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[Aceme Nyika]

Epidemic outbreak of bacterial meningitis in Kano

In 1996 there was an epidemic outbreak of bacterial (meningococcal) meningitis in Tudun Wada, a very poor residential area in central Kano, Nigeria. The overpopulated, filthy and hot conditions prevailing in Tudun Wada were ideal for the spread of the infectious disease. A non-governmental organisation (NGO) called Medecins Sans Frontieres (MSF) assisted the government by providing free emergency treatment at the Infectious Diseases Hospital, a government hospital in Kano. In an effort to save as many lives as possible, the Nigerian government encouraged people of Kano through state radio announcements to take infected children to the government hospital in Kano for treatment, and the people thronged the hospital for treatment. The epidemic swept through the poor communities leaving an estimated 15 000 people dead and thousands of children permanently disabled.

Treatment of patients and testing of Trovan at the government hospital in Kano

As the Nigerian government was battling to contain the epidemic with the help of the MSF, a team of Pfizer researchers came into the country and joined the government and the MSF at the government hospital in Kano. The Pfizer team was recruiting children into a trial of a drug called Trovan, or Trovafloxacin, which had never been administered to children orally. At least 200 children were recruited into the trial. The control group was given low doses of chloramphenicol, an approved antibiotic for treatment of bacterial meningitis. The government hospital and the MSF were using chloramphenicol to treat children presenting with bacterial meningitis.

In response to wide-spread criticism, Pfizer argued that the meningococcal meningitis epidemic had an overall mortality rate of 10-30%, and asserted that Trovan lowered the mortality rate to 6%, while chloramphenicol lowered the rate to 9.1%. The Pfizer researchers are alleged to have left Kano once they had completed their studies in spite of the fact that the meningitis epidemic was still ravaging the community.

Scientific rationale for testing Trovan in children

The main scientific rationale put forward by Pfizer for testing Trovan in children was that it is a flouroquinolone, and other similar drugs in the same antibiotic class had been successfully tested in children before. Ciprofloxacin, a flouroquinolone, was cited as an example that had been used in infants without any serious side effects. However, ciprofloxacin was not tested in a disease outbreak.

Ethical Approval and Informed consent

Pfizer argued that they could not obtain informed consent from parents or guardians of the children recruited into the trial because they (the parents and guardians) were illiterate. As for ethical approval, Pfizer claimed that the trial was approved by an Ethics Committee at Kano Hospital, and a letter they produced to prove their claim was dated March 1996, a date when no ethics committee existed at Kano. Consequently, there have been allegations that the approval letter was forged and back-dated to 28 March 1996, which was six days before the commencement of the Trovan Trial. Pfizer collaborated with a local Nigerian team of health personnel led by a local physician who, according to Pfizer, oversaw the Trovan Trial at Kano.

The aftermath of the Trovan Trial

The Nigerian government set up a committee of medical experts to investigate the circumstances surrounding the Trovan Trial. The committee concluded that the drug trial by Pfizer was illegal and unethical. In 2001, 30 Nigerian families who claim that Trovan caused the deaths or permanent disability of their children as participants in the trial sued Pfizer in a federal court in New York, USA. The lawsuit was dismissed on the basis that what happened in Nigeria was outside the jurisdiction of the US courts. Lawyers representing the Nigerian families appealed against the ruling and the legal battle is continuing in the USA as well as in Nigeria.

DIFFERENT SCHOOLS OF THOUGHT

There are various schools of thought regarding the Trovan Trial, and some of them are listed below:

1. Pfizer researchers took advantage of the following situations that were prevailing at the time of the meningitis epidemic to conduct their Trovan Trial;
(a) The absence of a functional ethics committee (institutional one at Kano or national one).
(b) The desperation of the affected poor, illiterate people.
(c) The emergency situation that greatly facilitated recruitment of participants at a single site.

