With the Human Genome Project complete for over a decade, the benefits of genomic data are now trickling into the business and practice of medicine. The passage of the Genetic Information Non-Discrimination Act in 2008 and the Affordable Care Act in 2010 have set the rules of the road, and made the critical investments necessary to lay the ground work for new advances in American genomics research. In the coming years, as the price of whole-genome scans come down and the medical community enters a new era of personalized medicine, we will have a new set of tools with which to study the origin of diseases affecting specific populations.

Genetics can reveal useful information about an individual’s health status, but they can also reveal unexpected information about group identity. The Latino community is both genetically and culturally diverse; and as gene-based medicine advances, Latinos will need to make sure that new medical technologies serve that diversity.

I believe that to capture the necessary genetic diversity to study the drivers of health disparities, America’s research agenda must include a broad swath of the Latino population. The National Institutes of Health (NIH) has so far committed $61 million to observe more than 16,000 Latinos over six years through the Hispanic Community Health Study, the nation’s largest longitudinal study of Latinos. Yet there is still so much more to be gained by incorporating the study of Latino populations into other research projects. But the research process does not end with research funding decisions. Clinical and biomedical research practices must also be more responsive to patients, who should be empowered to tell researchers and doctors what kinds of questions they want research to answer.

Every step of the biomedical research process — from genetic testing to clinical trials — can be made more inclusive, addressing the broad range of genetic and economic diversity in the U.S. The Latino community will need to work together with research institutions and private companies to overcome the barriers that exist with regards to inclusive biomedical research. These barriers range from economic inequalities and provider biases to lack of awareness, distrust, or cultural and linguistic differences.

Doctors can play a major role in making Latino patients more fully aware of clinical trials or genetic studies by communicating the possible risks and benefits. Doctors should also inform patients of the privacy protections afforded by laws like the Genetic Information Nondiscrimination Act and the Health Insurance Portability and Accountability Act in order to build trust and allay fears of discrimination in employment or insurance. This kind of communication will become a necessity in the future as medical research and clinical care become ever more closely intertwined.

The Department of Health and Human Services has already laid out recommendations for more inclusive research practices in a 2009 report. It recommends the building of a more diverse scientific and health care workforce; outreach to trusted community members who can promote the benefits of research; and the building of cultural awareness surrounding diet, work-life balance and access to resources. The report also elaborated on a research model known as “community-based participatory research,” which would involve the Latino community in the design and conduct of the research, creating a sense of community “ownership” over the results and a greater adherence to the outcomes.

These practices have the potential to create actionable, results-oriented research processes that incorporate the histories, lifestyles and values of Latino patients. The last thing we want is for the research establishment to become overly reliant on a single indicator, measurement or classification that does not account for the needs of individuals in the Latino community and other communities. Only by making sure that every community’s voice is heard, can we be sure that personalized genetic medicine will truly be personalized.

This op-ed is reposted from the Huffington Post. Michael Rugnetta is a former research assistant for Science Progress and author of the new report, “Addressing Race and Genetics: Health Disparities in the Era of Personalized Medicine” .

Two scientists brought this suit to enjoin the National Institutes of Health from funding research using human embryonic stem cells (ESCs) pursuant to the NIH’s 2009 Guidelines. The district court granted their motion for a preliminary injunction, concluding they were likely to succeed in showing the Guidelines violated the Dickey-Wicker Amendment, an appropriations rider that bars federal funding for research in which a human embryo is destroyed. We conclude the plaintiffs are unlikely to prevail because Dickey-Wicker is ambiguous and the NIH seems reasonably to have concluded that, although Dickey-Wicker bars funding for the destructive act of deriving an ESC from an embryo, it does not prohibit funding a research project in which an ESC will be used.

To translate this a little, Lamberth held that all federally-funded ESC funding violates the Dickey-Wicker Amendment, which prohibits the use of federal funds for “research in which a human embryo or embryos are destroyed.” Even though no federal money goes to studies that actually destroy an embryo, Lamberth concluded that such research requires scientists to build upon previous research that involved the destruction of an embryo, and that this is not allowed.

Lamberth’s decision, however, cannot be squared with Supreme Court precedent. Under the Supreme Court’s decision in Chevron v. NRDC, judges are normally supposed to defer to an agency’s reading of a federal law unless the agency’s interpretation is entirely implausible, and the Obama administration quite plausibly read the Dickey-Wicker Amendment to only prohibit federal funding of the actual destruction of an embryo — not federal funding of subsequent ESC research. Accordingly, the court of appeals reversed.

Today’s decision is a very hopeful sign that Lamberth’s questionable understanding of this law will no longer undermine stem cell research. Both of the judges who joined today’s majority opinion are conservative Republican appointees. Judge Douglas Ginsburg is a hardcore tenther who once called for a return to an Depression-era vision of the Constitution that struck down child labor laws and other very basic legal protections. Judge Thomas Griffith was appointed by George W. Bush.

Their decision did leave open a slight possibility that Lamberth could try to suspend stem cell research once again. The appeals court expressly decided not to weigh on two alternative claims by the plaintiffs, including a claim that federal ESC funding is illegal “research in which a human embryo or embryos are . . . knowingly subjected to risk of injury or death,” because these claims were not first considered by the court below. Nevertheless, the appeals court made clear that “the plaintiffs have not identified, nor have we found, any precedent for upholding a preliminary injunction based upon a legal theory not embraced by the district court.”

So it appears very likely, if not entirely certain, that stem cell research will ultimately be upheld against all challenges.

Ian Millhiser is a Policy Analyst and Blogger at American Progress. This is reposted from the Wonk Room.

In the last year, scientists all over the world have been closely examining the DNA of many different preparations of human pluripotent stem cells, and they all have come to a similar conclusion: they have mistakes in their DNA sequences (publications are listed below). This is not surprising, because every time a cell divides, there’s a chance that the DNA sequence doesn’t get copied perfectly. This happens every day in our own bodies as our cells renew themselves; our cells can tolerate a lot of little changes without causing problems. DNA mistakes are a normal part of life.

However, not all errors in DNA are benign. Cancers involve changes in the DNA that make cells grow wildly out of control, but these changes are unusual—such as the breaking of chromosomes, inactivating genes that suppress tumor formation or hyper-activating genes that enhance growth. Even these changes don’t usually cause problems because our immune systems recognize these grossly abnormal cells and wipe them out.

