"WONDER drug to be introduced on March 10, will relieve patients of painful injections," blazed a recent front page news item in several Indian dailies. One paper went on to describe how Deferiprone, the thalassaemia treatment drug developed by George Kontoghiorghes of London"s Royal Free Hospital, was recently cleared by the drug controller of India (DCI), following trials on 200 child patients in Bombay, Calcutta, Delhi and Chandigarh. This alternate drug, the report claimed, would not only be cheaper than the original Desferal injections but also less painful.
What the reporter neglected to say was that an 18-year-old male beta thalassaemic on the clinical trial panel of this "wonder drug" died of systemic lupus erythematosus (an ill-understood disorder of the connective tissues) which several doctors in Bombay suspect was drug induced. A Bombay-based haemotologist, B C Mehta, and his colleagues also found that the immune systems of some other thalassaemic patients who had been on the trial had been abnormally altered.
M B Agarwal, the doctor conducting the trial, claims that the "adverse effects following its administration are essentially in the form of isolated incidence of transient toxicity...Most patients put on Deferiprone have been able to continue the drug without any complaints or apparent complications." S V Iyer, of Cipla, the Indian manufacturer of the drug, is very upbeat. What is inexcusable is that it did not mention the death of the 18-year-old, although Mehta had informed them.
V P Chaudhury, a thalassaemia expert from the All India Institute of Medical Sciences (AIIMS), who has also conducted trials on 51 patients, confirmed 8 deaths of the 800-plus patients on whom the drug has been tried in 16 countries. But, he demurred, "No drug is completely safe. If you wear winter clothes in the summer, you are bound to be affected." In India, he says, the drug will only be sold through prescription.
Clinical trials are the only scientifically acceptable way of judging whether a new drug is effective and safe on humans. Preclinical trials are first carried out on animals to ensure that they do not have any toxic effects, or to check whether they have long-term effects on succeeding generations. Clinical trials on human volunteers and patients are carried out later.
These 2 steps are mandatory in most countries. To achieve precision, these trials, especially in their premarketing phase, are usually carried out at many centres involving several hundred patients.
Most trials are funded by those pharmaceutical companies which plan to eventually market the drug. But fudging is more than possible, circumventing the mandatory supervision of doctors. The deliberate plastic surgery of data, incomplete information to poor and illiterate patients about contraindications, and the lack of a follow-up of the patients to determine the long-term effects are allegations that run a swathe through tests.
Even in the consumer-happy US, trial procedures are often ignored. According to the US Food and Drug Administration (FDA), almost 70 per cent of the clinical trials carried out there between 1977 and 1989 violated the regulations. An independent agency, the FDA is among the most vigilant drug examiners in the world.
Last year, the US scientific research community and women suffering from breast cancer were shaken when the Chicago Tribune revealed that the National Cancer Institute"s studies on treatments for early breast cancer were based on fraudulent data. The report said that Roger Poisson of the St Luc Hospital in Montreal had falsified and fabricated data for some 90 patients. He had changed the dates on patients" records and listed a patient who had refused to participate.
Only rarely do such machinations come up for public scrutiny in India, despite the fact that they happen more blatantly. Says A S Paintal, former director general of the Indian Council of Medical Research (ICMR), "Influence is applied on the ethics committee members and on the authorities to approve the drug for further extensive trials, or for general use. I have myself been a near victim of this influence: a clinical trial revealed the highly undesirable side-effects of a particular drug, but the manufacturers insisted that the effects be overlooked and the drug be approved."
Thousands***(how many?) of drugs and drug formulations are sold under different brand names in India. Many have been banned in other more stringent countries after patients developed adverse reactions. Moreover, according to experts from public interest groups like the Voluntary Health Association of India (VHAI), as many as 90 per cent of the drugs sold in India are inessential, or plain harmful. Analgesics like Analgin, which cause a fatal blood disorder called agranulocytosis (lack of white blood cells), are sold freely over the counter.
