OPENING A MEDICAL CAN OF WORMS
On Making Clinical Trials Fair

By Meryl Nass, MD

January 19, 2002 - Looking into the subject of human clinical trials and the informed consent of their subjects opens a big can of worms.

What pops out at you immediately is how much money is spent to get a drug into the market, and how many human subjects are required.

The cost of developing one new drug today, according to the pharmaceutical industry, can typically be as much as $500 million. So, the manufacturer aims to earn this much back, plus profit, before the drug goes off patent.

In 1998, 3,278 drugs were undergoing human clinical testing. Therefore, the drug industry needs several million people per year to become subjects in drug studies. The industry also needs to get these studies completed as expeditiously as possible to recoup their investment.

As in the developing Enron story, the most desirable way to proceed is down the path of least regulation. That means most of the studies are no longer conducted in university medical centers, and many are conducted in places like China. In fact, I was recently invited to a conference to learn how to conduct clinical trials overseas.

The FDA has found that the number of overseas investigators (performing clinical trials for drugs to be licensed in the US) has increased over five-fold during the past decade.

To rapidly find subjects, private physicians are given large honoraria, often over $1,000 for each of their patients enrolled in a drug trial. Private contract-research organizations have sprung up to meet the industry’s need. Prospective subjects might be told that the drug being studied is likely to be a better treatment for their illness than already licensed drugs. The FDA has had to crack down on misinformation in advertisements for subjects.

Human subjects begin to be tested once animal studies show that the drug looks like it will be effective and probably safe. The Phase 1 study is performed, not to provide the human subjects with any benefit, but only to establish safety in the human species. If the result is positive, Phase 2 studies are undertaken in small numbers of people to further assess safety, and also effectiveness. If these results are promising, Phase 3 studies are undertaken in more (usually several thousand) people, to confirm the drug’s safety and effectiveness.

How well informed are the subjects themselves? A recent study in The Lancet by Steven Joffe at Dana Farber Cancer Center, Boston was eye-opening. Questionnaires were sent to subjects enrolled in Phase 1, 2 or 3 trials of cancer treatments at one of three Boston hospitals. Study subjects received ‘top of the line’ informed consent, with half the consent discussions lasting at least an hour.

Although 90 per cent of the participants were satisfied with the informed consent process, 70 per cent were not aware that the treatment being used had not been proven to be best for their cancer. And 54 per cent of the clinicians providing the informed consent discussion were unaware that “the main reason cancer clinical trials are done is to improve the treatment of future cancer patients.”

Since these treating doctors appeared not to recognize that participation might not be in their patients’ best interest, they are unlikely to recognize their own potential conflicts of interest in conducting the trials.

I often wondered how one gives a patient an informed consent discussion for a Phase 1 trial. How do you say that no benefit is anticipated, that the drug is not a treatment for the subject’s medical conditions? Instead, the drug is being given solely to see whether it causes harm. If the subject is paid enough (sometimes they are paid, sometimes they are not) it might not matter.

How does one honestly tell a cancer patient that you are conducting a Phase 1 trial on him? It would seem to be adding insult to injury. I’m not sure that helping the next generation of cancer patients would be my priority, in that situation. Nor would helping out my doctor.

A 1998 Lancet editorial mentioned two human studies in which healthy volunteers were fed pesticides to identify the toxic dose. One study’s purpose may have been to generate data that would lead to lowering of the safety threshold for the pesticide in the United States. Were the subjects told of the possibility that the pesticides they ingested may cause chronic neurological illnesses? Although a pesticide may be a drug (for instance, to kill parasites), in this case, the humans were part of a toxicity study that appears not to have been intended to develop a drug for human use. What were the subjects told about the purpose of the trial, and their role?

A recent case, in which a study subject died after an adverse reaction to hexamethonium used in an asthma trial, is instructive. The investigator did not consider hexamethonium a drug, and did not get permission for its use from FDA. (I knew of it as a component of antibacterial soaps.) But it had once been used as a drug, so FDA said it still was one.

A recent death in a study subject who received methionine is another example of a “non-drug”’s toxicity. Methionine is an amino acid, a component of food proteins. Given in a mega-dose, however, it caused death. What is a drug, and who is responsible for regulating the use of non-drug substances in trials?

We obviously need drugs and toxic substances to be tested adequately. The process just has to be fair to all involved. And to accomplish this, the oversight mechanisms require serious strengthening. The formation and conduct of institutional review boards that oversee clinical trials need plenty of attention.

Instead of being another rubber-stamp committee filled with harried professionals, these boards need to compensate their members adequately, and take their time to perform careful and comprehensive reviews of all human research studies. The bioethicists need to help us out and develop better guidelines for all involved. And the human subjects need to really understand all the implications of participating in a clinical trial.

Recommended Reading

Organophosphorous compounds: good, bad, and difficult. Lancet 1998. Aug 15; 352 :499.

Safeguarding participants in clinical trials. Lancet 2000. June 24; 355: 2177.

Examining informed consent to cancer clinical trials. Lancet 2001. Nov 24: 358: 1742.

Joffe S, Cook F, Cleary PD. Quality of informed consent in cancer clinical trials: a cross-sectional survey. Lancet 2001. Nov 24; 358:1772-7.

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