Why do pluripotent stem cells have errors in their DNA? The techniques we use require that the cells be expanded from a single cell to a million cells before we can examine their DNA. This means that they have to double at least 20 times, which makes 20 chances for mistakes to be made in copying the DNA sequence. Some errors give the cells a growth advantage—think of evolution and survival of the fittest. If a cell grows just a little faster than its neighbors, eventually, over many cell doublings, it will become the dominant cell type in the culture. This dominant cell type is the one that we detect by sophisticated DNA analysis methods.

So, there are errors in DNA in cancers and there are errors in both human embryonic stem cells, which are derived from embryos, and induced pluripotent stem cells, which are derived from adult tissue. Should we be worried? I think we should be careful, but there are several reasons why we shouldn’t be worried, yet.

First, by far the greatest uses of pluripotent stem cells will not involve transplanting them to humans. Cultures of these cells will be valuable for understanding human disease. They will be very helpful for drug development, where they can be used to improve the testing of drugs in culture dishes before they are tested in people. DNA abnormalities are not important in cultured cells, unless they affect some critical function that is necessary for the assays and experiments that researchers use.

Second, the recent reports of DNA abnormalities in these cells will encourage other scientists in both basic and clinical research to look more closely at the DNA of the cells they are using. This is an important step forward that will improve the quality of stem cell research everywhere.

Last, these new reports strongly argue that when cells are destined to be transplanted to people, they must be checked for abnormalities that are related to cancer. We have not yet determined whether any of the aberrations we have seen in stem cells actually increase the chances that they become cancerous. Small mistakes in DNA are normal, as pointed out earlier. They do not harm us. We are working to identify what, if any, DNA changes reported in the recent scientific papers are dangerous. After we do this, we will know what to worry about.

Jeanne F. Loring is Professor and Director Center for Regenerative Medicine in the Department of Chemical Physiology at The Scripps Research Institute.

References

Gore, A., Li, Z., Fung, H.L., Young, J.E., Agarwal, S., Antosiewicz-Bourget, J., Canto, I., Giorgetti, A., Israel, M.A., Kiskinis, E., Lee, J.H., Loh, Y.H., Manos, P.D., Montserrat, N., Panopoulos, A.D., Ruiz, S., Wilbert, M.L., Yu, J., Kirkness, E.F., Izpisua Belmonte, J.C., Rossi, D.J., Thomson, J.A., Eggan, K., Daley, G.Q., Goldstein, L.S., Zhang, K., 2011. Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63-67.

Hussein, S.M., Batada, N.N., Vuoristo, S., Ching, R.W., Autio, R., Narva, E., Ng, S., Sourour, M., Hamalainen, R., Olsson, C., Lundin, K., Mikkola, M., Trokovic, R., Peitz, M., Brustle, O., Bazett-Jones, D.P., Alitalo, K., Lahesmaa, R., Nagy, A., Otonkoski, T., 2011. Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58-62.

Laurent, L.C., Ulitsky, I., Slavin, I., Tran, H., Schork, A., Morey, R., Lynch, C., Harness, J.V., Lee, S., Barrero, M.J., Ku, S., Martynova, M., Semechkin, R., Galat, V., Gottesfeld, J., Izpisua Belmonte, J.C., Murry, C., Keirstead, H.S., Park, H.S., Schmidt, U., Laslett, A.L., Muller, F.J., Nievergelt, C.M., Shamir, R., Loring, J.F., 2011. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8, 106-118.

Historically, neuroscientists have had a range of tools to manipulate and observe neural circuits in the brain. These techniques, however, have often lacked the ability to isolate the contribution of specific neurons or types of neurons to the overall network. With optogenetics, researchers can now discretely control neuronal activity by using pulses of light to activate or inactivate specific populations of neurons. These tools are giving neuroscientists the potential to unlock many of the remaining mysteries of how individual groups of cells in the brain control perception and behavior.

The term optogenetics was first coined by one of its pioneers, Karl Deisseroth at Stanford. The technique, which recently won the 2010 Nature Methods method of the year award, makes use of a group of ion channels and other proteins discovered in bacteria and algae called “opsins.” These proteins are light sensitive and can therefore be activated by pulses of light of an appropriate wavelength. Depending on the opsin expressed, this will either excite or inhibit the neurons. The expression of opsins in mammalian neurons is achieved by inserting the encoding DNA into the target cells, which then produce the opsin proteins. The process of DNA addition is called transfection, and is typically accomplished by using a specially selected virus as a carrier to deliver the new DNA. Variants in the viral delivery and DNA coding sequence allow for specific subtypes of neurons to be targeted. Once opsins are expressed in the neurons, the firing rate can then be controlled in vivo by light from an implanted fiber-optic cable or through a small window in the skull.

This technique gives researchers enormous flexibility and control of the behavior of specific cell types in a given brain region. Spatial resolution comes from the location of the injection and the neural cell-type specificity of the viral vector. Temporal control is produced by the frequency of the delivered light pulses, which via the opsins drives the cells to fire at the same frequency as the pulses of light, or alternatively prevents them from firing at specific times.

For example, a group of neurons in a specific area of the brain could be transfected with an opsin that excites the cells, and then is activated at various frequencies to see how this changes the animal’s perception of a stimulus directed to this area of the brain. It can also be used to completely silence a set of neurons during specific behavioral tasks in order to determine the effect of those neurons on that behavior. With this level of precise control, many systems neuroscience questions that had imprecise answers previously can now be addressed by observing awake, behaving animals.

Some of the recent articles published using this technique have demonstrated new insights into previously vexing problems in neuroscience. For example, there has been a tremendous amount of debate about the mechanism of deep brain stimulation, or DBS, utilized to treat movement disorders resulting from Parkinson’s disease.

This treatment uses electrical stimulation targeted to a region of the brain involved in motor output and control, and its mechanism of action is not well understood. It has previously been difficult to assess whether this intervention affects the neurons nearby the electrode directly, the inputs to those neurons, or the targets of the output from these neurons in this circuit.

Researchers utilized a mouse model of Parkinson’s disease and optogenetics to dissect the circuits of the brain involved in the response to electrical stimulation of the targeted area. Their results suggest that rather than leading to a simple excitation or inhibition of the neurons in the targeted area, DBS is activating connections arising from another area, and that this activation is necessary for the effectiveness of the treatment.

