© 2012 D.O. Bădărău
Abstract: Using as starting point references to the Kano, Nigeria research study, the paper will analyze the inherent conflict of interests and the necessity of a disclosure policy in conducting international public health research studies on human subjects. According to newspaper reports in both the US and Nigeria, such as the Washington Post investigation, the giant company Pfizer conducted a research study during a meningitis epidemics in Nigeria, without the approval of the relevant regulatory authorities, without an ethics approval or informed consent (Emanuel Ezeome and Christian Simon). The Kano study’s impact is deepened by the context in which the research was conducted and the behavior of the parties, both the drug company, the investigators, physicians and not least, the federal government of Nigeria and the Kano state. Reportedly, the Nigerian ethics review was not proper and there are allegations that a local investigator backdated the certificate (Report of the Investigation Committee on the Clinical Trial of Trovafloxacin) . Accusations of fraud have been formulated in relation to the letter that was provided through Dr. Dutse. All this parties failed to carry on with their legal and moral attributions, which resulted in inflicting harm and failure to protect the most vulnerable of all subjects: children. The paper will address the ethical questions surrounding the dynamics between researchers and funding agents and correlate them with a potential conflict of interest and the disclosure policy rule.
Conducting biomedical research is a dynamic activity that raises many issues especially when conducted on human subjects. The safety of the individuals enrolled in research should be a priority for the researchers, as it is enforced by national and international regulations. Nevertheless, other aspects of ensuring a voluntary and informed participation are as important, because not only the physical welfare of the individuals should be protected, but also the rights they have. Being fully informed when agreeing to participate in research is an essential process in ensuring persons’ autonomy and voluntariness. An intricate question arises regarding the disclosure degree and the researcher’s duty to reveal conflicting interests.
Conflict of interests in research
International research poses additional problems concerning ethical research behavior and conflict of interests, especially when conducted in developing countries. The different actors involved, scientists, research staff, physicians, fellows, the funding source and also the publishing journals, are bound by multiple interests, which can conflict with research ethics’ standards. Depending whether the country where the study is being carried has research regulations in place, there might be an inclination to produce results by overslaughing ethics concerns. The risks and the benefits, but most importantly the potential financial gains that a new drug could bring for the pharmaceutical funding company and the researchers, can have a negative impact on the study. If researchers and all other parties that have a degree of control over the study do not disclose conflict of interests and make from the potential gains their main goal, the research will be biased and probably conducted in an unethical manner.
Before 1980, the collaborations between academic researchers and the industry were rare, but as research was increasing, these ties became stronger. The final research product needed the free market’s system in order to reach the broader public and to make use of the scientific knowledge (Resnik, 2005). As a direct result, the Bayh-Dole Act was passed to facilitate the public-private research cooperation, which by 1995 leads to a general encouragement for researchers to consult with industry. The intricacies of such collaborations, issues regarding disclosure, bias and physicians’ potentially conflicting interests were brought to public debate after the death of Jesse Gelsinger, a patient who agreed to participate in a public-private gene therapy trial.
The public places its trust in researchers’ methods and way of conducting research with high regard for moral standards. However, there are cases when ethical conduct is overlooked, either intentionally, with the prospect of attaining academic recognition or financial gains, or unintentionally (Soskolne et al, 2009). Research misconduct represents the failure to engage in research with integrity and consists of falsifying data, misuse of subjects, plagiarism, deviations from reporting. As it is mandatory to report conflict of interests, failing to do so can be classified as scientific misconduct. Nevertheless, complying with the rule of reporting such conflicts does not imply that the research has been ethically conducted.
International research particularities
In international research the conflict of interest issue bares a more significant degree of complexity, as the danger of using human subjects and exposing them to unnecessary harms is greater. Several studies have been subjected to such criticism as they involved researchers and big pharmaceutical companies that conducted studies in questionable situations. The motivation behind carrying studies that pose a high degree risk for the subjects lays in the potential financial profits of launching new pharmaceuticals. It is questionable if researchers can maintain their integrity in case of vested interests, such as a predisposition towards bias and providing the sponsor with the expected results. Self-interest arises when researchers receive consultancy fees from the private funding companies, are hired by them or are holding stocks within the company.
One of the most controversial cases that poses conflict of interests issues in an international context is the Trovafloxacin (trovan) study that took place in Kano, Nigeria. The trial was conducted by Pfizer Inc., a large pharmaceutical company that tested an unapproved drug on children during a meningitis epidemic (Lenzer, 2006). The trial has raised questions of whether researchers were motivated by profit over the cause of saving lives or they only took advantage of a meningitis epidemic in a developing country to conduct a study in children for which they did not get approval in the U.S.
