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When clinical trials go awry

Mak Wen Yao , 09 Jul 2017
Clinical trials, despite being a niche area with strict safety control, are inherently experimental. Patients who voluntarily enroll into a clinical trial acknowledge that there is a chance of suffering injury or worse, death if the trial is not conducted appropriately.

Despite the importance of clinical trials in pushing the boundaries of medical sciences – such as the recent breakthrough in CAR-T therapy for multiple myeloma – the conduct of clinical trials must adhere strictly to multiple safety regulations. This is particularly true when the patient is involved in early phase trials where safety data is mostly extrapolated from animal or preclinical work.

When clinical trials go wrong

Patient safety has not always been the top priority in clinical trials. Scientific curiosity, or worse, a pursuit of personal fame and glory, have frequently clouded investigators’ judgment. In these situations, the patients more often than not are left vulnerable to exploitation.

The most notorious examples of clinical trials that went wrong are the experiments conducted by the Nazi Germany on Jews and prisoners of war during the second world war. In general, historians divide the unethical medical experiments conducted by the Nazi Germany into three categories.

The first category of experiments was conducted to facilitate the survival of military personnel where prisoners were used as subjects to investigate treatments for hypothermia. They could also be used to test different methods of making seawater potable.

The second category focused on the development of medical and pharmaceutical treatments for injuries and illnesses. Nazi scientists experimented different immunisation compounds for contagious diseases – such as malaria, typhus, tuberculosis, typhoid fever, yellow fever and hepatitis on prisoners of various concentration camps. These unfortunate subjects were being used to test the efficacy of sulfanilamide drugs, too.

The third category – and perhaps the most notorious one – was conducted to advance radical Nazi ideology. The most infamous of all was the experiments conducted on twins by Josef Mengele.

After the war had ended, those who were responsible for these inhuman medical experiments were brought to trial. Dozens of these Nazi officers were sentenced to death and many received prison sentences in what was later known as the Nuremberg Trials. From these countless atrocities and war crimes, the Nuremberg Code was formulated by a panel of judges to serve as the blueprint for medical research ethics.

We are not done with our past

One would be naïve to believe clinical trials conducted today are fully compliant with all ethical standards. Despite the establishment of the ICH-GCP guideline and the Helsinki Declaration, the safety and well-being of trial subjects are sometimes being overlooked by investigators.

In recent years, there have been reports that indicate certain trials conducted in India had violated the basic principle of medical research ethics. For example, vulnerable subjects from the Delhi jail were subjected to repeated phlebotomy in a 1968 trial; or an industrial-sponsored trial which did not undertake appropriate informed consent procedure nor did it has proper supervision from an ethics committee.

In the mid 21st century after the Indian government permitted the early phase clinical trials to be conducted in the country, the number of new trials exploded within a short period of time. Unfortunately, while the clinical research field in India grew rapidly, the availability of quality Ethics Committee (ECs) failed to keep up with such speedy expansion.

A survey conducted in 2010 revealed that almost 30% of EC members did not receive any Good Clinical Practice training. Other surveys also indicated that as much as 90% of study participants reported that the informed consent procedure was not conducted in a proper manner. These events had collectively prompted the introduction of a much more stringent regulation on Indian clinical research environment in recent years.

Not just a third world problem

It will be wrong to think that such blatant violation of research ethics only occur in third world countries. Similar abuses of clinical trial subjects happened in developed countries as well. In early 2017, a report was published in the New England Journal of Medicine that detailed the incident where three patients were left blind after they were enrolled in a bogus clinical trial.

In the paper, the authors wrote "the consent forms signed by all three patients do not mention a clinical trial. The patients paid for a procedure that had never been studied in a clinical trial, lacked sufficient safety data, and was performed in both eyes on the same day. Experimental bilateral intravitreal injections are both atypical and unsafe."

Moving forward

Despite the efforts in ensuring that trial patients are protected, the reality is much worse than what we would like to believe. In the face of lucrative profits, what is the worth of a human life? What is the worth of a patient's dignity and integrity?

These judgements inevitably lie in the hands of the trial investigators. As evidence indicates that profits always distort ethical judgements, a greater awareness of research ethics is much needed to rectify the dire situations. MIMS

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