Another recent article demonstrated the importance of a single type of neuron to cocaine addiction in mice, suggesting a target for future clinical interventions. Because this particular type of neuron represents only 1 percent of the cells in the investigated area (the Nucleus accumbens), they have been difficult to study up until now, and their function has been the subject of much debate in scientific literature. The precise genetic targeting of the opsins allowed for just this population of neurons to be manipulated during the experiment.

The implications of this new technology for the field of systems neuroscience are profound. Its potential is being realized as the technique is implemented more broadly and more difficult circuits and systems are teased apart. A better understanding of the circuits underlying psychiatric and neurological disorders will hopefully also lead to improved clinical treatments.

One question for the future is whether or not these new techniques may be directly used to treat some human disorders as well. For example, a future version of DBS might be coupled with optogenetics to provide more specific targeting of cells in the basal ganglia, directly affecting the firing patterns of the cells responsible for disrupted movement in Parkinson’s disease. In addition, research efforts in the past year have successfully demonstrated the feasibility of utilizing optogenetics in nonhuman primates. Use of this technology in humans, however, would combine the ethical dilemmas of gene therapy with those of brain-machine interfaces such as DBS. While the road to safe and efficacious use of this technology for treatment in humans is uncertain, it is already providing great benefits to scientists in understanding circuits and their complex regulation in the brain.

As Congress turns back this week to the continuing resolution to fund the government through the end of fiscal year 2011, it is important that we keep in mind the essential role of federal funding in facilitating scientific advances like optogenetics. The original project in Dr. Deisseroth’s laboratory, the first attempt to integrate the microbial opsins into mammalian cells, was funded by a grant awarded by the National Institutes of Mental Health and National Institutes of Health, as are many of the above-mentioned projects that followed. The first scientists describing the light-sensitive proteins in 1971 could not have predicted that their findings would lead to such a profound change in neuroscientific research. These discoveries are one of the best arguments for continuing to fund basic biological research as well as more translational research: We often don’t know where the breakthroughs are going to come from that will be the basis for the next generation of treatments for disease, or that will allow us to better understand the complex systems that make up our daily habits, thoughts, and decisions.

John A. Wolf, Ph.D., is a neuroscientist at the Center for Brain Injury and Repair in the Department of Neurosurgery at the University of Pennsylvania.

More than 60 years later, George Annas, the distinguished professor of law, bioethics, and public health, finds himself revisiting a similar defence for torture, spying, and violations of basic American constitutional rights. The need to win the “war on terror” was a key rationale offered by members of the Bush—Cheney administration as they rode roughshod over basic civil and human rights in the grim shadow of the 9/11 slaughter. Annas persuasively argues in Worst Case Bioethics that basing policy on extreme nightmare possibilities leads to a distortion of fundamental ethical principles and legal protections.

Whether fighting declared enemies in war, terrorism, and drug cartels, or fighting such threats as a pandemic or cancer, governments and their leaders cannot let fear and paranoia set the moral tone for such battles. Annas offers two defences of his claim that worst case thinking has distorted military, public health, and clinical ethics. The first is that fundamental human rights cannot be compromised out of worries about remotely possible scenarios of utter destruction and death. The second is that the avoidance of death, and the corresponding need to save lives, does not justify throwing our moral compass out the window.

I find these arguments persuasive but only to a point. It is absolutely true that the USA’s concern with national security has led to pressures upon US medicine and psychology to become involved with torture, cruel prisoner interrogations, and forced feeding practices of incarcerated individuals that violate the fundamental ethical norms of these professions. War, as the Nuremberg judges rightly concluded, does not mean all ethical bets are off. Annas rightly condemns contemporary arguments that permit the cavalier disregard of fundamental values and rights. Yet, despite endless disputation since 9/11, we still do not have a carefully articulated set of moral algorithms to guide medical practice…

You can read the rest of this article at the Lancet.

Arthur Caplan, PhD, is the Director of the Center for Bioethics and the Sidney D Caplan Professor of Bioethics at the University of Pennsylvania.

Lots of folks seem to think we have too much regulation of drugs and devices already—among them Paul Howard at the Manhattan Institute and Scott Gottlieb at the American Enterprise Institute—so much so that it is choking innovation to death. But, if that is so, then why are there so many scandals?

One possible answer is that the companies know they have problems but sit on that knowledge. If that’s sometimes (or oftentimes) the case, then we need a regulatory system that can get around that kind of immoral behavior. We don’t have that system.

What we have is a regulatory system that is too skewed toward looking at the earliest stages of research. Moreover, the way it is designed makes recalls almost inevitable. The diabetes drug Avandia is the latest in a long parade of failures of our current post-clinical trial drug approval process.

Avandia went through the usual approval process with the U.S. Food and Drug Administration. The drug was a blockbuster. But sales began to fall after a 2007 study of people taking the drug suggested that Avandia could cause heart attacks and strokes. I first learned about this while serving on a bioethics advisory board for GlaxoSmithKline, the developer of the drug—a panel that was looking at research ethics issues in poor nations. The panel, on which Science Progress Editor-in-chief Jonathan Moreno also served, came to an abrupt halt.

In response, the FDA put a black-box warning on the drug telling doctors of the heart attack risk. GlaxoSmithKline was not happy. There was a lot of back and forth about the safety of the drug. Over the past few months more evidence become public that shed doubt on Avandia’s safety. Worse, it appears the company withheld data about serious side-effects. The FDA appointed an advisory panel this July to consider these allegations, but the panel itself quickly got caught up in charges of conflict of interest among its members. It is likely that more black-box warnings to doctors will follow, should GlaxoSmithKline choose to keep Avandia on the market.

Avandia is not alone. The drug’s problems in the marketplace follow hard on the heels of Prempro, a hormone replacement therapy made by Wyeth Pharmaceuticals, now part of Pfizer Inc., which became caught up in lawsuits alleging it caused breast cancer. More recently, the FDA released a warning about the Afluria flu vaccine, made by CSL Ltd. of Australia, concerning high fever and seizures. Prior to that was Merck & Co.’s widely publicized recall of Vioxx, which came after problems with Astra Zeneca’s Seroquel, Abbott Laboratory’s Meridia, Pfizer’s Rezulin, C.R. Bard Inc.’s G2 filter, Bayer’s Baycoll, Boston Scientific Inc.’s Express Stent, and on and on.