2. Pfizer went to Kano to assist the Nigerian government during a seriousepidemic, and they offered free treatment. Whereas some of the 200 children they treated with Trovan may have experienced some serious side effects thatin some cases led to death, some participants in the trial responded well to Trovan and thus benefited. After all, some patients in the government and MSF camp responded poorly to chloramphenicol treatment and died. Thus the deaths would probably have occurred anyway even if Pfizer had not come on board.

3. The trial was led by a local Nigerian physician, with some local Nigerian nurses and doctors participating.They obviously were acting in the best interest of the poor communities affected by the epidemic. Thus even if there was no approval and oversight from an ethics committee and/or government,participants were afforded respect and protection by the local Nigerian collaborators. Pfizer merely provided the antibiotic to be tested and other resources.

4. The fact that Pfizer left Kano before the bacterial meningitis epidemic was significantly contained shows that they were not in Nigeria on a humanitarian mission in the first place.

5. The bacterial meningitis epidemic was fuelled by the squalid conditions in which the communities of Kano were living, and that is what needed to be addressed urgently. Pfizer did not cause or exacerbate the epidemic; it only came into Nigeria to help and to test a drug that could potentially improve the treatment of bacterial meningitis in children.

WHAT DO YOU THINK ABOUT THIS CASE STUDY?

(1) Did Pfizer exploit the poor desperate people with severely ill children?

(2) Does illiteracy justify the fact that Pfizer researchers did not obtain proxy consent for the children they enrolled into their trial?

(3) Did they help to fight the meningococcal meningitis epidemic at all or they had their own agenda?

(4) If indeed Pfizer researchers used lower than the recommended doses of chloramphenicol in the control arm of their trial, would such an experimental design support their claim that their Trovan lowered the death rate to 6% as opposed to 9.1% for chloramphenicol?

(5) Are the local health personnel who collaborated with Pfizer researchers to blame for the unethical recruitment of children into the Trovan trial?

(6) Who had invited Pfizer to come to Nigeria in the first place, and for what purpose?

(7) The trial took place in Nigeria and the children who were enrolled into the trial were Nigerians, but Pfizer is an American company and the legal battle is being fought in America, with American lawyers representing the Nigerian families. Are there no legal mechanisms of dealing with such issues locally (i.e. in Nigeria or in Africa)?

WHAT LESSONS CAN WE LEARN FROM THE KANO TROVAN TRIAL CASE STUDY?

(8) Is it ethical to test a new drug whose effectiveness is not well known in a devastating epidemic without scientifically sound supporting data when a safe, proven drug is available? Suppose the drug did not work at all, when would the study have stopped?

(9) What are the responsibilities of local health personnel in ensuring the protection of the welfare of health research participants? Should they only focus on their career development at the expense of the protection of research participants?

(10) What is the responsibility of the following in preventing unethical health research from taking place in developing countries?


a. Collaborating researchers from the developed countries?
b. Local collaborating researchers
c. Ethics committees in the developed countries
d. Local ethics committees in the countries where the research is taking place
e. Institutions where the research is based
f. Local drug regulatory authorities
g. Ministries of Health
h. The participants themselves once they know their human and civil rights
i. All stakeholders have complementary roles to play

(11) Public trust is essential in promoting public health interventions. To what extent do such incidents as the Trovan Trial hamper future public health programmes?

[Thulisile Cele]

Dear colleagues,

I would like to say that the way the Trovan trial was conducted was very unethical because I do not think that the researchers would have done it if the epidemic was in some developed country.

I also want to ask; if there were no deaths or disabilities caused by the trial, would we have been discussing the unethical way it was conducted?

There could be many more such unethical studies going on in Africa and other developing countries but are not scrutinized simply because no deaths or some other serious events have occurred.

Thanks,
Thulie.

[sarr samba]

By all means Pfizer made a effort to give an image that they were on humanitarian mission ie therapeutic intervention while actually they had another agenda ie RESEARCH INTEREST. Because of the following: 1) 200 recruited participants only? 2) leaving site after their agenda was complete, before the end of the epidemic, why? 3) Control study? for an therapeutic intervention? Definately this in research 4) they actually wanted at the same time, to prove that Trovan is better than chloramphenical, hence the reason of involving the chloramphenical, and administering lower doses.