Thrombophob, an epidermal ointment produced by German Remedies, is freely available as an anticoagulant, but is completely ineffective. According to the VHAI, it contains an anti-clotting agent called heparin, but there is no scientific evidence that this ingredient is absorbed by the skin. Says VHAI, "The benefits of a huge drug list are essentially to do with trade, not health. The advantages of a restricted drug list include having fewer bad drugs and a reduction of drug-induced diseases, better information and less confusion about which drugs to use."
Fortunately, the medical community in India is beginning to question the methodology and reporting of clinical trials. In the case of the Deferiprone, Mehta and his colleagues wrote to the DCI, to Cipla, and published several papers in reputed medical journals, advising that the drug be withheld pending more studies.
Mehta"s credentials were questioned by the members of the Thalassaemia and Sickle Cell Society (TSCS) of Bombay. (It is no irony that Agarwal, TSCS secretary, was the main investigator in the trials, which ended with 1 fatality.). The president of the TSCS is a senior executive with Cipla. M G Deo, director of the Bombay"s Cancer Research Institute (CRI), who challenged the trial procedures of several leprosy vaccines, earned the opprobrium of his colleagues, most smitten by the fact that one of the vaccines was sponsored by the World Health Organisation (WHO). Deo also raised questions about the scientific validity of testing the WHO-sponsored vaccine, and the preliminary trials, which in other countries showed that it was not effective. To ensure that there was no interaction between the BCG vaccine against tuberculosis and the leprosy vaccine, about 300,000, including children in Tamil Nadu"s Chingleput district, were deliberately denied the protective BCG vaccination.
Moreover, in a letter to Paintal in 1990, who was then director general of the Indian Council for Medical Research, Deo had written, "It is also important to record that some of the mandatory requirements for conducting pre-clinical toxicology were relaxed in the case of the WHO vaccine."
He had also stressed, "Posterity must know that the Indian drug regulatory authorities compromised on quality control in allowing human trials of the WHO anti-leprosy vaccine, which is a product of inconsistent quality. No scientifically advanced democratic country would allow this."
Other doctors like S K Pandya, neurosurgeon at Bombay"s King Edward Memorial Hospital, are organising themselves into groups like the Forum for Medical Ethics (FME), and are addressing issues related to the conduct of clinical trials. They have prepared a questionnaire which they plan to send to pharmaceutical companies to evaluate the quality of trials being carried out in the country.
The introduction of new drugs into the Indian market is regulated under the Drugs and Cosmetics Act 1940 (DCA), the Drugs and Cosmetics Rules 1945 (DCR) and its subsequent amendments. The DCI gives the final OK to a drug based on clinical trials. The DCI"s permission is also essential before trials on human beings can be carried out, or even to extend the trials. The whole process is spread over 3 phases.
Medical experts believe that although Indian trial regulations are precise and stringent, ground realities are very different. Says Harish Grover of the Indian Medical Association (IMA), "The absence of an independent monitoring agency to follow the trials being carried out in hospitals is the single biggest stumbling block, as it ensures that no one other than the investigator has control over the process."
Most new drugs released in India by multinationals have been through the market rollercoaster abroad. As a result, clinical trials in the country are treated as mere pesky technical requirements to obtain the DCI"s clearance.
Pandya says that the system of pharmaceuticals and not medical professionals kickstarting trials (and there could be 5,000 of them being conducted at any given moment) is causing much concern within the community -- particularly the distressing fact that it is the pharmaceuticals who pick and choose consultants and invigilators. Too often for Hippocrates" comfort, pharmaceutical companies bankroll the participating doctors with "honorariums" in cash or all-expenses-paid holidays. Moreover, the FME says that it discovers that at times the company funding the trial ensures that negative findings are not published in any indexed journal.
Under the law, it is mandatory that detailed trial protocol be drawn up by doctors. The ICMR"s guidelines recommend that these protocols be cleared by the ethics committees of participating hospitals. These committees, experts point out, should ideally comprise both the general public and medical experts, "because issues of medical ethics cannot be left to the discretion of doctors alone".