So is there a real phenomenon here or just more PR associated with recalls? And if there are more recalls going on then what is wrong with the oversight of new drugs and devices?  It is not clear from the literature whether there are more recalls taking place in recent years—there is no real database that would show such a trend. There are certainly more stories about recalls and more people studying the objectivity of the marketplace surveillance being done by pharmaceutical, biotech, and device companies.

No one seems to have reliable numbers on recall trends, yet the Institute of Medicine and other groups still warn that the existing system of drug protections after the FDA approval process is complete does not seem adequate to handle the products that are reaching the market. Fortunately, there is a way to fix the system.

The major problem today is that too many lousy or dangerous drugs and devices get to you without adequate safety review because drug and device regulation is heavily weighted in the United States toward early stages of research. Every drug has to be tried in animals to roughly determine safety. Then drugs are introduced into a small number of humans to further check safety—so-called phase one trials. Then dose and mode of administration are checked for safety, biological activity, and signs of effectiveness—phase two. Only after all this safety testing is a drug or device ready to go to phase three clinical trials. In these studies hundreds or sometimes thousands of subjects are recruited to receive the drug or product for periods of time that range in nearly every case from a few months to a year.  Phase three trials are almost always placebo controlled randomized, blinded studies.

So there is a lot of effort to try and make sure that subjects are not hurt in phase three trials. The deaths of subjects in phase one clinical trials, among them Ellen Roche and Jesse Gelsinger in early stage studies over a decade ago seem to have reinforced regulatory anxiety about the risk of deaths in first in-human studies.

Meanwhile, the weakest link is the fourth and final step in the research process—phase four—in which drugs are to be monitored when out in actual use in the world for adverse events and problems. Drug companies sometimes promise to do these trials to get final product approval but don’t. These studies are heavily weighted to support the funders of these studies, Big Pharma, which results in much more rosy reporting then studies done by independent groups.

Reporting of problems in phase four is left to doctors and patients who rarely do so.  And there is no systematic tracking of a subpopulation taking new drugs or other medical products to see what is going on with real patients in real world conditions. Deaths have to mount rapidly and obviously to get regulatory or physician attention before phase four studies are ever seriously undertaken.

But a lack of independent, well designed phase four trials is not the only problem.  Approving drugs based on current standards for phase three testing has its own built-in limits. Testing drugs and devices in randomized, blinded, placebo control trials is great, but it means that approval is given on the basis of highly controlled studies on highly selective populations—often subjects who are not that old, not that sick and are highly compliant. That’s not the real world, where patients take lots of drugs, some legal some not, are poorly compliant, have multiple diseases, and can be very old or very young.

So what looks safe in a phase two or phase three study can prove lethal when given to real people in uncontrolled, unsupervised environments. What’s more, phase three studies are also relatively short. What looks safe after three months exposure or six may not be after three or six years.

The seemingly endless parade of horrors of FDA approved drugs gone bad merits a reexamination of a regulatory system that is not keeping us safe.  The issue is not too much bureaucracy and too much red tape, but a strategy of safety that puts the emphasis in the wrong place—early not late—and then uses techniques that by themselves cannot ensure safety for real people in the long run.

Update August 17 2010: CNN Money reported that the number of drug recalls in the U.S. surged to 1,742 in 2009, up 309 percent from the 2008 level. Recalls so far in 2010 are also on pace greatly exceed previous levels. However, not all of these recent recalls were due to the drugs themselves being unsafe—some were due to problems with the manufacturing process of generic, over-the-counter drugs.

Arthur Caplan, PhD, is the Director of the Center for Bioethics and the Sidney D Caplan Professor of Bioethics at the University of Pennsylvania

Informed consent protects the rights of people who participate in research studies. Research subjects may be medically, psychologically, and socially vulnerable, and they are therefore entitled to have their personal autonomy respected by providing them with the information they need to decide whether or not to participate in the research.

Informed consent historically grew out of scandals and tragedies during human experiments from the 1960s and 1970s. But it’s now being applied to the collection of human tissues for laboratory research in a way that may not make sense and interferes with promising medical science.

Two recent cases illustrate the problem: an Arizona Native American group that objected to the medical use of anonymous blood samples for research purposes other than that specified in the original consent form; and embryonic stem cell consent forms that, again, specified only research on a certain disease. The materials in the first case were returned to the tribe, and in the second the National Institutes of Health is not permitting research funding on the cell lines affected by the consent restrictions.

We don’t advocate violating the consent forms once they are in place, but it is more appropriate going forward to treat these materials as gifts. The donors would have no ongoing rights and the materials would not be restricted in their research uses. Donors would still have the possible lab uses of their tissues explained to them, but with the provision that they understand they are giving them to science rather than “consenting” under the conditions of a form.

A gift model has another important advantage over a consent model: It would be clearer to donors that they would not stand to gain in any commercial value that might come from products of work with their tissues.

Of course, all the needed privacy conditions would also apply so that the researchers would not be able to trace the materials back to the donors. There is no reason that a gift approach can’t be just as ethical as an informed consent model of tissue donation.

The idea of informed consent for these kinds of donations seems to have grown up accidentally as part of the medical research system in a similar way to clinical trials. But it seems to us that it’s time to revisit the reasoning behind this system since a tissue donor is not directly involved in the research and the system is often impeding important medical studies.

Jonathan D. Moreno, Ph.D., is the David and Lyn Silfen University Professor of Ethics and Professor of Medical Ethics and of the History and Sociology of Science at the University of Pennsylvania, and the Editor-in-Chief of Science Progress.

Significantly, the policy includes a uniform disclosure form that authors submitting manuscripts to all of the journals represented by the committee’s editors will use. The form covers everything from grants to consulting fees, gifts, and stock options that researchers might receive as support from outside groups for their scientific work; it also requests information on other significant relationships outside institutions might have with an author’s family members.

As Vivian Cheng explains in her SP feature on “Financial Conflicts of Interest 101,” disclosing potential conflicts is particularly important in biomedical research because they can influence study results or clinical trials. “In some cases, such conflicts may result in experimental data that favors a particular commercial product,” she writes, “in others, they may shape unnecessary or dangerous risks for trial participants.”

Moreover, as Patti Tereskerz of the Center for Biomedical Ethics and Humanities at the University of Virginia School of Medicine explains, protecting research integrity by mitigating the influence of conflicts supports the basic principle of trust, what she called “the crown jewel of the research enterprise.”