[sarr samba]

The local health personnel are definitely to blame, because their primary role is to save and protect peoples, which in this case was the vulnerable children who could not defend for themselves. In any case health personnell will be to BLAME, they did not follow ethical guidelines for reasons they know best themselves. And even if they claim to be ignorant about ethics in health research, IGNORANCE IS NO EXCUSE

[sarr samba]

Pfizer i[b]nvited themselves[/b] into Nigeria claiming to help the government in containing the big meningitis problem, BUT actually it is now very clear that they had not the slightest interest in help the Nigerian government and its people because Pfizer left way before the government had solved the problem. Pfizer had solved its own problem which was to collect data for their Trovan Trial. They had their own business interest, and did not have the slightest sympathy for the poor Nigerian children, some of who were put on insufficient levels of drug doses as control studies, without caring for the children about the prolonged suffering of these children let alone death that was waiting for them round the corner

[sarr samba]

The Trovan case indicates presence of some kind of Evil Collaboration between Government of Nigeria and Pfizer. No way can any one believe that a new and unregistered drug can enter a country without being stopped at control points. Definitely Nigeria has adequate technical expertise in Clinical Trials, Drug regulations and human subject ethics to foresee evil intentions from people like Pfizer. Nigeria can not say it was taken by surprise, not convincing.

[Nkiruka Odunukwe]

ETHICAL ISSUES:
1, There was no ethical committee in place at the time of the said research in Kano, therefore the document provided by Pfizer could have been fraudulent.
2. Drug trials should not be allowed during epidemics because it is unethical. This community must have been coerced or unduely induced.
3.One should question if the drug was approved by the National drug regulatory body.
4.It is clear that the researchers exploited the community since there was no informed consent.
5.The fact that the researchers used lower doses of known potent drugs indicated that their action was driven by personal economic gain at the expense of medical ethical principles. This is against the principle of best practices.
6Illiteracy was not a justification for avoiding informed consent because in the community there must have been at least one literate fellow.
7. The fact that they left while the epidemic was still on strongly suggested that they had no good intention for the participants.
8. It is likely that the local collaborators were either corrupt or ignorant of medical research ethics.

[sarr samba]

It is known Nigeria has got legal mechanisms in place to deal with cases like the aftermath of Trovan Trial, we also understand that the local collaborators (Nigerians) are standing trial for their deeds in Nigeria. Although it is fair to say that the legal mechanisms in Nigeria are weak, because they could not stop a new , unregistered drug from entering Nigeria let alone being used. What is the Drug Regulation Control doing? However, the American Pfizer has been clever all the way, and managed to run and find safe hiding in America. Unfortunately, Nigeria does not have the muscle to uproot those Pfizer criminals from America. :evil:

[Karani Anna Kagure]

THE TROVAN TRIAL CASE STUDY –
GROUP 2
Members: Karani Anna Kagure – Chairman (Kenya)
Other members:
Aissalou Tore (Senegal), Peter Mageto (Kenya), Joel Somanje (Zambia), Saibou Maiga (Mali), Edith Ngirwamuou (Tanzania), Hilder Gideon (Tanzania), Alida Kouojip (Cameroon) , Baganan Cheik (Burkina Faso) & Paulina Tindana (Ghana).

