials, not into corporate overhead" and will be "dedicated to seeing if the compound can work in a variety of human cancers", although it would not be "fair" to call it a "virtual company". She also announced tentative plans of the JHU to hire a contract research organisation to help implement clinical trials that received the approval of the FDA.

An earlier report in The Gazette Online said that in the latter half of 1998 the JHU had signed an agreement with one of the largest pharmaceutical contract research organisations with offices in about 28 countries, including India. The move was aimed at finding clinical research opportunities for the university's corporate-sponsored clinical drug research. There are indications that the organisation's Indian arm was involved in the drug trials at the RCC.

However, it is yet to be known whether 'Biocure Medical, Minnesota', the company Huang referred to in her interview with The Baltimore Sun, is the same as the one proposed through the letter of intent and whether the $2 million funding that she said her study had did indeed come from Ang Tiong Loi. The JHU newspaper report also mentions Ted Poehler, Vice Provost for Research at the university, as saying that the arrangements for the "new start-up" had come with "unusual speed" and that there were "a number of parties, including Ang" who were very impressed with the work Huang and her team had done until then, and "how far they have been able to take it".

Significantly, The Gazette Online had also reported that businessman Ang knew Huang "both through family connections and through her reputation in Asia" and that he had decided to support the business because he believed in the programme and in Huang. However, the stand of the JHU now, after the RCC trials set off a controversy, is that "the source of the funding for the trial remains a focus of its investigation".

According to RCC Director Dr. M. Krishnan Nair, Huang first approached his institution with the proposal to conduct clinical trials of the new chemicals in June 1998, much before the application for the patent was filed.

In a press statement issued on August 3, following the JHU's denial that it had authorised the clinical trials conducted at the RCC, the cancer centre's Finance Manager (Projects) K.R. Bhaskaran Nair said: "A section of the media has reported that the M4N clinical trials at the RCC were not funded by the Johns Hopkins University. The RCC denies this baseless news report. There is very clear documentary evidence that RCC had received funds from Johns Hopkins University for the clinical trials conducted under the leadership of Dr. Ru Chih Huang (Ordering bank: First Union National Bank, New York; Ordering customer: Johns Hopkins University, Baltimore). This statement is being issued to remove the wrong impression that people may have because of the news report."

Dr. Parvesh Parikh of the Tata Memorial Hospital, Mumbai, who constitutes the one-man commission appointed by the State government to inquire into the controversy, also said that he was in possession of documents that proved that funds had been sanctioned with the authorisation of JHU authorities and that the documents had been signed by the "treasurer" of the university.

After the signing of the letter of intent on June 27, 2000, a few months after the first trials for M4N and G4N (the latter not mentioned in the JHU statements) chemicals were conducted, did Dr. Huang go ahead with the project on her own, without the knowledge of her university, as the JHU statements indicate? Did she obtain funding from sources other than Ang Tiong Loi? If the RCC was to receive only Rs.25 lakhs a year for coordinating the trials in its clinic and in three other hospitals in India, who funded the study at the JHU laboratories until then? Where did the rest of the $2 million from 'Biocure Medical, Minnesota' go?

These are a few of the gaps in the Hopkins-RCC jigsaw puzzle, which remain to be filled by the JHU inquiry. It is unusual that the study by Huang did not attract attention within the JHU because she was a Biology Professor at the university's Krieger School of Arts and Sciences, where hardly any drug research is done. Moreover, she is a non-medical scientist who tested the experimental anti-cancer chemicals earlier only in mice and, ever since the controversy erupted, has been asked by the JHU not to take part in any other human trials. The JHU also asked Huang to cease all activities regarding her current work and stick to basic research in her laboratory.

The gaps in the jigsaw assumed a serious dimension on August 10 when counsel for one of the patients, who had earlier approached the Kerala State Human Rights Commission, produced "RCC documents" before the Dr. Parvesh Parikh inquiry commission. Counsel demanded that the death of two patients within less than 50 days of their participation in the trial in early 2000 was caused by the injections that they received. The relatives of a 60-year-old woman patient who was suffering from "terminal malignancy" told mediapersons, after they deposed before the commission, that the doctors had asked their willingness to include the patient in a new project of the contract research organisation (with which the JHU had signed an agreement in 1998) that would provide her free of cost five doses of the experimental drug, worth Rs.10,000. They said that the woman's condition had worsened before the fifth injection.

Dr. Parikh said the commission would inquire into the deaths and go through the entire sequence of events relating to the trials. The commission is expected to submit its report in three weeks. Meanwhile, the inquiry ordered by the Central government is also progressing.