Pfizer's Trovan drug trial in Nigeria during the meningitis epidemic

Drug Testing in Nigeria

Operational Analysis

Strategic Analysis

In the article analyzed, Drug testing in Nigeria, the researchers, Debora Spar and Adam Day, describe the situation of a clinical test of an experimental drug, Trovan, conducted in a Third World country under suspect conditions, with shoddy supervision and for questionable reasons. Though the Trovan trial was perhaps exceptional, it is also considered an example of what can happen when pharmaceutical corporations conduct research on humans in poor countries with bad supervision.

A nervous system infection, Meningitis can kill a child in a matter of hours if left untreated. It killed more than 12,000 children in six months in and around Kano, a mostly Muslim city. Pfizer, a pharmaceutical giant drug company saw this scenario as an opportunity to do clinical research on 200 live humans, while possibly helping sick people. Half of the 200 children received Trovan and the other half received a "proven meningitis treatment," ceftriaxone, though they administered a dose lower than recommended. Pfizer has maintained its records demonstrate that not one of the deaths could be linked to Trovan or to substandard treatment, and that the clinical study shows there is a better survival rate for patients on Trovan than for patients who receive the standard drug. Survivors sometimes sustain brain damage or other complications from the disease, even if they are "cured" (AP, p. 1).

Nigeria alleges Pfizer did not obtain the required approval for tests, nor did it get proper consents from patients. Pfizer countered by saying the alleged victims were affected by meningitis and not the drug, and that Trovan saved many lives (Oboh, p. 1).

There was a compelling reason to look at Trovan because it was an oral formulation, it was known to have shown efficacy in meningitis and was a five-day treatment so it was perfect for an epidemic setting," Edozien told Reuters (Oboh, p. 1).

In the United States, blockbuster drugs are like gold. The financial analysts said Pfizer would make $1 billion per year if Trovan won approval by the FDA for use against several ailments. Pfizer wanted to test its use against meningitis, and in Africa there was an epidemic of it. Meningitis is rare in the United States, so researchers came to Kano to test it against the dying (Stephens, p. 1). But a hostile reception was faced by Pfizer in Kano, which has a history of rejection of Western medicine. The state government actually banned vaccines against polio in 2003 for nine months, saying the immunization campaign was a U.S.-led plot and the vaccine caused HIV and infertility. This caused a resurgence of the polio disease in Africa.

Analysis

While 11 of the 200 stricken children enrolled in Pfizer's experiment died, others suffered an inability to walk or talk, deafness, blindness, lameness, seizures, and disorientation, which are meningitis-related symptoms, Pfizer records show (Stephens, p. 1). This analysis will look at the operational, strategic and ethical ramifications of these results.

Pfizer said it wanted to study the effectiveness and safety of the antibiotic while providing a breakthrough treatment for this suffering Third World country. It validated its practices, given the horrendous conditions found, by showing how many children's health improved while maintaining a fatality rate of 6%, comparing favorably to bacterial meningitis victims treated by hospitals in the U.S. A company spokeswoman said the Trovan experiment was approved by the Nigerian ethics board to be "sound from medical, scientific, regulatory and ethical standpoints" (Stephens, p. 1). However, it was later revealed that there was no Nigerian ethics board. In addition, the samples were not tested correctly, resulting in study results so tainted that the results wee not accepted (Spar, p. 3).

As far as operational analysis, it took Pfizer researchers just over six weeks to prepare the study, instead of a year or so, as is common in the U.S. And here meningitis patients usually receive intravenous medicines, while the researchers gave the Nigerian subjects oral Trovan, which had never been tested (Stephens, p. 1).