This study can be used to analyze and exemplify the complexities of academic-private entanglements and the thin line between acknowledging conflict of interests and having ones integrity undermined by biasing influences. Not following good research rules can produce dangers to research results that could lead to compromising all study findings (Porter et al, 2009).
Ethical issue(s) in international public health research
Transparency regarding conflict of interests is a key aspect in ensuring conformity with the regulations and ethical standards and a failure to disclose inflicts negative consequences on the research environment. A suspicious and untrusting atmosphere is created and the public could adopt a critical attitude towards academics and industry collaborations (Nature, 2010). Conflict of interests is an issue hard to address because it is relative and does not necessarily imply that if it exists then the research is unethical. The negative effects of such existing conflicts have their source in researchers’ internal processes and are therefore hard to identify. In order to determine if the arising conflict of interests produce unethical research, they have to be correlated with other ethical issues.
Conflict of interests could account for a number of ethical issues and disregard for international guidelines surrounding the Trovan trial. The study took place in Kano, Nigeria, in a particular situation during a meningitis outbreak. This aspect is relevant in determining if developing countries participated and if there was a need for an intervention in those countries. According to Macklin, research should be first conducted in developed countries, in order to avoid adopting a paternalistic approach (Macklin, 2004). At the same time, it is hard to identify if different regulations and guidelines adopted by the researchers country of origin and the study country should have been taken into considerations in designing the study and applying it. In some of these countries there may not be the resources to develop a national regulation framework or they may differ from the international ones or from the existing legislation in the investigators’ country (Bhutta, 2002). International guidelines, though not binding legally, can have moral weigh and shape the way in which the industry and the funding agencies conduct research.
One of the most stringent issues regarding the study is related to the study design and the gathering of a research team only six weeks after the meningitis outbreak was reported. The study team was lead by Scott Hopkins, M.D., who received the support of Abdulhamid Isa Dutse, a Nigerian physician. Given the circumstances of approving the study after Trovan was not approved by FDA for use in children in the US and the following accusations regarding harm and injuries to the subjects, questions regarding the conflict of interest and disclosure to the study participants and/or their guardians, appear.
The trial raises the question of whether the researchers sought profit over the cause of protecting the subjects and complying with international guidelines when conducting research in a foreign country. Furthermore, the study has highlighted issues that not only relate to ethics but also concern existing international requirements in research. This refers to understanding the complexities of conducting international research, observing issues or problems that are faced in the foreign country and adopting an approach that is ethically and legally sound. Issues regarding the study methods and the motivation of the researchers when there are acknowledged conflicts of interests reflect possible violations of the standing principles of ethics that govern good research. Failure to present the serious adverse events and attribute or disclose the results of analyzing the connection between the adverse events and the tested drug, suggest lack of transparency. This may be due to poor safety methods or monitoring processes included in the study design. These violations could represent an example of how in international research nations can be used as ‘experimental’ grounds for other nations to test products which could be more beneficial or affordable in the researchers’ countries (Mills and Singh, 2007).
Conflict of interest
Conflict of interest issues arise when the researcher cannot maintain his scientific objectivity and becomes biased due to the antagonistic claims that the industry, the research community, the researcher personally and the subjects have. Tensions and competition over study control occur and it can be argued that it is preferable if these problems should assume the responsibility in resolving them without compromising subjects or data.
Research requirements in US refer to an IRB and FDA approval for research studies, to which supplemental compliance steps may be necessary. Conducting research studies in an international setting imposes the existence of an ethics committee approval from the country where the study will take place and the foreign government’s permission previously to obtaining the IRB and FDA approval in the investigator’s country of origin. The FDA approval in the Kano study is questionable because in order for Pfizer to obtain it, it had to provide proof that the study had passed through an US IRB and had the approval of a Nigerian ethics committee beforehand (Report of the Investigation Committee on the Clinical Trial of Trovafloxacin). Reportedly, the Nigerian ethics review was not proper and there are allegations that a local investigator backdated the certificate. Nevertheless, the study had an US IRB approval, but this is flawed and was obtained based on documents that are questionable and could be proven false. Accusations of fraud have been formulated in relation to the letter that was provided through Dr. Dutse (Ejembi, 1998). Thus, though the proof that the conflict of interests influenced the study negatively by exercising a sufficient power on Dr. Dutse’s mental state that led to forging official documents is not sound enough, the public can tend to see these conflicts as highly unethical.
