Adventures in Ethics and Science

The Independent reports that drug giant Pfizer has agreed to pay a $75 million settlement nine years after Nigerian parents whose children died in a drug trial brought legal action against the company.

It’s the details of that drug trial that are of interest here:

In 1996, the company needed a human trial for what it hoped would be a pharmaceutical “blockbuster”, a broad spectrum antibiotic that could be taken in tablet form. The US-based company sent a team of its doctors into the Nigerian slum city of Kano in the midst of an appaling meningitis epidemic to perform what it calls a “humanitarian mission”. However the accusers claim it was an unlicensed medical trial on critically-ill children.

A team of Pfizer doctors reached the Nigerian camp just as the outbreak, which killed at least 11,000 people, was peaking. They set themselves up within metres of a medical station run by the aid group Médecins Sans Frontières, which was dispensing proven treatments to ease the epidemic.

From the crowd that had gathered 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 a proven antibiotic from a rival company.

Eleven of the children died and many more, it is alleged, later suffered serious side-effects ranging from organ failure to brain damage. But with meningitis, cholera and measles still raging and crowds still queueing at the fence of the camp, the Pfizer team packed up after two weeks and left.

That would probably have been an end to the story if it weren’t for Pfizer employee, Juan Walterspiel. About 18 months after the medical trial he wrote a letter to the then chief executive of the company, William Steere, saying that the trial had “violated ethical rules”. Mr Walterspiel was fired a day later for reasons “unrelated” to the letter, insists Pfizer.

The company claims only five children died after taking Trovan and six died after receiving injections of the certified drug Rocephin. The pharmaceutical giant says it was the meningitis that harmed the children and not their drug trial. But did the parents know that they were offering their children up for an experimental medical trial?

“No,” Nigerian parent Malam Musa Zango said. He claims his son Sumaila, who was then 12 years old, was left deaf and mute after taking part in the trial. But Pfizer has denied this and says consent had been given by the Nigerian state and the families of those treated. It produced a letter of permission from a Kano ethics committee. The letter turned out to have been backdated and the committee set up a year after the original medical trial.

Some important things to note:

1. There’s an important distinction between a humanitarian mission and a clinical trial.
A key difference is the level of uncertainty inherent in the clinical trial — you don’t know ahead of time how well (it at all) the experimental therapy will work. You’re doing the research to build this knowledge. If you already knew the answer, then performing the clinical trial with human subjects would count as “unnecessary duplication” — crossing an ethical line by exposing the human subjects to risks that were not outweighed by a benefit (like building new knowledge).

In a humanitarian mission, presumably, you are doing everything you can to help. This would include offering the best proven treatment, or at least directing the people who need help to those who can offer the best proven treatment.

Pfizer was able to dispense Rocephin, a proven antibiotic. And, being mere meters away, the team of doctors from Pfizer was certainly able to point people toward the Médecins Sans Frontières medical aid station. That they did not gives lie to the “humanitarian mission” cover story. That the Pfizer team packed up and left while the meningitis epidemic was still raging further undermines this cover story.

2. In research with human subjects, deception is generally a very bad thing.
The recognized ethical standards for research with human subjects include respect for persons — and this includes taking steps to protect, rather than undermine, the autonomy of the human subjects.

Setting up a clinical trial that looks like a humanitarian aid station mere meters from the Médecins Sans Frontières medical aid station that is dispensing humanitarian aid seems bound to create confusion at the very least. Even if it were not clearly intended to mislead, that’s an easily foreseeable outcome.

3. In research with human subjects, informed consent is required.
Since the formulation of the Nuremberg Code, the need to obtain the consent of human subjects to participate in research has been a central tenet of the ethical standards governing research with humans. In the absence of such consent (given either by the subject or, in the case that the subject cannot render consent himself or herself, by someone with the legal authority to give such consent who is able to evaluate the subject’s best interests), a clinical trial is prima facie unethical.

The parents who brought the legal action say that they were not informed that their children were being given an experimental, rather than a proven, treatment. Pfizer says that they did obtain such consent from the families and from the Nigerian state, but the letter of permission produced to bolster this claim originated from a local ethics committee that wasn’t set up until a year after the clinical trial was conducted.

Unless the team of Pfizer doctors also had a time machine, this makes it hard to believe that they obtained the consent of human subjects or their representatives prior to the clinical trial.

4. Firing an employee who raises concerns within the company about whether clinical trials meet ethical standards does not contribute to the sense that your company cares about ethics.
Even if Juan Walterspiel’s job with Pfizer was on shaky grounds for legitimate reasons, Pfizer CEO William Steere might have done better to keep Walterspiel on while he got to the bottom of the ethical concerns Walterspiel had with the Nigerian drug trial. Taking responsibility for conducting ethical research is the kind of thing a pharmaceutical company ought to do, not only because it’s required by various regulations, but also because it is more likely to generate good will with consumers and potential subject pools for future clinical trials. The alternative — taking responsibility after the fact, when you’re caught having messed up — generates a bad reputation, and multimillion dollar settlements hurt the bottom line.

