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I noticed that your book does not index the term “conflict of interest.” This seems to me to be an important consideration when examining the scientific and ethical decisions that determine whether or not a clinical research trial moves forward. A recent issue of the Journal of the American Medical Association (May 2, 2107) focused on issues of conflict of interest in medicine and research, but they seemed not to address issues you raised in “Lethal Decisions.”  JAMA articles discussed conflict of interest that focused on payments and other benefits that might be given to physicians and researchers from pharmaceutical companies and other commercial healthcare related sources. One article pointed out that, “Meta-research studies have shown that financial conflicts of interest, including commercial research sponsorship, are associated with publication of research outcomes that favor the financial interest. The association between financial conflicts of interest and favorable outcomes has also been established for meta-analyses, systematic reviews, editorials, and letters to the editor. The influence of financial ties on research outcomes appears to be due to a variety of types of biases. For example, research agendas can be influenced by funding sources.” But the JAMA articles implied that the financial sources were primarily industry related.

I believe you are trying to say that concern about conflict of interest can result from financial gain, whether direct or indirect, and should be considered no matter the funding sourceindustry, government, USPHS, NIH, charitable organizations.  

 

By B. Rush MD

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One of the most frequent questions asked by individuals who have read Lethal Decisions is, “Are there not institutional and government oversight committees that review the priorities for clinical research as well as the ethical and scientific standards that govern their conduct?” The answer is theoretically yes, but there are exceptions. Failures are many and some of them have been particularly egregious, resulting in the public apologies to those who have been wronged from US Presidents Clinton and Obama (Timeline of Ethics in Clinical Research, Ghosts of Tuskegee)

The official mission of National Institutes of Health (NIH) is, “…to acquire new knowledge to help prevent, detect, diagnose, and treat disease and disability.” NIH is composed of 27 different Institutes and Centers with individual research agendas and an annual research budget of more than $30 billion. The funds are allocated to intramural research (research conducted within and by NIH itself) and extramural research (research conducted by research organizations and individuals within academic institutions). With so much research conducted by large numbers of individuals, organizations, and academic institutions, and with such large amounts of funding devoted to clinical research, it is unfortunately relatively easy to identify specific research studies that fail to conform to the stated mission of NIH.

It is true that institutional review boards (IRBs) have been established to review, approve, and monitor clinical research involving humans but the sheer volume of new research protocols and the lack of expertise of individual IRBs to provide adequate ethical and scientific review assures that many clinical research protocols will be approved that violate ethical and scientific principles. (Are IRBs Uninformed About Informed Consents)

Since review boards are most often within the same institutions that are applying for research funds, and since they indirectly or directly benefit from the funds through overhead costs, there is an inherent conflict of interest in the approval process. The amount of money obtained from NIH for indirect (overhead) costs is significant reaching hundreds of millions of dollars for individual institutions and more than 5 billion total in 2013. The percentage of indirect costs range from 20% to as much as 103%.[1] It would be difficult to believe that this amount of money would not influence the approval process of clinical research. Added to the influence of the amount of funding is the influence of prestigious researchers and institutions.

All this is worrisome. Recently the priorities for deciding what clinical research is important and what research is duplicated or necessary have been called into question [2,3]. Further, some academics have questioned the validity of clinical research results indicating that many of the conclusions are false and cannot be replicated by other investigators [4]. Whether this is a new phenomenon related to large increases in the availability of research funds and/or the proliferation of research discoveries as a result has not been thoroughly analyzed. Regardless of the cause, increasing pressure is put on IRBs to modify the criteria for ethical standards to facilitate more rapid approval while at the same time ignoring the fact that many IRBs do not have the expertise to conduct an adequate scientific review [5]. (Institutional Review Boards, Are IRBs Uninformed About Informed Consents)

In Lethal Decisions we have identified specific instances where the scientific review and the ethical review of clinical research has failed and has resulted in exploitation of vulnerable women and children in poor countries. These have not reached a level of widespread public attention, and in spite of numerous attempts to obtain additional review by NIH, IRBs, and even the US Government Office of Human Research Protection, the insular nature of the current review process virtually excludes public scrutiny. Solutions are available, the most important of which are to avoid conflict of interest and ensure that the expertise of the IRBs is sufficient to provide credible ethical and scientific evaluation. Rather than the current institutional review board process it is likely that independent review boards, unaffiliated with the academic instruction seeking approval, will be required.

 

References

[1]    Ledford H. Indirect costs: keeping the lights on. Nature 2014; 515(7527): 326-9.

[2]    Begley CG, Buchan AM, Dirnagl U. Robust research: Institutions must do their part for reproducibility. Nature 2015; 525(7567): 25-7.

[3]   Begley CG, Ellis LM. Drug development: Raise standards for preclinical cancer research. Nature 2012; 483(7391): 531-3.

[4]    Ioannidis JP. Acknowledging and Overcoming Nonreproducibility in Basic and Preclinical Research. Jama 2017.

[5]    Faden RR, Beauchamp TL, Kass NE. Informed consent for comparative effectiveness trials. N Engl J Med 2014; 370(20): 1959-60.

