May 13, 2006

It started as a routine clinical trial, like many others that are performed to test the safety and efficacy of new drugs before they are released for general use by doctors. However, this time the experiment proved to be a disaster.

In March this year, scientists in England were evaluating the safety of a medicine called TGN1412, developed by a pharmaceutical company in Germany to treat leukaemia and autoimmune diseases, such as rheumatoid arthritis, lupus and Graves’ disease. They recruited seven healthy young men, almost all immigrants or unemployed students, who were primarily attracted by the compensation ($3,500 or about Rs210,000) offered by the company to participants in the two-week trial.

On the face of it, it seemed like an excellent opportunity to earn some easy money for little or no work. However, later events showed that this was anything but easy money.

Tragically, within minutes of taking the experimental medicine, a milky-white mixture, the six volunteers became critically ill; ravaged by chills and nausea, their hearts, lungs and kidneys showed signs of catastrophic failure.

The seventh had not been given the medicine. All six had to be hospitalized and were placed on life-support machines. One of them later described the feeling he had after taking the medication as “being submerged in arctic ice”.

Although none of the participants has died, some may have suffered lasting and irreversible impairment of their vital functions. The drug, TGN1412, had never been tested in humans before, but all animal tests, in mice, rats and even in monkeys, had demonstrated it to be safe and there was little reason to suspect that it would act differently in humans.

The medical problems that afflicted the trial participants were so startling and unexpected that they were reported as headline news by the American and European media as well as covered in scientific journals. Furthermore, they have heightened public concern about the safety of procedures employed for clinical trials.

The search for a cause of the disaster initially focused on the nature of the medicine being tested. The information released by the manufacturers indicated that it was a monoclonal antibody, belonging to a class of proteins that are normally generated by the body’s immune system to fight infection.

Monoclonal antibodies belong to a special class of antibodies that are produced artificially in the laboratories by scientists that —unlike natural antibodies that are diverse in shape and property —have identical molecular structures.

Scientists, both in industry and academia, have developed a range of such antibodies that can powerfully and specifically attack malignant, cancer cells. However, in various clinical studies, they have shown inconsistent success rate in treating cancer.

A complication associated with the use of monoclonal antibodies is the potentially uncontrollable stimulation of the body’s immune cells, the so-called T-cells, leading to a massive release of cytokines. The latter are small toxic proteins that cause severe pains, fever and other life-threatening complications in patients.

Doctors believe that the new drug, TGN1412, stimulated the outpouring of cytokines in the young volunteers, causing the sudden onset of their malaise. It seems that at least one prudent practice was not followed by the British researchers. Instead of administering a drug with unknown risks to one person at a time, they administered it to all of them almost concurrently.

Thus, there was no window of time to observe if it caused an adverse reaction in the first participant, a precaution that might have spared others. However, according to the American journal Science, the British Health Care Regulatory Agency failed to find a simple explanation for the accident, but has moved to ban further testing of such drugs until more information becomes available.

Apart from raising some ethical questions, the British studies have also initiated debate of a different kind in the United States. Is all the relevant information about a drug made available to the scientists who have the responsibility to review its safety and effectiveness and make the decision to approve it?

The answer is not an unequivocal “yes”. While the monitoring system has worked well for decades, there is now a growing realisation that it needs some revamping. The Federal Drug Agency (FDA) in the United States has in recent years come under increased pressure from the industry to expedite the review and approval process.

From their perspective, the sooner a drug can be brought to market, the more money it can generate for the company that invented it. Not all such demands originate in the industry however. In some cases, when patients find out that a drug is under study that might help cure their illness, they join the campaign for its quick approval and release.

The results of speedy approvals have not been uniformly benign. Some critics worry that it may have compromised the public safety by prompting some scientists to be less stringent in evaluating the design and results of clinical studies.

Even more disconcerting is the possibility, raised in a recent article in the respected British journal Nature, that some scientists, supported by drug companies with interest in the positive outcome of clinical trials, may be selectively suppressing some of the negative, unfavourable findings.

Thus, a drug might be approved based on data that are incomplete or have been manipulated. Ultimately, the evidence that a drug has harmful side effects emerges sometime after it has been release for wide use. Unfortunately, by that time, the damage caused to many patients may be irreversible.

One of the most publicised recent cases in which a medicine was found to have unacceptable side effect was that of an antidepressant, Paxil (paroxetine), made by GlaxoSmithKline Company. Until recently, this drug was widely used in the United States to treat depression in adults and school-age children.

In 2004, evidence surfaced that Paxil made children more prone to committing suicide, an alarming side effect. Paxil is no longer prescribed to young patients. Many critics, however, have charged that its potential risks were known to GlaxoSmithKline long before they were recognised experientially by physicians, yet it did nothing to warn the public.

The company denies the charge, but has settled a law suit by paying $2.5 million to the complainants. Paxil is only one of two dozen medicines which were approved for treatment of various diseases in the US, but were later found to pose severe health hazard and some have been withdrawn from circulation.

It would be unrealistic to believe that serious side effects are associated only with western medicines and that herbal drugs that have long been used by the practitioners of indigenous medicine in Pakistan, India and China are free of them.

While herbal remedies used in the Unani and Ayervedic systems have been examined only sparingly by the modern research techniques, some of those employed in the ancient Chinese and Korean systems have received a greater degree of scrutiny in the west.

For example, Ginkgo extracts, a popular Chinese medicine is touted as an antioxidant, beneficial in the treatment of Alzheimer’s disease. However, it has also been shown to be cause blood circulation problems and gastrointestinal disorders.

Finally, all medicines have some potential for being harmful to our health and well-being. But, on the whole, modern medicine has done far more good than harm, as evidenced by the fact that people live longer and healthier lives today than they did only a century ago.

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