Tuesday, July 10, 2007

Informed Consent and Clinical Trials

This is an issue that has been bothering me for a long time, and I've decided to post about it after reading an article in Nature Medicine about a lawsuit the Nigerian government has brought against Pfizer.

There are a few main points that comprise the main issue, as I see it.

1. We need drugs for many diseases, and these drugs have to eventually undergo clinical trials in humans.

2. Many drugs being brought out now target diseases, such as HIV, that have a large number of sufferers in developing countries (the term Third World is a throwback to cold war terms and I think it is distinctly inappropriate in today's world).

3. Clinical trials need large cohorts of people, both those who have the disease and those who don't.

4. Drug companies want to save money on clinical trials.

All these parts of the problem are linked and interdependent and none can be cited alone as the reason for the increasingly popular practice of conduction clinical trials in developing countries.

I am not against the practice, in fact I am more or less in favour of it. For many years "developing country diseases" have been neglected in the drug development process largely because the countries that suffer the most often have the least resources to support the expensive process of drug development. As a consequence of that expense, many people in developing countries do not have access to many drugs. So, if clinical trials are actually held in these countries, it may make access to the drugs being tested easier in these countries. Also, the fact that the trials are conducted in these countries mean that drugmakers have to consider factors that they would not have otherwise, such as heat-stability of drugs in hot equatorial countries; cultural factors that may influence the taking of medicines with meals etc. That the drug companies are moving south and east purely in search of greater profits doesn't bother me so much, as long as the outcome is beneficial.

Anyway, I digress. The two core tenets of conducting clinical trials are informed consent and that no harm should be caused. Informed consent is obvious, the people making up the cohorts of the clinical trial should know what they are getting into. They should know that they face potentially lethal side effects, that the drug may not work, and that they may be in control groups where they receive only placebos. They should know all of these things, and should sign documents attesting that they know and understand these things and choose to participate in the trial willingly and with full awareness of possible consequences.

No harm gets a little more involved. Clearly, if the drug starts to show bad side effects during the trial, it should be stopped. All drugs have side effects, one has to weigh the relative benefits against the side effects, and call a halt when the the relative benefits are far outweighed by the negative effects. Also, if the drug works, then one cannot, by any ethical moral or human standard, continue to withhold the drug from ill people in the placebo group. Once you start to treat your control group, interpreting the results automatically become much harder to interpret. And how do you determine what has caused harm, the drug or the disease? Most people participating in clinical trials are very ill, its hard to say what makes them worse, diseases progression or treatment. Its a very tough call.

Informed consent is a much clearer issue. You just have to have it. Informed consent is valid when it is solicited from prosperous educated people who have resources and are willing and able to analyze the issue objectively. Is it valid when it is obtained from poor illiterate desperate people? Is it valid when sick, frightened people are offered the vague potential of a medicine that they would not be able to afford otherwise? Are they able to make the decision to participate in the clinical trial objectively and with a full appreciation of the consequences? Illness makes even the most coldly analytical personal more prone to emotional choices, what of people with no other recourse? Poor and desperate, the prospect of a cure is offered you, what would you do?

It is in these situations that drug companies should be especially vigilant about their practices regards obtaining informed consent. Sympathetic counselors, fluency in the local language and a clear unhurried explanation of all the consequences are absolutely vital. If there is any question at all as to how informed consent was sought and got, then the conductors of the clinical trial risk crossing the line between recruitment and outright exploitation. And that is what worries me about the conduct of clinical trials in developing countries. Huge numbers of sick people, less stringent regulations, less enforcement of what regulations exist: these are all the reasons that make developing countries such "desirable" places to conduct clinical trials, but these are all reasons that makes the conduct of the trials in these places prone to misconduct. Conductors of trials have to be extraordinarily vigilant to avoid abuse, my questions is are they always so?

I don't know and I don't pretend to know much about clinical trials and the ins and outs of the daily conduct of these trials. I am a lay person, but I am concerned. I want very much for my country and other developing countries to have access to valuable drugs and I can see the huge advantages of having drug trials conducted in these countries, as a scientist and a human being. I think that all of us who think about these things should be concerned and should ask the hard questions, so that drug companies and the governments of these countries feel the pressure of accountability.

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