However, according to R P Ravindra of Bombay"s C U Shah College of Pharmacy, "Most research institutions in India either do not have an ethics committee, or, when they do, they lack adequate representation of laypersons." Ideally, explains Pandya, ethics committees should investigate whether a particular study or trial is going to yield new results and whether the study is based on approved scientific principles. New research is especially important if the drug is already being marketed abroad.
Moreover, the committee should also look into whether the research involves cruelty to human beings and animals, and whether anyone"s financial interest is at stake. He, however, contends that usually the ethics committees are sloppy and haphazard and are closed circuits, in which researchers and members on the committee are constantly feeding off each other.
Although these committees should judge whether the trials are being carried out according to the approved protocol, he is uncertain whether this happens in reality. In fact, he points out that more often than not, the members of the ethics committees don"t even get to see the final reports of trials.
K S Reddy of the AIIMS also stresses the need for more active ethical monitoring of the trials. Although monitoring a trial is the responsibility of the ethics committee of the hospital, most doctors point out that once the trial protocol is cleared, the committee does not involve itself in what the doctors are doing.
This shortcoming, according to Pankaj Shah of the AIIMS"s endocrinology department, leaves the trial process open to misconduct on the part of the investigator. Says Shah, "In such a situation, when there is no close monitoring, who is to see whether the investigator is carrying out the trial legitimately or not? If the trial protocol asks for 50 patients, the investigator could have only 10 and the records could still be made for the required 50."
The absence of effective ethical and monitoring committees assumes especial importance when the trials on a particular drug are carried out under several investigators at different places. Says Grover, "In the multicentre trials sponsored by the pharmaceutical companies, there is virtually no communication between the centres. And if the trial results coming from 1 or 2 centres do not support the expected pharmacological action of the drug under trial, these are not submitted to the DCI."
Public information on details of how the clinical trials are conducted is meagre, says Ravindra. Although the results of clinical trials are supposed to be published in refereed medical journals, making the knowledge of a drug"s effectiveness and its possible side-effects known to the medical community and the public at large, this is often not done. Pandya points out that it has been brought to the notice of the FME that the pharmaceutical company funding the trial ensures that research findings which do not validate its claims of efficacy and safety are not published.
Reddy is also concerned that the trials are often carried out in the absence of expert clinicians. "Although trials are carried out under the supervision of doctors who may be experts in their fields, they are not necessarily clinical experts," says Reddy. "Clinical trials should include a clinician who would have control over the design of the trial."
This lacuna is also felt at the time the trial data is evaluated. Reddy points out, "Since most trials sponsored by pharmaceutical firms tend to be phase III trials, these are only seen as a formality, and in the absence of a clinician, not much stress is laid on the statistical analysis of the results."
N A Kshirsagar, a pharmacologist at Bombay"s KEM Hospital, who has been involved in monitoring clinical trials for the WHO in China, explains that though the statistical design of a trial is usually acceptable, the way the trial is actually carried out leaves a great deal to be desired. In some Chinese villages, for example, she found that measuring the volunteers" body weight itself was fraught with errors. This can have serious implications for the results of the trial, she says.
Then there are problems of standardisation. In multicentre trials in India, the varying infrastructure in different hospitals leads to the downgrading of the protocol criteria, says Kshirsagar. She adds that the money-minting pharmaceuticals are parsimonious about funding infrastructure development.
Under the law, the written informed consent of all patients or volunteers involved in a trial is mandatory. But the amount of information about the drug, and its possible benefits or side-effects that a doctor is expected to put down in writing for the volunteers is not specified.
Most doctors are extremely sceptical about the way the consent is obtained by investigators from their largely illiterate patients. Grover says that more often than not, essential information "is never passed on to the patient, who remains entirely in the dark."
For instance, many of the women who trial-received the contraceptive Norplant 2 had no idea what the contraceptive was and what its possible side-effects could be. A counsellor with the ICMR unit at the Kasturba Gandhi Hospital, Delhi, who was involved with the Norplant 2 trials, agreed that complete information -- which could have put the women on the guard and prevented later complications -- was not given. And even while she spoke of a major language problem, she still admitted: "we never told them in as many words that the contraceptive was still being tested." (DTE, March 15, 1994.) Ravindra is, however, adamant. He says, "Very few (researchers) make the attempt needed to cross an educational or cultural barrier, and communicate sincerely with the patient or the subject."
