CLINICAL TRIALS – Human clinical trials are an important last hurdle in the development of new drugs and therapies. Today, The Conversation takes a closer look at this vital scientific endeavour with three articles that look at different aspects of the process.

Two large US-funded studies on cervical cancer screening in India are being investigated by the US Office of Human Research Protection for ethical violations. Concerns were raised about the trials after a large number of women in the control groups died from cervical cancer.

One of the studies was sponsored by the US National Cancer Institute (NCI) and the other by the Bill and Melinda Gates Foundation. Both aimed to compare the efficiency and success rates of different methods of cervical cancer screening.

Cervical cancer is the second most common cancer in women worldwide. About 86% of cases occur in low-income countries, mainly due to the lack of widespread screening programs that usually detect pre-cancerous symptoms. In India, the disease kills more than 70,000 women each year.

The routine detection of pre-cancerous cells in high-income countries is through Pap smears, but they require more money and expertise than is available in most low-income nations.

The issues raised by complaints about the trials echo ongoing debates within bioethics communities. The first relates to the quality and validity of consent given by participants, and the second to the standard of care provided to control groups. The control groups included more than 76,000 women, and at least 98 of them have died since the studies began.

The trials

The trial sponsored by the Gates Foundation recruited more than 130,000 women from various rural areas and divided them into four groups.

Three of these groups underwent three types of screening – pap test, acetic acid test and DNA test for the presence of the human papillomavirus, which is responsible for the vast majority of cervical cancer.

The fourth group (the control) was provided with health education, which included being told they could seek screening on their own.

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The NCI-sponsored study recruited more than 150,000 women (mostly uneducated) women from the slums of Mumbai.

About half of these women were screened for abnormal tissue using a low-tech method that uses acetic acid for detection of pre-cancerous cells. They were offered free treatment if their results were positive.

The other half of the participants were given health advice and informed that they could seek a Pap smear (the standard screening method) on their own – according to the researchers.

Applying acetic acid, followed by visual detection is currently the cheapest available method for screening for cervical cancer.

Obtaining informed consent

One of the most serious allegations about the latter trial concerns obtaining informed consent from the participants. Consent has been a cornerstone of research ethics since its beginnings, following the Nuremberg trials.

There is consensus in the bioethics community that consent to participate in clinical research has to be taken from each participant, after they have been told about the research, its experimental nature, and its associated risks.

Consent has to be both voluntary – free of coercion, deception, or manipulation – and include adequate information – participants must be given information about the potential risks and benefits of participation, as well as existing alternatives.

Information must be presented in a way that is understandable and likely to be understood. Although written consent is the standard, it is usually supplemented with oral explanation for people with poor literacy.

It appears that many of the women participating in the NCI trial may not have been adequately informed that they were participating in research, or of alternative diagnostic options; and the translated version of the informed consent form does not explicitly say that alternative screening methods were available in India.

R Barraez D´Lucca

If the consent procedure was not carried out adequately, then the trial clearly violated ethical standards. But the ethics community is still divided over what constitutes an adequate consent procedure (written or oral).

And there are outstanding questions about the primacy of consent in contexts where trust in physicians or other authority figures might trump other considerations in the minds of participants.

The gold standard of care

The second crucial concern – one that has divided the ethics community about research carried out in the context of scarce resources – is the standard of care afforded to those participating.

In this case, the controversy lies around the control groups in both studies. If these studies were to take place in the United States, they would not have been approved by the ethics committees reviewing the protocols.

That is because ethics standards stipulate that while one or more groups may be given the experimental diagnostic tool, the control group must receive the existing gold standard of care. The gold standard is the currently accepted diagnostic or treatment method.

International ethics guidelines as well as those of the Indian Council of Medical Research say researchers must have a very good reason not to provide the existing standard of care.

Reasons include it not being possible to prove the effectiveness of a new method if compared to an existing method, and if the existing method cannot possibly be made available to the participants.

In the case of these cervical cancer trials, researchers have argued that providing no treatment to the control group was acceptable, because the standard of care in India is “no care” for much of the population.

But others have pointed out that such a trial design may not have been justified, given that similar studies in other countries had not relied on unscreened control groups.

Jon Hurd

It has also been argued that the acid test should, in fact, have been considered the standard of care in India, since it is offered by government hospitals (although access is limited for many women, due to poor infrastructure).

In other words, given the existing although limited care in Indian hospitals, and the evidence from similar studies, researchers were, arguably, not ethically justified in including unscreened control groups.

Not as it may appear

Neither study fits the stereotypical image of poor, illiterate participants exploited as human guinea pigs for the sole profit of greedy pharmaceutical companies.

The motive for both was to develop low-tech methods that could potentially reach women living in poverty, and thereby prevent tens of thousands of deaths every year. The researchers in both trials concluded that, if widely implemented, the acid test could prevent up to 22,000 deaths in India annually.

Beyond questions of ethical violation, studies such as these, highlight some of the most difficult questions in the ethics of international research:

what should a consent process ideally look like?

what is due to participants, even when trying to save their lives?

are ethical standards evenly applicable in all contexts? and

who, ultimately, is responsible for protecting the interest of participants?

And we mustn’t forget that, in international trials, the complex web of sponsors, review boards, researchers, and participants is complicated by sheer geographical distance, underlying professional aspirations and differences in opinion, as well as differing laws and regulations.

This, combined with the fledgling system of oversight, implementation, compliance and transparency in places such as India, provides for rather fragile support for protecting participants.

Whatever may be the final result of the ongoing investigations of these two studies, there are most certainly, and most unfortunately, more such trials to come.

Click the links below for other articles in the package:

Abandoning clinical trial safeguards won’t boost local industry

Looking back on the chequered past of drug trials

From the archives:

Clinical trials are useful – here’s how we can ensure they stay so

What Australia should do to ensure research integrity

Register all trials, report all results – it’s long overdue

Remove industry bias from clinical trials before it’s too late