Sunday, May 07, 2006

WP Charges Ethical Failure in 96 Nigerian Drug Trial

Read the full article by Joe Stephens in The Washington Post of Sunday, May 7, 2006.

The article leads with the following paragraphs:
A panel of Nigerian medical experts has concluded that Pfizer Inc. violated international law during a 1996 epidemic by testing an unapproved drug on children with brain infections at a field hospital.

That finding is detailed in a lengthy Nigerian government report that has remained unreleased for five years, despite inquiries from the children's attorneys and from the media. The Washington Post recently obtained a copy of the confidential report, which is attracting congressional interest. It was provided by a source who asked to remain anonymous because of personal safety concerns.

During a meningococcal meningitis epidemic in Nigeria in 1996, it seems that Pfizer treated 100 children at the Infectious Diseases Hospital in Kano, Nigeria, with its antibiotic trovafloxacin (Trovan). Results of the treatments were recorded and used as part of the clinical trials of the drug.

Trovan was later released in the United States, but WP reports
the FDA never approved Trovan for use in treating American children. After being cleared for adult use in 1997, the drug quickly became one of the most prescribed antibiotics in the United States. But Trovan was later associated with reports of liver damage and deaths, leading the FDA to severely restrict its use in 1999. European regulators banned the drug.

The situation is more completely described in a 2001 article in Science magazine, and a couple of articles in The Guardian (article 1, article 2). However, it seems that Trovan was effective in "about 90%" of the 100 patients who took the drug -- a success rate slightly better than observed in the "gold-standard" ceftriaxone given to the control group. The kids who died or were left with disabilities did not seem to be suffering from the damage attributed to Trovan. Pfizer officials report that informed consent was in fact obtained for all the subjects in the trial.

WP notes the response from Pfizer later in the article:
"The Nigerian government has neither contacted Pfizer about any of the committee's findings nor are we aware that the committee has approved a final report. Therefore it would be inappropriate for the company to respond to specific points in the document.

"However, as we have stated repeatedly over the past several years, Pfizer conducted this trial with the full knowledge of the Nigerian government and in a responsible way consistent with Nigerian law and Pfizer's abiding commitment to patient safety."

Pfizer said it had previously tested the drug in thousands of patients and found it effective. Local nurses explained the experiment to Nigerian parents, it added, and obtained their "verbal" consent. The company said that Trovan demonstrated the highest survival rate of any treatment at the hospital.

"Trovan unquestionably saved lives, and Pfizer strongly disagrees with any suggestion that the company conducted its study in an unethical manner," the statement said.

The Ethical Issues

The testing of drugs in developing nations should concern us all. At a point in their development, drugs must be tested in people who are sick to see if they work. Thus their testing requires a population with the disease. The terrible burden of disease in poor countries means that suitable groups for tests can often be found there.

Testing drugs in poor countries, however, involves major challenges. Among these are the poor education frequently found in patients and their families, the lack of alternative medical services availability for those involved in the testing, weak governmental protection for their citizens rights, and (indeed) often a high level of corruption in all sectors.

Assuring the ethical conduct of research is difficult always, but especially in developing nations. The most obvious problem is that rich people buy more and benefit more from most medical goods and services than do the poor. Testing a drug in a poor population almost always raises the issue that people in other countries are to benefit more from the studies than people in the country where the tests are conducted.

Moreover, freely given informed consent to participate in a medical experiment, the keystone of ethical research, is difficult to assure. How does one assure that the uneducated parents of a sick child actually understand the potential risks and benefits of an experimental treatment and its alternatives? What does the local culture say is ethically required? How do you deal with differing national and international laws? In cultures where record keeping is deficient, what paper trail assures the process to be ethical? How does one protect against corruption in the process?

I managed programs funding research on human subjects in developing nations, and I can assure the reader that these problems are difficult! Certainly we required documentary evidence that proposed research protocols had been approved by appropriate ethical review panels, and certainly we sent teams of independent experts to investigate any report of ethical problems, but we also lived with concern that in spite of these efforts, problems existed.

The WP Article

Is the WP article credible? The expert committee report on which it is based, we are told, was provided by an source who remains anonymous. WP does not vouch for his credibility. That document is described as the report of a panel of Nigerian medical experts designated by the Nigerian government officially to review the case. We don't know who the "experts" were, what their qualifications were, nor whether they had any interests in the case. The WP article does state that the official committee report has never been released, but does not consider the possibility that it was rejected as not credible. WP suggests that there were very few copies of the official committee report in existence, but does not explain how one of the few found its way to the Post.

It should be noted that there are apparently financial interests at stake, as the families of children involved in the study have been suing New York-based Pfizer. I get emails with the Nigerian scam almost every day, so I can easily imagine someone trying to improve the chances in a law case by faking a report that no one admits having seen.

So What?

It seems likely that there was something wrong in the study done ten years ago. There seems to be agreement that the Nigerian physician most involved faked a letter of approval for the study from the hospital ethics committee. A physician, Juan
Walterspiel, who worked for Pfizer at the time and who appears to have had a long career in clinical research since, also expressed concerns about the study in writing. And indeed, a U.S. team flew into Nigeria in a chartered plane, did their study, and left while an epidemic was raging that eventually killed 15,000 people. Still, from what I can read, there seems to be little to indicate that Pfizer executives or medical staff was unethical.

Indeed, I would suggest that sometimes people disagree about the ethics of a specific medical research project without it in fact being unethical. Medical research is a dangerous business, and it is important that people review its conduct thoroughly and feel free to express their opinions. However, I think we must have an ethical review system that makes decisions, sometimes to go ahead, even in the case of lack of consensus.

The research in question was done in Kano, in Northern Nigeria. This is an area in which polio vaccine was refused for a time in this decade, and in 2004 a polio epidemic broke out in children in the region. The region has since reestablished its polio campaign. However, people infected with polio from northern Nigeria appear to have transmitted the infection to many other countries since that occurred, and it has taken an exhaustive effort of the international public health community to stop the epidemic.

Unreasoning fear of public health efforts is a major problem. Before the WP or any other medium publishes an attack on the credibility of those involved in public health, it should be very sure of its grounds. At the very least, the WP should have provided its readers with more grounds and better tools with which to judge the credibility of its report!

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