During the trial, the ten doctors, including physicians practicing medicine in developing countries, meningitis specialists and pediatricians, were interviewed about Patient 0069's death and were troubled by her case. They focused on whether doctors "left the child on the drug too long while her health declined." Normally, if a human subject is not responding to an experimental drug, they are given already proven medication and are removed from the test. In addition, guidelines urge researchers to conduct a second spinal a day or so following commencement of treatment to see if the medication is having the desired affect. Pfizer researchers said they did not perform a second spinal tap on Patient 0069 and left her on the drug until she died. Pfizer chose to make such spinal exams optional in Nigeria. A Nigerian physician still working in Kano said "The patient died because [the doctor] refused to help." (Stephens, p. 2).

Pfizer spokeswoman said Patient 0069 could have died with treatment by any antibiotic and their researchers did not suspect Trovan was not working (Stephens, p. 1). A Nigerian doctor hired by Pfizer to run the experiment, Abdulhamid Isa Dutse, said physicians should change medication of any patient who is not improving on the current one. "To be very, very honest, in retrospect, maybe we should have done something about that," he said of the girl. Dutse has since been removed from his post, (Stephens, p. 1).

Patients did not understand they were part of an experiment, said the doctors who had been involved in the experiment. "The patients did not know if it was research or not," agreed a Nigerian laboratory technician who took part. "They just knew they were sick." Pfizer disputes that, and said local nurses explained to families who participated, but did not have them sign consent forms (Stephens, p. 1).

In the United States Pfizer got approval to sell Trovan to adults, but bringing it to market turned out badly. It was never approved for use by children in the U.S. Or in Nigeria. Regulators found dozens of discrepancies in Kano experimental results. They advised doctors that use in adults might cause liver damage and death. European regulators forbid sales altogether (Stephens, p. 1).

As far as strategic critiquing, Pfizer's Nigerian clinic opened and closed in a relative short time: Three weeks after they arrived in a chartered plane, the team flew out again. The doctors involved returned once more to examine their patients but did not follow up for long-term recovery. "If I had the power," said a doctor who watched the experiment across the compound, Dr. Lodi of Doctors Without Borders, "I would take away their medical licenses." (Stephens, p. 1)

For Pfizer, the timing was oddly fortuitous. The New York-based, then-$11 billion-a-year corporation was pushing to submit Trovan for FDA approval. A bacteria fighter, Trovan had shown promise against a broad range of infections - sinusitis, bronchitis, gonorrhea and pneumonia. Thousands of patients had enrolled in international drug studies in the company's biggest testing program ever. Wall Street analysts predicted that Trovan could be one of the most financially successful new drugs of its kind in years. There were worries, however, about possible side effects in children. Trovan belonged to the quinolone class of antibiotics, and quinolones had caused joint damage in experiments on young rabbits and puppies (Stephens, p. 2).

We had to move quickly," explained Pfizer's Betsy Raymond. "You would not be able to find those numbers of children with spinal meningitis in the U.S." (Stephens, p. 2)

Hopkins who then headed Trovan development, pushed for the experiment in Africa, saying its success would make all their drugs look good (Stephens). So Pfizer authorized the venture to win FDA approval for Trovan use in meningitis epidemics. Hopkins says that the designation proved the experiment philanthropic rather than a cheap, unethical way to get drugs approved for use on American children (Stephens, p. 1).

But of course Pfizer was hoping to gain from this venture. Even though the drug was not approved by the FDA, had never been used with an oral administration, and the experiment was conducted under the worst conditions by unethical supervisors, under unsanitary and haphazard conditions, with faulty record-keeping, Pfizer still hoped to gain a useful drug which would be in demand. A specialist, Creighton University pediatrics department Chairman Stephen Chartrand, said use of an oral drug under those circumstances would be "unconscionable." (Stephens, p. 1)

Though most of the trials in Third World countries and Russia are conducted without troubling issues, there are enough instances of breakdowns in the scientific process and ethical abuse to create a concern. Other charges concerning other trials which have endangered unwitting patients or which were followed through lacking proper ethical review have occurred over the years. (Lustgarten, p. 1)

Some of the materials we needed to establish that Pfizer was fraudulent only came out after we filed the suit," said Irukera of the trial now going on in Nigeria. An earlier suit only levied a lesser charge of "fraudulent representation." (AP, p. 1)

We stand by our previous statements on this issue," Pfizer said. "The Trovan study was approved in advance by the federal government of Nigeria, it was conducted in an ethical and appropriate manner, and it helped save lives. To our knowledge there is no additional information in the case. Any purported new facts more than 11 years after the study was conducted are simply rehashed allegations dressed up differently, and equally without merit." (AP, p. 1) This statement only underlines the unethical basis upon which Pfizer stands, as the fact that its "approval" by the Nigerian board of ethics was found to be fabricated.