Answers to Questions
1. YES– Because they exploited the vulnerable group during the epidemic
2. Illiteracy doesn’t justify proxy consent in children enrolled in the trial
3. Somehow they managed fight the outbreak because some children responded positively to treatment BUT they had their own agenda because they left as soon as ey completed the study. This included the recruitment sample of 200 children. They did not care about the epidemic . They had the moral obligation to stay on and there was no evidence or mention of their support.
4. NO – Pfizer researchers used lower doses of recommended chlorophenical in control arm of the trial because you cannot have lower dose. It cannot support the claim that the Trovan is better. No conclusion should be reached without the recommended dose.
5. YES because they are supposed to be gatekeepers and should have followed ethical procedures.
6. There is no information on who invited Pfizer to Nigeria.
7. Legal mechanisms are there in Nigeria and Africa but since the case involve multinational company perhaps it is best for the case to be handled by international tribunal.
8. NO. The effectiveness was not known. There is no scientific information. If drug did not work, it should have been stopped immediately. When side effects were noted.
9. The responsibilities include: a ) Moral obligation b) To follow existing health research guidelines. c ) Should not focus on career development only but also protect research participants or subject.
10. a) Need to follow regulations for host countries b) Guide c ) Approve d ) Guide & approve e ) Guide ,approve & monitor f) Approve & Monitor g) Guide, approve & monitor h) Follow procedures & guidelines.
11. Hinder health promotion programmes

[Tunde]

The case of Trovan in Kano, Nigeria was a very pathetic case and a slap on the face of the Nigerian government and all those that were meant to protect the helpless citizens. It is obvious that the ethical approval was not obtained through the due process if truely they had one. The trial was a clear case of exploitation of the helpless people during this epidemic. Obviuosly it is not ethical to conduct drug trial during an emergency situation moreso a drug that has not been approved for that application in the country of origin. The people were not given the opportunity to chose between the standard treatment and the new drug since informed consent was not taken before recruiting the patients. Even if the patients were illiterates there should still be an interpretation of what should have been the consent form in the local languages since the local health workers were present. The local health personnel as at that time could not protect the people because (1) They know little or nothing as regards ethical considerations in research (2) Going by what I read in the Washington Post of December 17, 2000 by Joe Stephens "A Nigerian physician who said he was present during the Kano experiment, for instance, felt it was a bad thing, but he did not object because pfizer's test appeared to have backing from the government". "I could not protest" said the physician.
Such incident as the Trovan trial will make the Public to be resistant to future public health programmes even if it is for their own good. Such was the problem encountered during the Immunization programme in the Northern part of Nigeria.

[StellaSmith]

The whole thing about the Trovan trial bothered on ethical issues.
1. The study was conducted without prior ethical approval as there was no ethical committee then and such trials or any trial for that matter cannot be conducted without ethical approval.
2. It is not ethical to conduct a drug trial during epidemics and I know that Pfizer knew that in mind and had only the aim of research in their mind
and not concern for the community.
3. The researchers (local health personnel) who went along with the Pfizer team is totally to blame for allowing outsiders to exploit the poor innocent citizens who believed in them and they allowed such callous acts to be conducted for the sake of filthy gain.
4. Using Illiteracy to justify the reason for not getting informed consent too is totally unacceptable as they are various ways of getting the illiterate understand such trials and obtaining legal informed consent.
5. The fact that the Pfizer group left even when the epidemic was still ravaging shows they had no other agenda than to conduct research, the partcipant care was not uppermost in their minds. There was even no arrangements for post trial benefits even if they claimed that some success rate had been achieved.
6. Lastly, the matter should not just be allowed to die a natural death, more enquiries should be made as to who allowed the Pfizer group to Nigeria and what was their ultimate mission. Africa as a whole should no more be made scape goats where they can be used andf dumped anyhow for research that is not beneficial to the community as a whole.

[Opara Rose]

THE TROVAN TRIAL CASE STUDY 1

The case of trovan trial was very opportunistic because Pfizer took advantage of the severely ill children in a poor environment in Nigeria to test its drug which was never tested in children or given approval in US

Illiteracy was no excuse to justly inability to obtain proxy consent for the children recruited into the trial. Thumbprint after full explanation in local language by Pfizer (the nurses recruited) was necessary and required for full consent. In this situation it difficult for parents or guardians to comprehend the process of the study when a child is critically ill.