"Primum Non Nocere." But Who Should Protect Research Subjects From Harm?

There have been numerous provocative questions sent to me since the publication of my book. A recurring theme relates to the issue of whether physicians, especially those caring for patients with HIV in the US, should be engaged in clinical research of HIV in vulnerable subjects in poor countries. To many of the readers it seemed incomprehensible that physicians would do anything less than provide the best of care for the patient, whether in the US or in Africa. It is interesting that most of these questions came from people who are not directly engaged in clinical research and in fact, individuals who are not in the medical professional at all, but can visualize themselves as the patient or research subject. Their questions can be summarized as, “How can it be ethical for a healthcare professional providing the best standard of care for HIV infected individuals in the US, and seeing their remarkable return to health (the Lazarus effect), subsequently conduct a research study in poor countries knowing from personal experience that withholding treatment, or providing inferior treatment, will result in HIV advancing to AIDS and death?” 

To nonmedical individuals the answer is obvious. They often refer to Hippocratic Oath, taken in some form by most graduates of US medical schools. In particular they ask, “Isn’t part of the Hippocratic Oath the ethical responsibility to ‘First do no harm.’” (Latin: Primum non nocere).

The original Hippocratic Oath was written in Greek in the late fifth Century BC and was perhaps the earliest doctrine defining the ethical relationship between physicians and their patients. Several modern versions adapt the original concepts to contemporary circumstances e.g. “Into whatsoever houses I enter, I will enter to help the sick, and I will abstain from all intentional wrong-doing and harm, especially from abusing the bodies of man or woman, bond or free” adapted to “I will prevent disease whenever I can but I will always look for a path to a cure for all diseases.” (Louis Lasagna, Academic Dean of the School of Medicine at Tufts University, 1964)

In her book, For the Good of Mankind? The Shameful History of Human Medical Experimentation, Vicki Oransky Wittenstein wrestles with the same question as she recounts the numerous instances of unethical research conducted by US physicians when they engaged in both care for patients and research in patients. She observed, “By the 1870s new scientific knowledge of bacteria, drugs, and vaccines spurred demands for human experimentation. Doctors were excited about innovative technologies, such as x-rays and stomach tubes. Suddenly, there were promising new treatments and cures. And humans were needed to test them. The doctor’s role became forever transformed. No longer was a physician simply a practitioner who observed and attempted various cures. Now the ideal doctor was a scientist. His authority and knowledge came from experimentation.” 

How then can a physician both advocate for the best treatment for a patient and at the same time conduct research to evaluate treatments which are known in advance to be inadequate in controlling disease progression resulting in harm or death? There are several explanations given by those defending the dual role of a physician. One is that it is ethical to compare two different treatments because the treatments are not available in the country where the research is being conducted. This argument is troublesome because first, the researcher has the resources to provide the best treatment to the research subject second, if the treatment is not available then participation in the research study is of no lasting benefit to the research subject and third, the logical extension of this rationalization is clinical research could be conducted, even including placebos, if a country were chosen that had little to no healthcare or was politically unstable. The ethics under these circumstances becomes entirely relative— determined by whether the physician is a caregiver or a researcher or whether they reside in a wealthy country or in a resource poor country.

Another argument is that the physician’s role when conducting clinical research is to maintain the scientific integrity of the study by ensuring that the research outcome is statistically and/or scientifically credible and it does not benefit the research subjects if the study is poorly designed or executed. Again, this is a difficult argument to accept when clinical research studies result in significant harm such as HIV advancing to AIDS, or as pointed out in the book, when the endpoint of the study is death which could be prevented—the physician becomes the defender of science and the patients are sacrificed for the sake of science.

I believe that the questions from the readers are valid and must be addressed by the clinical research community. Importantly, who should protect research subjects from harm? If that is the responsibility of a physician caring for patients should it not also be the responsibility of the physician engaged clinical research? The current weaknesses in the ethics and science of clinical research stem from the conflicts of interest associated with the conflict between a dual role of physicians as protectors of patients from harm vs protection of science; inadequate scientific and ethical review of clinical research protocols, especially those conducted in poor countries; the lack of truly representative advocates for the patient welfare and protection. 

 

Arthur Ammann MD

Lethal decisions - what must be done now to correct them?

Isn’t it true that by 1996 all of the means of preventing and treating HIV were in place but that public health organizations and certain clinical researchers failed to implement them. By 1998 , in the US and Europe, where implementation was occurring quickly, new HIV infections were rapidly falling, individuals treated with highly active antiretroviral therapy (HAART) were living longer/healthier lives with fewer clinical visits and hospitalizations, and new HIV infections in infants were disappearing. Instead of implementing successful measures for prevention and treatment, WHO made the unscientific and unprecedented recommendation to delay treatment. WHO, UNAIDS, and certain clinical researchers, in defiance of HIV experts, incorrectly hypothesized that women and children in Africa and other poor regions of the world might not respond in the same manner to the treatments that were being successfully used in wealthy countries. The delays allowed the HIV epidemic to continue at a rate that cost the lives of millions over the decades that followed.

By B. Rush MD

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