Worse, the firing of Walterspiel may set up a climate where Pfizer employees don’t believe higher-ups in the company care about the ethics (or the legalities) of research. In such a climate, if voicing your concerns within the company can get you fired, you may as well just start by bringing your concerns to those outside the company (like the government or the media) so they don’t get buried.

A note in passing: this clinical trial was apparently the inspiration for John Le Carré’s book The Constant Gardener, which was made into a movie I mentioned here some years ago. It’s kind of appalling to learn that the events depicted in the movie were based in actual misdeeds.

Comments

  1. #1 Noumena
    April 8, 2009

    I agree with your points 2-4. But some of your phrasing under point 1 seems to suggest that conducting a clinical trial should never be part of a humanitarian mission, or that conducting a clinical trial should never be done in an epidemic situation.

    Suppose Pfizer had made it very, very clear that this was a purely experimental treatment, gotten adequate informed consent from the parents of these children, and had some preliminary data suggesting that the new treatment (a) was more effective than the established treatment, and (b) did not have side-effects that were much worse than those of the established treatment. In particular, suppose that the preliminary data for (a) and (b) would be enough to warrant a standard clinical trial in this country. There might be lingering worries that Pfizer would be `tricking’ people into participating in this clinical trial by holding out false (or at least premature) hope, but again, suppose that Pfizer went out of their way to stress that this was a potentially dangerous and unproven treatment.

    In this (admittedly very hypothetical) case, would there be any reason why Pfizer could not conduct a trial in the middle of the epidemic, or in connection with a humanitarian mission?

  2. #2 Janet D. Stemwedel
    April 8, 2009

    I think it’s complicated.

    Your hypothetical case is the kind of situation I think most of us have in mind when we talk about access to participation in clinical trials as a good that ought to be justly distributed.

    But, describing what is actually a clinical trial as a humanitarian mission strikes me as at least a little deceptive. It’s not the case that the researchers are being purely altruistic — they want something (data) from the human subjects.

    And, I wonder if an epidemic is a situation that introduces an element of coercion into the equation. If you are fearful for your life — or for your child’s life — and you perceive that the clinical trial is your best or only viable option for treatment, how free can your consent really be?

    Of course, our decisions in real life are constrained all the time. But I think that researchers conducting clinical trials have a duty to create conditions as free from coercion for their human subjects as possible.

  3. #3 Neuro-conservative
    April 8, 2009

    And, I wonder if an epidemic is a situation that introduces an element of coercion into the equation. If you are fearful for your life — or for your child’s life — and you perceive that the clinical trial is your best or only viable option for treatment, how free can your consent really be?

    This statement seems extreme. How do you propose that new treatments for life-threatening, emergent conditions should be tested?

  4. #4 Dr. Osagie Ogiemwonyi
    April 9, 2009

    Janet, it really is a complicated situation. Unless you have witnessed one before, the situation during any kind of epidemic in Nigeria is pure bedlam. You can’t begin to imagine the kind of situation Pfizer walked into. I think due diligence is advisable in terms of what really happened. Your reference to former Pfizer employee, Juan Walterspiel, is capable of misleading readers. You write as if there is a proven connection between his exit from Pfizer asnd his criticism of the organisation. I won’t go that far without concrete evidence. In any case, the real issue is the Trovan trials.
    I have seen the papers Pfizer filed in defence of its conduct and I am amazed that people continue referring to some phantom ‘tricks’ played by Pfizer. The Nigerian government approved the trial. So did the Kano State government. So did the National Agency for Food and Drugs Administration and Control. Hausa-speaking nurses were brought in to explain to the patients and their relatives what the trials were about – in their local language. Then on the issue of Pfizer’s departure after the trials, I think you need to ask some of the officials involved in the whole process at the time. One particular reference which would have been helpful is still in court, so comments may be prejudicial.
    But I would like to make this point with serious emphasis: Nigeria is not a banana republic where a pharmaceutical company can just walk in and use the citizens as guinea-pigs. It is simply impossible. I can’t claim to know every particular detail of what went right or wrong because my information is based on my knowledge of my country and the papers filed in the court which are in the public domain. The kind of terrible epidemic situation in which Pfizer operated unfortunately happened again this year. Thousands of our people have died of meningitis this year – and there was no help coming from any quarters because the government itself did not plan ahead.
    Many Nigerians are happy that Pfizer is settling out of court but no one is under any illusion that the allegations in court can be proved beyond reasonable doubt. I am all for ethics. I just happen to think that the flip coin of the matter is that an organisation should not be presumed guilty without comprehensively considering its own side of the story. At the rate at which many foreign commentators are trying to establish a link between the movie “The Constant Gardener” and the Trovan trials, the film should be a box office hit by now, but it is not.
    Anyone out there who can help us with meningitis drugs should rush their consignment to the same city where Pfizer operated to save those on death row because of the current meningitis epidemic.
    And by the way, Kano is not a ‘slum city’ as you described it. For hundreds of years, Kano has been an important trading point of the Trans-Saharan trade.

  5. #5 Neuro-conservative
    April 9, 2009

    Shhhh — Dr. Ogiemwonyi — you’re bursting Janet’s bubble!