This new policy is of course not the final word on conflicts of interest in the medical research world—the committee editors explain as much by calling the first five months of the policy a “period of beta testing.” But streamlining the process of disclosure across many influential outlets will light the way for future policies to maintain objectivity in health science.

According to Nature, the International Committee of Medical Journal Editors has required, since 2000, that authors submit trial information to databases like ClinicalTrials.gov in order to have their manuscripts published.

But one study, appearing in the Journal of the American Medical Association, examined published articles that relied on registered trials and found that only 45.5 percent were adequately registered—that is, researchers submitted data before the end of the trial and clearly specified the outcome.

Results from industry-sponsored trials registered at ClinicalTrials.gov lead to publications in only 40 percent of cases, according to another report appearing in PLoS Medicine. NGO-funded trial results saw publication 56 percent of the time, but government-funded trials only 47 percent.

He joined CAP senior fellow Jonathan Moreno to discuss his new book, Everyday Practice of Science: Where Intuition and Passion Meet Objectivity and Logic. The short text aims to help anyone interested in science—lay readers and experts alike—understand the nature of experimentation and what science looks like on a daily basis. According to Grinnell, there’s a lot more to think about than most people might assume at first. To listen to the podcast of the conversation, see the audio player above, download the mp3, or subscribe via iTunes.

Many practitioners, for instance, do not realize that their scientific research may have ethical ramifications, Grinnell said. When scientists repeat their experiments, they accumulate ten to fifteen notebooks with many sets of data that eventually become a paper. Since this is a typical process in research, “Data selection has to occur. It’s inevitable,” he explained. However, because there are responsible and irresponsible ways to select data, scientists need to establish a “transparent” and “reasonable” method. Since “golden data for one person may look like nonsense to another,” leading to accusations of “dishonest data selection,” students must learn about and always be aware of this very thin line, Grinnell said.

It is also important for people interested in U.S. research to understand how science is funded and supported, as grant awards often dictate a scientist’s professional life for years at a time, Grinnell said. These funding cycles can create a “soft money lifestyle” for some scientists, where “faculty have become responsible for raising some or all of their own salaries as part of their research grants,” a process, he explains, which “creates all sorts of conflicts of interest.”

“There’s a certain degree of tension that’s created in that system and a certain degree of uncertainty because from year to year, depending upon what Congress does, there may be more money or less money,” he said. This year, the Recovery Act provides additional research dollars, but many scientists are already worrying about what will happen several years down the road when the additional funding stops, yet these additional projects are underway. “Does that mean that they’re all going to be competing at the same time for money and then the success rates will go down?” he asked.

Grinnell himself recently won funding to extend his own research grant for the next four years, which will take him “beyond the end of the stimulus package.” From a practical point of view, he is happy, but he acknowledges many other researchers may not be as lucky. The system is inherently chancy, he said, since the success of an application is affected by nonscientific factors such as the time at which you submit your proposal.

Grant proposals, like research papers, are dependent upon peer review. In the peer review process for funding, other scientists help read proposals and determine whether the research is worthy of support. This is a valuable process for the science community, but it may have unintended consequences, Grinnell said.

“The people who are the peer reviewers are the ones who often understand the work the best, but they’re also the ones who have the best opportunity to potentially utilize or at least be influenced by this advanced knowledge.” The result, he said, is that peer review “is an advantage for the peer reviewer that people who are not peer reviewers don’t have.” Moreno, a reviewer himself, agreed, noting that he learns a lot about what is happening in his field by reading other people’s grant applications.

The National Academies’ definition of conflicts of interest has two parts, Grinnell noted: one covers financial conflicts, and the other indicates that anyone with a personal advantage is in conflict. Paradoxically, he said, peer reviewers gain a personal advantage  because they read about cutting-edge research before their colleagues, and that inevitably influences their behavior.

In the last chapter of his book Grinnell explores a different apparent conflict between faith and science. On the issue of whether intelligent design should be taught in science classes, he offers a clear “no,” since “it’s just not science.” However, science and religion are not necessarily in opposition, Grinnell said. To explain, he draws an analogy from the quantum physics model of of complementarity. “You can have two things that are complementary in such a strong sense that they are both right. And because they are separate, however, you can’t judge one against the other,” he said. On the one hand, he said, a claim that the Earth is 6,000 years old doesn’t make any sense. But if religion makes the claim that “life has meaning,” that’s just not a claim that science can judge very well.

A conflict of interest arises when financial or personal considerations have the potential to compromise or bias professional objectivity. These conflicts are a special concern in biomedical research because they have the potential to influence the outcome of study results or clinical trials. In some cases, such conflicts may result in experimental data that favors a particular commercial product; in others, they may shape unnecessary or dangerous risks for trial participants.

Conflicts of interest, commonly referred to in research literature as COI, may take different forms, including both financial interests and opportunities for professional advancement, which are known as “intangible COI.” However, financial conflicts of interest are simultaneously the most pervasive and easily remedied through policy, since intangible COI are difficult to identify.

A recent case clearly demonstrates the lack of transparency concerning financial conflicts of interest. Dr. Charles Nemeroff of Emory University received $2.8 million from drug company GlaxoSmithKline, but did not report a large portion of this financial COI to the institution. While GlaxoSmithKline paid him from 2000 to 2007, Nemeroff oversaw a project funded by a $3.9 million grant from the National Institutes of Mental Health to study five anti-depressants produced by the pharmaceutical company. But despite rules requiring that universities disclose corporate income in excess of $10,000 per year for researchers working on federal grants, Nemeroff consistently reported receiving far less money than GlaxoSmithKline records showed. The National Institutes of Health rules are designed to ensure that such financial ties do not compromise patient safety and research integrity.

A recent national study on industry sponsorship and research integrity (co-authored by SP Editor-in-Chief Jonathan Moreno) found that “knowledge of compromises in research integrity is widespread” among investigators and is directly correlated to industry support. Respondents to a survey on first-hand knowledge of conflicts indicated that such compromises were present in research participants’ wellbeing, research initiatives, publication of results, interpretation of research data, and scientific advancement. Nine percent of the respondents said they witnessed a situation that compromised research participants’ safety due to industry sponsorship, and participants’ wellbeing were “seriously or significantly compromised” in 40 percent of these instances.

