Randomized Pediatric Clinical Drug Trials – Africa and America

In 1996, Pfizer needed a randomized trial for a new broad spectrum antibiotic and sent a team of its doctors into the Nigerian slum City of Kano during a meningitis epidemic. It was represented, to be a "humanitarian mission.”

A team of Pfizer doctors arrived at the Nigerian camp where meningitis had killed at least 11,000 people.  They set up near a medical station run by Doctors Without Borders who were providing standard treatment. At the Kano Infectious Diseases Hospital, 200 sick children were picked. Half were given doses of the experimental Pfizer drug called Trovan and the others were treated with an established antibiotic.

Eleven of the children died and many more, it is alleged, suffered serious side effects ranging from organ failure to brain damage. After two weeks Pfizer summarily left the camp. Pfizer denies these allegations. The company claims only five children died after taking Trovan and six died after receiving injections of the certified drug Rocephin, (ceftriaxone). It is alleged that parents were not told that their children were to receive an experimental drug. It is reported, by Pfizer, that consent was obtained from the Nigerian state and produced a letter of permission from a Kano ethics committee which was a document that was alleged to have been a backdated form approved by the committee for a medical trial performed one year after this incident. 

Certainly, such conduct raises serious ethical questions, which reportedly targeted Pfizer with civil and criminal actions. In December 2000, the Washington Post published a lengthy examination of the trial. The Washington Post similarly found that Pfizer carried out the experiment on 200 children at a makeshift epidemic camp in the northern Nigerian town of Kano. The articles reported that Pfizer had no signed consent forms for the children and relied on a falsified ethics approval letter to defend the design of the experiment. 

The Third Circuit Court of Appeals stated, regarding Pfizer’s conduct,  that "the administration of drug trials without informed consent on the scale alleged in the complaints poses a real threat to international peace and security…and  "fosters distrust and resistance to international drug trials, cutting-edge medical innovation, and critical international public health initiatives in which pharmaceutical companies play a key role. … As this case illustrates, the failure to secure consent for human experimentation has the potential to generate substantial anti-American animus and hostility."

Comment:

The fundamental ethical predicate in randomized clinical trials is that, based upon the state of knowledge at the time, it does not establish that either arm of the trial is superior to the other.  This is generally referred to as “equipoise” without which a randomized clinical trial may not ethically go forward. To administer an experimental drug to children with meningitis when an effective proven medication is available, needlessly and purposefully exposes patients to serious injury or death.

The attempt to avoid the legal protections for patients in the United States by carrying out randomized clinical trials in Africa, is particularly damning. We should, however, keep in mind that related problems exist in pediatric oncology Phase I Trials in the United States. Phase II and III trials analyze benefits and compare results to standard treatments. Phase I studies do not. They are, simply stated, experiments with no legitimate expectation of benefit to the research subject. In order to permit a child’s participation in a Phase I trial the law requires an informed consent to the parents or guardian. ( It is not legally clear whether a parent or guardian can consent to exposing their child to unnecessarily harmful experimentation.) Telling them about risks, however, does not discharge that requirement. It is an informed consent that must be obtained, not merely offered. It must be presented to the child and parents in an unbiased way, and it must also be comprehended. Neither research physicians nor the Institutional Review Boards (IRBs) have been effective in accomplishing this task.

The tendency of research subjects to confuse their participation in clinical trials with personalized medical care is commonplace. There is an inherent conflict of interest between research physicians and child research subjects due to a misconception that treatment will be provided. This conflict may be most severe when it involves pediatric cancer patients and their parents. Children suffering from a terminal illness, whose quality of life may be eroded by pursuing hopes for survival in a phase I drug trial, where no real hope exists, need rigorous protection. Their perspective is not only a product of hope but also the result of repeated and purposeful misrepresentations by researchers and university medical centers that research subjects in phase I drug trials will receive “treatment.” Experimental toxicity studies however are not treatment. This misrepresentation has often been referred to as a “therapeutic misconception.”  

For many people a university medical center inspires a sense of awe and can engender their confidence and trust. This may account, in part, for a child’s or parent’s belief that there will be some benefit in participating in a Phase I trial.  There is a tendency in the recruitment process in Phase I trials to exploit this trust.

In a study published in the Journal of  Oncology (Perceptions of Patients and Physicians Regarding Phase I Cancer Clinical Trials: Implications for Physician-Patient Communication, three hundred twenty-eight patients and 48 physicians completed surveys regarding expectations regarding treatment outcomes. Although 95% of patients reported that quality of life was at least as important as length of life, only 28% reported that changes in quality of life with treatment were discussed with  physicians. In contrast, 73% of physicians reported that this topic was discussed.  As to risks of the Phase I trial, 91.5% of the physicians believed that they discussed the risks, while only 73% of the patients recalled discussing of risk.

Discordance Between Patients and Physicians About Consultation Content
                                                                              Physician       Patient     
Discussion Topic                                                   No.     %         No.     %             P*
Changes in quality of life with treatment              171     73.4      65      27.9     < .0001
Changes in length of life with treatment               140     59.6     69      29.4     < .0001
Changes in quality of life without treatment         145     62.5      67     28.9     < .0001
Changes in length of life without treatment          123     52.8      67     28.8     < .0001
Possible side effects from treatment                     217     92.0   184     78.0     < .0001
Possible benefits from treatment                           212     90.2    185     78.8     < .0001
Possible risks from treatment                                214     91.5    170     72.7     < .0001
*McNemar’s test.    

It is important to note that the word “treatment” is used with respect to a Phase I clinical trials. Yet, a Phase I Clinical Trial is not “treatment” it is experimental testing which, hopefully, will lead to a treatment.

IRBs are required by statute to determine, without any specific guidelines to help them, that there are adequate provisions for “…monitoring the data collected to ensure the safety of subjects."  Yet, no monitoring is generally done by IRBs. The President’s Council for Bioethics found that:

" Amazingly, no one – not the director of NIH, the commissioner of the FDA, or a representative of the Pharmaceutical Researcher and Manufacturers of America – knows how many people participate in biomedical or other research studies in the United States each year. … no comprehensive data exist on specific aspects of research. No one can say how many research participants suffer serious, unexpected adverse events each year, either for a specific study or in general, and of those, how many sustain a permanent disability or die unexpectedly. "

The problem is perhaps best described by the Chairman of the Council, Leon Kass who, in his discussion with the panel of the President’s Council, raised the issue of simply being honest with research subjects:    

"If one simply says ‘they are the only subjects that are possibly available to advance our knowledge,’ however truly necessary that it is as a condition for using them, the question is whether it’s sufficient and whether one doesn’t want to try some kind of honest way to elicit their identification with the enterprise and not simply exploit their desperation.  It’s not an objection to proceeding with the research, but the question is:  How should they be regarded?  How should they be treated?  How should they be spoken to?"

  Hence, we must not labor under the misperception that lack of candidness and legitimate informed consent in clinical trials is limited to villages in Africa. Problems exist in the United States and must be seen as work for clinical bioethicists to improve the process of informed consent in Phase I trials, especially with children, and to put in place protocols to expose conflicts of interests.

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