    American leftists have a number of pre-conceptions that you are challenging:

    #1) that Africans and other non-whites are primitive people
    #2) that corporations are evil
    #3) that well-meaning leftists can save #1 from #2 by watching movies and blogging

    Really, Dr. Ogiemwonyi, you should be more culturally sensitive to the feelings of the West Coast American leftist!

  6. #6 Janet D. Stemwedel
    April 9, 2009

    Neuro-conservative wrote:

    And, I wonder if an epidemic is a situation that introduces an element of coercion into the equation. If you are fearful for your life — or for your child’s life — and you perceive that the clinical trial is your best or only viable option for treatment, how free can your consent really be?

    This statement seems extreme. How do you propose that new treatments for life-threatening, emergent conditions should be tested?

    I propose that extra pains be taken to inform potential subjects of the potential risks and benefits of the experimental treatment, and to inform them of the availability of proven treatments, if such exist (as they did in this case). That’s probably the best you can do, but it needs to be done.

    Dr. Osagie Ogiemwonyi, in response to your comments:

    First, the reference to Kano as a slum city is in a passage I quoted from the article in The Independent. I’m happy to accept your judgment that this is a mischaracterization of Kano, but the mischaracterization is not mine.

    Next, as far as the court documents presented by Pfizer in its defense, I have not seen those. Again, I am relying on the reporting in The Independent. Perhaps The Independent was in error in reporting that the document that indicated permission for the drug trial originated from an ethics committee “set up a year after the original medical trial,” I expect that Pfizer will pursue legal remedies against The Independent under British libel laws.

    Now, it is possible that Pfizer obtained something like permission prior to the start of the clinical trial but that this permission was not properly documented. In such a case, it would seem very hard indeed for Pfizer to document that each set of patients (or parents of patients) had been fully informed by, and rendered appropriate consent to, the Hausa-speaking nurses you say were brought in for the study. Given the testimony of some of the parents that they didn’t know it was an experimental trial, the absence of good record-keeping on Pfizer’s part would leave them pretty exposed legally. And, more generally, sloppy record-keeping in a clinical trial increases the risk that human subjects are being exposed to risks that will not be outweighed by the production of meaningful scientific conclusions. It’s fair to say that the very conditions of “bedlam” you point to during the epidemic make the need for extremely organized record-keeping (encompassing both the scientific data and the obtaining of consent for each and every subject) more vital. Pfizer may not in this instance have walked into Nigeria and treated its people like guinea pigs, but if The Independent has reported this part of the story accurately, it let shoddy record-keeping jeopardize the scientific study for which human subjects undertook significant risks.

    With regard to the firing of Juan Walterspiel, you will notice that I made no claim about the actual cause. My remarks dealt with the appearance of his firing — and of Pfizer’s commitment to prioritize ethical conduct in its clinical trials.

  7. #7 zayzayem
    April 14, 2009

    This certainly is going to a good example to show future generations of pharmacos of “how it shouldn’t be done”.

    Yet, I’m still willing to let Pfizer have some benefit of teh doubt that they may have gone in with the best of intentions (or at least, not the worst) and been bamboozled a bit by the African SNAFU administration (or lack thereof).

    Translation and communication may have been also an issue. Pfizer amy have had the impression that informed consent etc. had been given. If that’s what their handlers told them, why should they doubt it?

    I agree strongly with points 2 & 3, and think #1 is also worth considering (I think an exception should be allowed when no existing proven treatment or therapy exists). #4 is a bit harder to deal with without knowing exactly what the internal issues with Walterspiel was. Threatening to complain about an ethics violation should not be a get-of-getting-your-assed-fired card if that was the direction you were headed already.

    The main things Pfizer should take from this, is that conducting trials under guise of humanitarian mission or in the developing world should not be an excuse for avoiding procedures (including accurate and detailed record keeping) expected in the developed world. Sadlyt avoiding red tape probably remains at least one of the motivating factors for MNCs to conduct such “missions”.

  8. #8 Abdullahi Ibn Mohammed
    April 16, 2009

    Interesting comments, but while you are all ‘blowing grammar’ as we say in Nigeria, how about sparing a thought for how the Pfizer settlement funds will be deployed? Have you heard that fake lists of Trovan patients are now in circulation in Kano? ‘Victims’ are crawling out of the woodwork. Let me share with you some stuff I came across on pharmamonitor blogsite:

    “It will be interesting to see how the final list of beneficiaries will be arrived at, considering the fact that the 13-year-old documents required in the case may not be all available.
    However, close watchers, especially civil society groups, agree that strict verification has to be carried out. They point to the recent disclosures in the newspapers that fake ‘Trovan victim lists’ have been in circulation in Kano. Many of those on the list, it was revealed, were born crippled but were smuggled into the fake lists to defraud the settlement process. It was in view of this kind of development that Pfizer is said to have insisted right from the onset that everything has to be transparent because that was the only way the funds could get to their intended destination. It is no longer considered prophetic to say that if the rules are not stiff and clear, most of the funds will end up in private bank accounts as has happened in other cases in the country.”
    Now I say that is the real challenge. Any takers?

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