Ravindra points out that according to the Charter of Nuremberg that guides these procedures, informed consent must be a free, enlightened decision by the person concerned, based on adequate information provided beforehand. If a patient chooses not to join a trial, or to drop out of it, it is the duty of the doctors attending on the patient to ensure that this refusal will also not diminish the quality of medical care provided.
After a patient participating in a trial is allowed to leave, he or she must be carefully monitored, experts agree, as the drugs can have long-term side-effects. However, more often than not the follow-up is very poor. Kshirsagar, who was involved in the trials for the contraceptive drug centchroman, says that all researchers do not bother to make the great deal of effort needed for this. In the centchroman trials, for example, despite intimation, several patients did not return for follow-ups. They have to be tracked down by a social worker, making the process long-winded and tedious.
Usually a drug is never completely free of side-effects when a drug is released into the market. In fact, most doctors are quick to point out that, in a sense, every time a drug is prescribed to a patient it is a trial in itself, as the doctor can never be 100 per cent sure how an individual patient might react to it.
Clinical trials, which are carried out on a limited number of patients for a short time, fail to pick up all the side-effects of a drug, which manifest themselves at a much later stage, says Reddy. "In such a situation, the reporting of adverse drug reactions, or ADRs, is of paramount importance."
These side-effects are usually monitored very closely in other parts of the world by doctors and the manufacturing companies. The WHO also has its own ADR monitoring centre, and it contains a database of over 900,000 entries.
However, says Reddy, in the absence of a well defined procedure, most doctors in India do not report the ADRs. "I have been practicing medicine for the past 20 years, and I have never reported an ADR," he says. This seems to be a common complaint of most doctors. K K Agarwal, who has worked on the reporting of ADRs says, "Though there are a number of centres identified by the DCI to report ADRs to, none of them function due to the lack of funds." And Paintal is even more agitated about drug companies trying to protect market interests by not reporting ADRs.
Post-marketing surveillance studies of newly introduced drugs is another area where adequate attention is not paid. The DCI"s office, lacking cash and manpower, is in no position to carry them out. S N A Rizvi of the department of medicine, Maulana Azad Medical College, Delhi, says, "Post-marketing surveillance studies for all the drugs is perhaps not possible, but such a process should be in place in the case of critical drugs."
Meera Shiva of VHAI is more critical: "The thalidomide crisis in the United Kingdom proved that the side-effects of a drug may manifest themselves at a much later stage, and clinical trials may not pick these negative effects. Post- marketing surveys in such a situation are a must."
Pharmaceutical companies are also cashing in on another legal lacuna. Drugs categorised by the DCI as ayurvedic or unani can sneak into the market without undergoing clinical trials at all, because the DCI has no jurisdiction over these.
Says Nitya Nand, former director of the Lucknow-based Central Drug Research Institute (CDRI), "Ayurvedic drugs are not manufactured according to a standardised method and there is no quality control." According to Rizvi, a large number of ayurvedic drugs contain metals like copper and cadmium, which can have harmful effects.
Experts also gripe about the present drug regime being toothless. Nitya Nand says, "The drug controllers office, as it exists today, cannot control or regulate the clinical trials. Most of the committees which look after the trials at the DCI"s office are ad-hoc, since it does not have the staff, nor an independent monitoring agency of its own."
Doctors and other clinical experts are convinced that something must be done to break the pharmaceutical companies" stranglehold over the drug market, and the threat they hold for the patients" health. "The only way to remove the shortcomings is to revamp the DCI along the lines of the FDA," says a vehement Nitya Nand. According to him, the DCI will have to acquire technical expertise to evaluate the protocols for trials and monitor the institutes engaged in carrying them out. And Paintal, who retired as the director of the ICMR (which is essentially called upon by the DCI to provide expert advice on drugs) says, "Society must insist upon accountability before it is too late."