While the authorities in the state and city of Kano blame the Pfizer controversy for creating suspicion of government public health policies, Islamic leaders in the mainly Muslim city of Kano have pointed at the Pfizer controversy as sure evidence of an overall U.S.-led conspiracy. (AP, p. 1).

Recommendations for better handling of this situation follow.

The issues listed above could have been better handled if Pfizer had been forthcoming and honest about its goals and plans for its product, Trovan, when it went to Nigeria. Then, even if it raised some hackles that it was setting up a separate clinic to administer experimental medications to dying patients, it would not have been considered as "underhanded." Also, patients would have been able to choose whether or not they wished to be a part of an experimental drug in the treatment of their disease. As it appears that this information was hidden from patients to some degree, the honesty issue is uppermost and bears on the operational and strategic analysis, as it weighs on the minds of the judges, the doctors and the patients.

Secondly, Pfizer could have been better prepared to handle their experiment in a more professional manner. The intake personnel, who saw the patients first, should have had forms ready for parents to sign, saying they knew this was an experimental drug and that they were entering the test of their own free will.

Thirdly, the doctors who treated the patients seemed to have been fixated on the test, rather than on the health of their patients, seemingly allowing some patients to be sacrificed for the goal of keeping the experiment clear-cut. The 10-year-old girl who died is probably the victim of this fixation on the part of the doctors, who were determined to find out if their drug would save or kill, even if they knew that another drug would save the life of the child.

Conclusion

The purpose of the project conducted by Pfizer, which has been treated in this paper, was to gain some research results to present to the FDA, in order to release a new drug which could be used on children or in epidemics of spinal meningitis. The results appeared to be favorable for Pfizer in that the drug maintained only a 6% fatality rate, compared to Ceftriaxone or other drugs used intravenously as antibiotics. The drug was administered orally in the form of a pill to young victims of the epidemic of meningitis in Nigeria.

If the motives had been to save the lives of some of the victims, then doctors would have consulted with their patients more often, and conducted the proper tests to discern how the disease was progressing. Unfortunately several different things occurred during the course of the experiment, which threatens not only the statistics, but the lives of Pfizer clients all over the world. The experiment was found to be flawed in that patients were not regulated in any way. This involved book-keeping and house-keeping. The study results showed that there were not the required number of tests performed on the patient and it may have been this which caused her to die. Book-keeping is supremely important and the patient's consent forms (or those signed by the patient's parents) are not to be found, if they ever existed. Secondly, a letter of consent from any branch of the Nigerian government was never obtained. Thirdly, preliminary testing results were never obtained before proceeding with experimentation on humans. The danger in first trials were not addressed and the book-keeping on the Kano experiments was so inadequate that when the drug was released in the United States, it was found to have dangerous side effects which were not recorded or were ignored in its trial.

House-keeping is important. The children were not treated with care, and follow-up tests were not performed to determine the results of administering the drug as the trial progressed. If the children had suffered side effects from the drug, it was not found because of the lack of follow-up testing. While side effects were suspected, they were never proven, and in at least one case, this was a deadly result.

As a result of this botched experiment, the article by Spar and Adam points out that the U.S. Department of Health and Human Services created a new Office of International Activities, formed to provide stringent oversight of clinical trials run overseas (Spar, p. 3). The Pfizer company lost money and slid in the stock market because one of its block-buster drugs turned out to be a dud. In addition to this disappointment, Pfizer is being sued for billions by the Nigerians and citizens of Kano.