Pfizer appears to have their own agenda i.e to study the effectiveness and satiety of its antibiotic that hitherto would not be allowed in children in U.S as priority. Although they helped to an extent to fight the epidemic, they did not wait to track the long term recovery or checks for the children in spite of the fact that the epidemic was still ravaging the community

Pfizers. Experimental design couldn’t have supported their claim that Trovan lowered the death rate to 6% as opposed to 9.1% for chloramphenicol. This is because reduction of the recommend doses of chlromhenical of the trial would have sapped the drugs strength and skewed any comparism to trovan according to drug manufacturer. Besides some 200 children treated with Trovan may have experienced some serious side effects and in some cases to death.

The local health personal were not to blame for the unethical recruitment of children into the Trovan trial. Because they were acting in the best interest of the poor community affected by the Epidemic. Besides Ptizers trial appeared to have backing from government of
Nigeria at the time (a military government). The local health personnel would only do what they were asked to do e.g. Nurses.

The news of the meningococcal epidemic came to Dr. Hopkins, group director for anti-infective clinical development of Pfizer central research through the internet site. The fact the Pfizer had a local office in Kano and had previously sponsored studies with a local physician in Kano with expertise in treating meningitis and who had agreed to undertake the clinical trial as P.I. made the visit possible. Hence the opportunity for Pfizer to fly into kano for the study –to test the antibiotic Trovan.

It is interesting that a legal battle being fought in America for Nigerian children took place in Nigeria., There are other legal mechanisms of dealing with such issues in Nigeria for example there is (a) The Cross Boarder Inter relations, (b) International relations on disputes
(c) Industrial disputes / conflict resolution.
Trade Dispute Courts. (d) Nigeria government can seek permission to supoenoa Pfizer to Nigeria for the trial



LESSONS TO LEARN FROM THE KANO TROVAN TRIAL
It is unethical to test a new drug where effectiveness is not well known in a devastating epidermic without scientifically sound supportly data, when a safe proven drug is available. This is so because Trovan had never been tested or approved for marketing for used by children in U.S. Besides it was given intravenously in adult & even then suspended due to the side effect. On the contrary Pfizer gave it in oral form in Nigeria. Seeing that the drug did not work, the study would have stopped immediately and the approval drug given.

Local health personnel have a responsibility to explain the procedure, the risks & benefits of the research process before parents sign the consent form. They have a responsibility to explain to participants of their rights to accept or reject to the process of the research but the situation was not favourable for decision making process.

In order to prevent unethical health research taking place in developing countries, the following responsibilities should be undertaken.
Collaborating researchers from the developed countries must ensure that approval is given to any health proposal by the Ethics Committee of the country where research is taking place. The local collaborating researchers most ensure that participants to be enrolled for such research are adequately informed. Of the process of the research before and ,during the research, the risks or benefits of the research and all relevant information to the participant rights, safety & well being. The informed consent form must be duely signed and witnessed. Provision should be made for thumb printing of participants who are illiterates.

The Ethics Committee in the developed countries and those of the local Ethics Committees in the countries where the research is taking place must ensure that review of proposal and ethical approval is given to the proposal before researches are undertaken. There must be approval for competency, mutual understanding by researchers and participants free of coercion. The food & Drug Administration in the Country (e.g NAFDAC in Nigeria) must give approval of such trial, drugs on human subjects. The study must be monitored and reports of the study sent to the committee at intervals for the dissemination.
The research must provide reassurance to the public and protect research workers from criticism and the participants from harm and exploitation

The Trovan Trial would definitely hamper future public health programmes if a developing country where the study is being carried out fails to adhere strictly to (a) Review of proposal and Ethical approval of the study by a local ethics committee. (b) Compliance of the Research Study to the process of the trial as approved in their home country – developed country (c) Review of the Research proposal with their supporting documents i.e Informed Consent with all support Information to protect participants. (d) Monitor and follow up of such trials including welfare of the participants
Institutions of Health in the countries where research is based must ensure that researches get permission to carry out the study. Ensure recruitment of qualified personnel who understand the objectives and procedure of the research and that participant’s welfare and confidentiality are protected.
The Ministry of Health as the supervisory Ministry must ensure that researchers get permission and approval from local Ethics committee through procedure for any research undertaken. They should monitor, and report result and disseminate accordingly.