Expert recommendations for how to reduce the number of financial conflicts and their impact on science include standardizing requirements for the dollar thresholds at which researchers must disclose financial conflicts, standardizing the formats for reporting conflicts across institutions, making them more easily discoverable, and requiring COI disclosure in scientific journals and research studies. Many academic journals have disclosure rules, but they are not yet mandatory or uniform, and author compliance is inadequate. Suggestions to prevent undue industry influence include developing rules that preserve the use of industry expertise in research and limiting that industry involvement to an advisory role. Such restrictions could prevent corporations from controlling research design and methods in academic research and clinical trials.

Financial conflicts of interest are a problem since even the appearance of a conflict may undermine the public’s trust in science. For example, it is reasonable to believe that a researcher’s financial relationship with a drug maker would skew his or her judgment on the drugs. Moreover, if investigators in human subjects research have conflicts of interest, influence on their conclusions could endanger subjects and future patients, as the survey participants mentioned above attest. In 2007, New York Times found that psychiatrists who received at least $5,000 from creators of antipsychotic drugs wrote three times as many prescriptions for the drugs, to children and adults, as psychiatrists who received less money or none. These drugs are not approved for most uses in children due to a high risk of side effects.

Why do conflicts of interest exist?

Conflicts of interest originate from research partnerships among industry, academia, and government. Corporate research funding substantially increased over the past 40 years while federal research and development funding remained relatively constant. Although these relationships are essential to the discovery process that can lead to new medical therapies that benefit society, increasing financial relationships between industry and scientists create suspicion that conflicts will cause dangerous partial professional judgments.

Academic researchers and industry grew closer when Congress passed what is known as the Bayh-Dole Act in 1980. The law fostered greater collaboration between researchers and industry by allowing universities to patent discoveries developed using federal funding. Academic researchers subsequently sought ties to industry, believing the connection would accelerate the marketing process.

How do types of conflicts of interest differ?

Conflicts of interest appear in a variety of scenarios that have distinct impacts. However, most COI are complicated because they are comprised of a combination of these characteristics.

Financial COI: Individuals may benefit financially from a certain outcome in a clinical trial or the extent of an invention’s development. Research funding industries may offer scientists different types of financial compensation:

• Equity Interests are a proportion of company ownership in the form of stocks. A scientist with equity interests may be biased towards the company’s products since the financial benefits are dependent upon the success of clinical studies and future marketing ventures. Institutional Review Boards evaluate any research on human subjects conducted at an institution, and members who own equity interests have an incentive to approve studies regardless of IRB rules since a product must be tested before it can enter the marketplace and produce profit for stock owners. IRB conflicts of interest therefore eliminate the independent review that is necessary for patient safety.
• Consulting Fees include income scientists earn by providing expert advice about a product to private companies. This is a less problematic scenario than owning equity interests because consulting fees are typically predetermined. Thus, the scientist’s consulting income is independent of drug testing outcomes. However, a scientist may feel indebted to a company if the consulting fee is substantial, leading to research bias towards the company’s products.

Conflicts of Interest in Clinical Trials: This type of conflict is especially concerning because preferential treatment to a particular experimental group in a clinical drug study could harm research participants and future patients. For example, biased research may signal to the Food and Drug Administration that it should approve a drug that does not actually meet safety standards. If the drug is allowed to enter the market, doctors prescribing it may endanger their patients since they are unaware of its actual risk.
Further, doctors who recruit their own patients into clinical trials for which they are investigators may be so hopeful for their patients’ improvement that they believe a treatment is more successful than it is in reality. Moreover, a doctor may have patients with similar health characteristics, and placing them in the same trial keeps it from remaining a randomized trial-a standard requirement for producing objective results.

Industry COI: Industry-funded studies are more likely to draw conclusions favorable to their company’s product. However, industry sponsorship does not immediately indicate a conflict of interest because a company would not fund a clinical trial if it did not believe it may be a success. Nevertheless, a company can exercise undue influence over a study’s design that may impact its conclusion.

Industry may also interfere with research by delaying the publication of negative results after the trial’s conclusion to avoid negative attention. In one case, a pharmaceutical company postponed for seven years publication of a study that concluded the widely prescribed levothyroxine was no more effective than a less-expensive generic.

As well, presenting physicians with gifts like expenses-paid meetings in exotic locations, complementary meals, and other small items branded with a company’s name may create an unconscious bias towards the industry sponsor’s products. Leading medical schools and hospitals, such as Johns Hopkins, acknowledge this form of COI and largely ban such items.

Institutional COI: A conflict of interest is institutional rather than individual if research at the institution could affect its investment holdings, patents, or funding sources. Researchers and physicians at the institution may collectively feel allegiance to the institution’s investments or funders. When funders include nonprofits like patient advocacy organizations, COI becomes more complex since corporations may form and run these nonprofits, using them to funnel payments to researchers. The American Medical School Association grades the level of COI at top academic medical centers based on the presence or absence of policies regulating interactions between students and faculty with pharmaceutical and device industries.

What is the current state of conflict of interest policies?

Conflict of interest policies aim to separate private industry and researchers just enough to avoid harm to scientific integrity and patients, but preserve the collaboration benefits. The Public Health Service, a division of the U.S. Department of Health and Human Services that includes NIH, requires that all institutions that receive PHS grants adopt policies on individual COI to promote objectivity. All PHS grant recipients are required to report significant financial interests, defined as financial gains over a $10,000 value, or equity stakes in companies in excess of 5 percent. This sum does not include salary from an investigator’s institution or income from participation in events sponsored by public or nonprofit entities, which is a problem since many for-profit companies create nonprofit counterparts to filter funds without technically breaking rules. There currently is no universal institutional policy, as rules vary in stringency and effectiveness across schools and research organizations.

Most peer-reviewed journals, such as the New England Journal of Medicine and Journal of the American Medical Association, require authors to disclose all potential conflicts of interest, but many do not have financial COI policies for peer reviewers or editors.

What policies could mitigate conflicts of interest?

The Institute of Medicine, part of the National Academies of Science, convened a committee to examine conflicts of interest in medical research and make recommendations, which were released in a report in April 2009. Although the IOM does not possess policy-making authority, it has influence over the FDA and Congress. The report cites disclosure as “a critical but limited first step in the process of identifying and responding to conflicts of interest.”

