Claims and contradictions

There are several unsettled questions that remain at the Johns Hopkins end and the Indian end with regard to the procedural and other aspects involved in the drug trials.

THERE are further twists to the controversial anti-cancer drug trials at the Regional Cancer Centre, Thiruvanantha-puram, and the business links associated with the Johns Jopkins University's (JHU) joint study with the RCC.

The purpose of the study was to prove in cancer cells the activity that was discovered by the JHU Biology Professor, Dr. Ru Chih C. Huang, and her associates in viruses. The objective was to prove in human trials the inhibition of growth in tumour cells that the JHU team had observed in studies conducted in animals.

Dennis O'Shea, JHU spokesperson, claimed that the university had never "directly" funded the study. However, his claim was contested by the RCC project leader, Dr. Manoj Pandey. According to Pandey, the RCC had received two cheques, signed by JHU treasurer William E. Snow Jr, worth $19,400 and was awaiting the third. Dr. M. Krishnan Nair, RCC Director, is also reported to have stated in March that the project is funded by the JHU. He said that the RCC was to receive Rs.25 lakhs and the amount could later be increased to Rs.1.25 crores. Interestingly, Pandey claimed that the JHU received permission from the U.S. government to import the tissue of Indian cancer patients for study.

O'Shea told the journal Science: "I am not saying we know where these funds came from. Just because Johns Hopkins cuts a cheque it does not necessarily mean that it approved the project being funded. Making sense of the financial transactions is a task for the new investigative panel."

O'Shea's remark that the study was not directly funded by the JHU assumes significance in the light of Huang's comments to Science. She told Science that the funding for the project came entirely from private sources, including the JHU and a Minnesota-based company, Biocure Medical LLC. The company was set up with the objective of designing and conducting clinical trials of compounds derived from nor-dihydro-guaiaretic acid (NDGA).

According to Huang, the supporters of the project have committed about $2.5 million to conduct pilot trials in four places in Asia. Dr. Krishnan Nair had stated that Phase II trials were also to be carried out at, besides RCC, the K.J. Hospital, Kanpur, and the Banaras Hindu University, Varanasi, under the RCC's supervision.

The catch was that let alone the Food and Drug Administration of the U.S., even the JHU's Institutional Review Board (IRB) had not approved the trial although Huang had submitted the protocol for the clinical trials to the IRB early this year. More pertinently, according to a press release issued by the Press Information Bureau (PIB) on behalf of the Union Health Ministry in the wake of the controversy, the approval by the Drug Controller General of India (DCGI) seems to have been granted only in February this year, months after the experiments were conducted.

The PIB press release said that the RCC was granted permission on February 2, 2001, to import M4N (tetra-O-methyl nor-dihydro-guaiaretic acid) from the JHU to undertake a study to evaluate its efficacy in advanced oral and cervical malignancies on the basis of pre-clinical and other relevant data submitted by the RCC Director.

"It is not a retrospective sanction. The proposal came to us only then. We do not know if the trials had been going on earlier," said S. Ramteke, Deputy DCGI. On the other hand, Dr. Krishnan Nair had claimed that the initial application for the trial had been submitted to the DCGI on September 12, 1998, and the Ethics Committee of the RCC had granted its permission for the conduct of the study on November 10, 1999. Meanwhile, according to Dr. Krishnan Nair, discussions were held with the DCGI and, based on his verbal consent, the study was commenced.

The DCGI refused to comment on Dr. Krishnan Nair's claim and said that a central committee had been constituted to investigate the issue. When asked about the granting of sanction after two years of trials, DCGI Ashwini Kumar said: "Clinical trials of new molecules, experimental drugs and so on are new to our country. The systems are still evolving. We shall know whether the trials had been going on since 1999 only after the investigating team submits its report."

Meanwhile, the three-member team constituted by the Union Health Minister to inquire into the controversy was in Thiruvananthapuram waiting for Dr. Pandey to return from the U.S. The committee was expected to submit its report by August 16.

The normal procedure for obtaining approval for clinical trials (Phase I, II and III) is to submit the toxicological data collected from animal experiments to the DCGI. The toxicological data are sent by the DCGI to the Indian Council of Medical Research's (ICMR) Toxicology Committee for evaluation and, if found to be safe, the DCGI gives sanction for Phase I trials.

However, Ranjit Roy Choudhury, chairman of the ICMR Toxicology Committee, said the committee had not received any proposal from the RCC for trials or any data regarding the proposed trials. He added that of late the DCGI did not refer all cases to the committee. Choudhury said that with many new drugs coming into the market, imported and otherwise, the DCGI had begun to refer the data to its expert committee or a chosen set of experts rather than to the ICMR committee.

Regulations with regard to Good Clinical Practices (GCP), Good Laboratory Practices (GLP) and Standard Operating Procedures (SOP) are still in the draft stage. However, N.K. Ganguly, Director General of the ICMR, said that the basic regulations governing clinical trials were put in place by the Drugs and Cosmetics Act, 1940 and several clinical trials on new drugs and molecules had been carried out in India in conformity with the Act. Moreover, the ICMR had brought out a base document on Ethical Guidelines for Biomedical Research on Human Subjects in September 2000.

The ICMR document makes clear the legal provision for clinical trials: "The proposed trial should be carried out only after the approval of the DCGI as is necessary under Schedule Y of the Drugs and Cosmetics Act. The investigator should also get the approval of the Ethics Committee of the institution before submitting the proposal to the DCGI. All the guiding principles should be followed irrespective of whether the drug has been developed in this country or abroad or whether clinical trials have been carried out outside India or not."

The DCGI is being evasive when he tries to make a distinction between an experimental drug for a research project and a new drug and says that the regulations for experimental studies do not exist. The Drugs and Cosmetics Act is clear on the definition of a new drug as part of the Rules framed under the Act and it includes any new chemical entity (NCE). Schedule Y of the Act states: "For new drug substances discovered in other countries, Phase I trials [the kind being carried out at the RCC] are not usually allowed to be initiated in India unless Phase I data from other countries are available. However, such trials may be permitted in the absence of Phase I data from other countries if the drug is of special relevance to the health problems of India." Since even Phase I data from the U.S. were not available, on what basis did the DCGI give its approval in February 2001?

According to informed sources in the ICMR, the RCC had applied for a financial grant for the study from the ICMR during 1998-99. The ICMR raised some objections about the proposal and rejected the application. The exact grounds on which the proposal was rejected are not known, according to them. Four and a half years ago, the ICMR had rejected an application for financial grant to conduct a study on foetal tissue transplantation in patients of retinitis pigmentosa under an India-U.S. collaborative research programme at the L.V. Prasad Eye Institute, Hyderabad. The application was rejected on the grounds that undertaking such clinical trials on Indian subjects for an experimental procedure, which were not done on U.S. subjects, was not ethical and hence not acceptable.

In a statement issued then, the ICMR said: "The ICMR stands by the decision unless documentary evidence is provided by the principal investigator that the conduct of such experiments in human beings will be done (or has already been done) on subjects of both countries collaborating in the project, the proposal cannot be considered ethical." Hence, the ICMR may have turned down the RCC's request for financial support because in the RCC- JHU drug trial case too no parallel studies on U.S. subjects were proposed to be done.