Given the speedy approval of the study, the short period of investigation and the reduced follow-up time, doubts regarding scientific integrity have a ground. Identifying and exposing the potential biases created by the funding agent’s interests, is essential in maintaining a certain degree of objectivity. Doubts over the accuracy of a clinical study reverberate into mistrust of the funding company and of research, in general, which in turn translates into liability for the company.
Keeping track of conflict of interests and ensuring that no bias is created is firstly the responsibility of the researcher and the academic’s institution that supports him and then the industry’s. Handling the confidentiality agreements between the researchers and the funding organizations and monitoring the exact payments is a difficult process. Researcher’s integrity, the trust placed in them and, in some cases, whistleblowers, is the first steps in guaranteeing ethical behavior in research (Kaiser, 2009).
A need for policy change
Following such conflicts and trespasses of research ethics, the National Institutes of Health shifted its stand on conflict of interest in 2004. It banned its scientists from having stock shares or options and receive consultancy fees from the biotechnology or pharmaceutical industries. The same year, issues regarding conflict of interests surfaced in relation to a controversial study published in the Lancet. The published article concluded that there are possible links between triple mumps, measles and rubella (MMR) vaccination and autism, but failed to mention that the leading investigator and Senior Author did not disclose potential financial conflicts (Fleck, 2004). Ethical questions arise concerning the way to ensure that all conflict of interests are disclosed and how much responsibility do all involved parties have.
In the MMR affair, Lancet decided to publish a retraction, along with statements from researchers, trying to justify the scientific behavior as being ethical. However, the Senior Author together with two other researchers did not subscribe to it. The implications of publishing inaccurate data lead to reluctance to vaccine and decreased immunization coverage. In this case, like in many others, the conflict of interest is in fact the internal motivation that drives research misconduct. The interpretation of research data could have significantly negative effects on public health. Conflict of interest alone is not unethical, but it can fit into the research misconduct definition as soon as it is the engine that drives scientific deviations from ethical standards and regulations and the MMR study reflects this.
Cooperation between industry and academia can give way to many speculations about failure to disclose financial gains and affect the public’s trust in researchers. Ensuring transparency not only that it would foment the trust that individuals place in researchers, but it will encourage research participation and eliminate possible doubts regarding misconduct. This, along with recent controversial studies and failure to report conflict of interest, encouraged the NIH to draft more strict regulations for its investigators who have industry ties. A 2004 congressional investigation led by Senator Charles Grassley questioned the sufficiency of existing regulations and proposed that institutions should detect and monitor their member’s outside incomes. As a result, the NIH banned in-house scientists from offering consultancy services to industry. These limitations were far more stricter than those for academia and extramural researchers began to be sought by institutions, based on their ties with potentially funding companies.
During the congressional investigation several cases of unreported payments from pharmaceutical companies have been discovered and disciplinary actions have been taken, in some cases. Therefore, the academia is looking to make the conflict policies tighter and to undergo a reform.
In 2010, the U.S. main leading teaching hospitals, united under the Partners Health-Care organization started a process to review the financial benefits that official members of the institution could receive from private companies that engage in business relations with the institution (Lo, 2010). At the same time, faculty members affiliated to the institution will not be allowed to act as speakers following private companies’ solicitations. All such understandings were to be reviewed by a conflict of interest committee.
Fundamental issues regarding conflict of interest
Scientific misconduct often can derive from conflict of interests, especially in academia-industry collaboration. These conflicts spark from different goals, as the academia is supposedly seeking to improve public health for the benefit of the many, while the industry is driven by the prospect of profit. It is essential to place trust in the researcher’s, staff’s, institution’s integrity, but also to enforce disclosure regulations. If there should arise, ethical issues related to conflict of interests should be carefully controlled and resolved. Especially when conducting international public health research, non-compliance disclosure policies can determine negative effects and endanger the study and probably all future international research in that country. Population’s morals, culture, standards and approaches to bioethics vary significantly across the world. Failing to show scientific honesty and admitting the ties with the pharmaceutical company financing the study could increase the level of suspiciousness towards foreign researchers.
Permissive legislation and poor scientific standards will affect research in general, by discouraging individuals to enroll in studies and by creating this myth of “bad science”. At the same time, the strictest framework will discourage academia and industry partnership and research will not develop to its full potential. Conflict of interests poses several specific problems and can be deemed unethical only in relation with other failures to follow ethical conduct in research. It is the motivation behind the misconduct, which makes it difficult to uncover and address.
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