Financial COI disclosure should be standardized so all institutions have the specific information required to accurately assess relationships between industry and scientists, the report suggests. In addition to disclosure, researchers with significant financial conflicts should be banned from conducting human subjects research. Medical institutions should create standing COI committees and NIH should require its research grantees to follow the committees’ rules, the IOM recommends.

The IOM advises that Congress create a national program that requires pharmaceutical, medicine device, and biotechnology companies and their foundations to publicly report payments to researchers, physicians, institutions, professional societies, patient advocacy groups, and continuing medical education providers. Payment information should be readily available on a public website so individuals, journals, and universities could verify disclosures.

What recent activity could lead to conflict of interest policy reform?

The Public Health Service sought public comments “on whether the HHS should amend its regulations on the responsibility of applicants for promoting objectivity in research for which PHS funding is sought and on responsible prospective” until July 7, 2009. Final rule changes, if any, are forthcoming.

In addition, U.S. Senators Chuck Grassley (R-IA) and Herb Kohl (D-WI) introduced S. 301, the Physician Payment Sunshine Act-legislation aimed at reducing COI and increasing transparency-on January 22, 2009. If passed, manufacturers and group-purchasing organizations would be required to report their payments to physicians and physician-owned entities if valued over $500. The bill is currently in the Committee on Finance, but Grassley’s aggressive investigations on apparent COI convinced at least two companies, Eli Lilly & Co. and Merck & Co., to abide by the bill’s rules beginning in 2009 nonetheless.

Vivian Cheng is an intern with Science Progress.

20,894: The total number of Challenge Grants applications received by the NIH.

At least $200 million of Recovery Act funds will support these new grants. These applications come on top of the 16,312 regular applications received for the current funding cycle. Some 18,000 reviewers will help read and score them all, a workload that has NIH Center for Scientific Review Director Antonio Scarpa worried about the time it will take for each reader and the inevitable low acceptance rate. The projects that are funded will generate jobs, grow the economy, and support the search for cures.

49,015: The total number of comments the NIH received on its draft Guidelines for Human Stem Cell Research.

Jocelyn Kaiser at ScienceInsider reports that the Institutes’ policy chief estimates the amount is roughly equivalent to when the NIH issued draft guidelines on the same issue in 1999.

$5,000: The threshold for earnings that should trigger mandatory disclosure under financial conflict of interest rules for NIH-funded researchers, as recommended by the Association of American Medical Colleges and the Association of American Universities.

The two major academic associations, which both represent significant proportions of the institutions where scientists conduct NIH-funded research, submitted their joint comments in a letter Wednesday. NIH grantees are currently obliged to report a financial interest if they earn more than $10,000 in income or own more than $10,000 in stock plus 5 percent interest in a company, but the AAMC and AAU believe the threshold is too low to ensure research integrity. The recommendations were in response to the NIH’s request for comments on promoting objectivity in research. Patti Tereskerz recently explained the complexity of managing the conflicts of interest that result from the necessary mix of public and private research funding in Science Progress—including those that arise from corporations funding research through foundations and nonprofit institutes.

The National Institutes of Health recently published advanced notice of rulemaking and a request for comments concerning the responsibility of applicants for promoting research objectivity related to Public Health Services funding.[1] This push for more stringent regulation of financial conflicts of interest, referred to as COIs, is predictable, given the intense scrutiny Congress has placed on these financial conflicts.

But managing conflicts of interest is a complicated policy matter, as researchers and their institutions often receive both public and private funding to support research that leads to new treatments. The proposed rules provide much-needed guidance that has been lacking in the past and support greater disclosure and transparency. But they fail to address other complex matters, such as the route corporate dollars can follow through non-profit institutions and into the salaries of biomedical researchers. Further, my colleagues and I have conducted research demonstrating that financial conflicts are widespread, ingrained within the research infrastructure, and in some cases endanger the well being of research participants.

A recent Congressional investigation, led by Senator Chuck Grassley (R-IA), revealed several unfortunate failures to disclose financial arrangements by investigators. In one reported case, a highly influential Harvard child psychiatrist, Dr. Joseph Biederman, whose research contributed to the increased use of antipsychotic medicines in children, earned at least $1.6 million in consulting fees from drug makers from 2000 to 2007. However, he allegedly did not report much of this income to his university officials.[2]

In the months that followed, the investigation led to accusations that another prominent Emory University psychiatrist, Dr. Charles Nemeroff, received $2.8 million dollars from a drug company and did not report much of the income. At the same time, reports indicated that Nemeroff was overseeing a NIH study on five anti-depressants produced by the research funder, GlaxoSmithKline, between 2000 and 2007.[3]

These are but two of the more public cases identified as part of the investigation.[4] And, just as this piece was being written, there came news that a former Walter Reed Army Medical Center surgeon, who was a paid consultant for a medical device company, published a study allegedly containing false claims and overstated benefits of the company’s product.[5]
Recently, my colleagues and I (including Science Progress Editor-In-Chief Jonathan Moreno) published a national study, funded by NIH through the Office of Research Integrity, on industry-sponsored research and research integrity which further illustrates the problematic nature of financial COIs, which inevitably attend partnerships between researchers and the private sector.[6]

Researchers and research institutions often receive both public and private funding to support their work. The majority of those we surveyed in our study who received industry support for research indicated that this funding was important to their research or publications. Yet, the more important the industry support was to respondents, the more likely they were to report first-hand knowledge of compromises in research integrity. And we found that knowledge of compromises in research integrity is widespread. Perhaps most alarming were respondents who reported first-hand knowledge that the well being of research participants was compromised because of industry sponsorship.

Other results from the study included first-hand knowledge of compromises in research initiatives (35 percent), publication of results (28 percent), interpretation of research data (25 percent), and scientific advancement (20 percent) in all cases because of industry support. Also of concern was that industry-supported research occurred more often among the most senior and prolific researchers, those who no doubt are more likely to be leaders in their fields and have the ability to influence young trainees. Our findings follow many earlier studies that have raised concerns about the undue influence of industry sponsorship on research.[7]

As with the individual cases uncovered by the Congressional investigation, this empirical evidence suggests that there is a gap between policy and practice, signifying that current regulatory measures to manage financial COIs are not sufficient to manage the public/private partnerships that have been an important component in the acceleration of translational research from bench to bedside.