[brimamusa]

It is clearly that Pfiza had exploited the poor people by conducting an unethical trial and not obtaining a proxy consent is amajor violation to protection of participants rights and illitracy dose not justify that.
Pfiza indeed did not help the people but complicated condition by using lower than the recommended dose of the standard drug a not known new drug resulted in increased fatality and disabilities.
Local collaporaters are responsible for protection of participants rights and safety so ther are to be blamed for conducting the tovan trail.
Pfiza was not invited by name but the Nagerial country call for halp from any organasation but Pfiza was interrested in just conducting the trial in that way.

[adugyasidennis]

I wonder when those with great influence in society will stop exploiting the innocent and poor ones. After the introduction of ICH-GCP principles, have we evolved principles by using human beings as animals for the pre-clinical phase? It is very obvious that Pfizer greatly exploited the poor and sick people in Kano in their trial.
They had no excuse to seek the consent of the participants even one by proxy would have been very ideal. In cases where a legal representative is needed to consent a participant, no matter the situation that subject should not be enrolled. The best known treatment should be given when the trial substance has not been tested in human. It only happens that waiver could be sort from the IRB in emergency. Even this can never be ethical to enrol about 200 subjects. They took advantage of the situation and Kano to trial their drug which they had developed.
The fact that Pfizer claim to have reduced the mortality rate in the children to 6% does not proof they helped with the condition. What comparison did they make? At what time of the outbreak did they make the conclusion? If the outbreak left about 15000 people dead and they worked basically on the 200, what justification do they have to compare mortalities with those treated from the government hospital. I may not be an expert but the way they conducted their study would present with a lot of flaws aside ethics. Bias, confounding issues in the data collection may not be addressed in such situation. I will not be surprise the study could have contributed to the high incidence. Why do I say this? The use if the new untried drug among some of the sick children could have compromised the herd immunity that if had been achieved could have reduced the incidence recorded. There is nothing like quick results in clinical trials and I expected the pharmaceutical giant – Pfizer to have known that.
Moreover, Pfizer used a lower dose of the recommended treatment in the control group. That’s is shear wickedness. Why did they do that achieve their target- to lower mortality rate? As I have said, they had no moral and ethical grounds to compare the two drugs. They were only interested in manipulation to achieve a better statistical power to buttress their immoral act.
As for those who acted as the local researchers, it could be presented as a two way issue. I will not be surprise Pfizer would contact people who have no knowledge in the conduct of clinical trials, the expected principles to be obeyed. They could do that to achieve their purpose of going to Kano for the trial. On the other hand, a selfish investigator could go ahead with such unethical trial knowing that he/she could be protected by Pfizer as it is happening according to the case presented. The issue therefore becomes a moral one when more times ethics has am limit when it come to the law. Pfizer though conducted the trial unethically, but because they played their cards well, they are still standing tall.
If we have been able to come out with ICH in diverse area of research, then i believe the international community should come out with other collaborations that would deal with issues of such exploitations.
This definitely affects other public health programmes. Now you don’t know who to trust. Your own government officials could connive and allow such brutes to harm innocent citizens. There is a case where residence of a place refused CSM vaccination because they thought they were going to be made impotent. They had a concern because YOU CAN NOT TRUST ANYONE BECAUSE OF GREEDINESS.

_________________
dennis adu-gyasi

[rokine]

i can't believe this took place in 1996 when the area of research ethics had greatly evolved.the researcher's interests clearly overrode that of the participants. This clearly defeated the principle of autonomy, a cardinal principle.
developing countries should aim at developing capacities of local ERBs and other regulatory bodies to avoid such situations.
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rafiq okine