Cases emerging from the Congressional investigation and data emerging from studies point to areas upon which there is need for much greater scrutiny, and the proposed rulemaking makes important strides in addressing some of the limitations of the current regulatory scheme. For example, current federal regulations do not provide specific guidance on managing COIs that involve projects supported by the Small Business Administration’s Small Business Innovation Research Program or the Small Business Technology Transfer Program, with the exception that support for Phase I clinical trials is excluded from COI regulations.⁹ Yet, there has been a substantial increase in NIH SBIR/STTR awards in recent years, but the institutions receiving the funds are responsible for managing COIs.¹⁰ SBIR/STTR programs are set aside programs of federal agencies’ extramural budgets to provide funding for domestic businesses to undertake research and development that has potential for commercialization. Often this involves partnerships between academia and industry, and in the case of STTR’s this is required.

In 2002, NIH requested that 300 of those institutions provide a copy of their policy on COIs and reviewed a representative sample of over 100 policies. At that time, 96 percent of the policies did not mention SBIR programs in the policy document. It is ironic that some of the most complex and difficult financial arrangements emerge with SBIRs/STTRs, yet circumstances specific to these COIs are afforded little to no federal guidance for identification and management. Clearly, this is an area that needs to be addressed.

Importantly, the NIH’s proposed rulemaking identifies additional areas where guidance has been lacking and is urgently needed. For example, the notice questions whether the new rulemaking should include required education of investigators, independent assurance of institutional compliance with the regulations, enforcement mechanisms, and the need to address institutional conflict. Articulated guidance in these areas, establishing effective regulatory requirements, would be an important step forward.

The proposed rulemaking also includes consideration for expanding the scope of the regulation and disclosure of interests and questions whether all financial interests should be disclosed, in contrast to current regulations that require disclosure when the money involved reaches certain threshold levels. No doubt the threshold levels for disclosure are arbitrary. But to require reporting of any financial interest may be unduly burdensome on institutional administrations.

While many of the matters under consideration for expanding the regulations are necessary, they may not be sufficient. The proposed rulemaking does not seem to take into account opportunities for circumventing the intent and spirit of the proposed rules.

For example, the proposed rulemaking appears content with excluding salaries that are remuneration from one’s own research institution. There are researchers whose institutions have had research contracts with a given industry sponsor for years, and this funding is used to support the researcher’s salary year in and year out. Clearly, it is not lost on the researcher as to who is floating the boat. This means that the opportunity for influence and developing loyalty to an institutional underwriter still exists, even if the money paid to the investigator comes in the form of an institutional salary. Does passing the funds through the research organization remove the conflict of interest or just keep it out of public view? These pass-through arrangements may be particularly egregious because of their lack of public transparency. Further, these conflicts may reach beyond the investigators to the institutions themselves, since research contracts with institutions typically provide indirect funding for the institution.

Likewise, financial interests from seminars, lectures, or teaching engagements, or service on advisory committees sponsored by public or non-profit entities are excluded from disclosure requirements. Again, the problem is that many for-profit companies can create non-profit foundation counterparts and have funds filtered through these entities to bypass the language of the rules.

The proposed rulemaking is grounded in the need for transparency. Complete transparency of any financial arrangement that has the potential to compromise research integrity should be absolutely required. But it should be necessary only for those conflicts that cannot be avoided in the first place. Disclosure can only do so much and won’t cure a moral wrong.[8] Emphasis should focus on preventing, rather than managing, COIs in research, whenever possible. And, to a limited extent, the proposed new rules suggest this by asking whether investigators involved in participant selection, informed consent, and management of a trial should be prohibited from having a significant financial interest.

But in some instances collaboration between investigators and industry is necessary for innovation to move forward. The example that comes to mind is in the development of medical devices. So overall the challenge remains the same—how do we continue to encourage public/private partnerships so that translational research can continue to move forward at a rapid pace without compromising research integrity?

Perhaps it is time to think outside of the box and consider completely new models to better avoid COIs in the first place. This may require some major changes in how we go about the business of underwriting privately sponsored scientific research in this country. Some experts have proposed such models, but no one has seriously pursued them.[9] The Obama administration puts a premium on research integrity, possesses the intellectual acumen to embrace creativity, and has the courage to promote change. So the time is ripe to challenge experts to devise new ways to encourage public/private partnerships but simultaneously shield research objectivity from financial conflicts of interest. It will not be easy, but it can be done.

Patti Tereskerz, JD, Ph.D. is an Associate Professor, Research and the Director of the Program in Ethics & Policy at the Center for Biomedical Ethics and Humanities at the University of Virginia School of Medicine.

Notes

[1] Department of Health and Human Services, “Responsibility of Applicants for Promoting Objectivity in Research for Which Public Health Service Funding Is Sought and Responsible Prospective Contractors,” request for comments, Docket No. NIH-2008-0002, RIN 0925-AA53, Federal Register, 74 (No.88) May 8, 2009, pg. 21610.

[2] Harris, G. and Benedict, CA., “Researchers Fail to Reveal Full Drug Pay,” The New York Times, June 8, 2008.

[3] Akre J., “Million Dollar Conflict-Of-Interest By Emory Psychiatrist Uncovered By Grassley,” available at http://www.uslaw.com/library/Personal_Injury_Law/Million_Dollar_ConflictOfInterest_Emory_Psychiatrist_Uncovered_Grassle.php?item=259739 (last visited May 13, 2009); Harris G., “Top psychiatrist didn’t report drug makers’ pay,” The New York Times, October 3, 2008.

[4] See http://thomas.loc.gov/cgi-bin/cpquery/13?&sid=cp1111Nlmz&l_f=1&l_file=list/cp111cs.lst&hd_count=50&l_t=14&refer=&r_n=sr013.111&db_id=111&item=13&sel=TOC_195021& (last visited May 21, 2009).

[5] Wilson D. “Doctor Falsified study on injured G.I.’s, Army says,” The New York Time, March 12, 2009.

[6] Tereskerz PM, Hamric AB, Guterbock TM, Moreno J., “Prevalence of industry support and its relationship to research integrity,” Accountability in Research 16:78-105, 2009.

[7] See, for example, Bekelman Justin E, Li Yan, Gross Cary P., “Scope and impact of financial conflicts of interest in biomedical research: a systematic review,” JAMA (January 22, 2003), 289(4):454–465; J Lexchin, LA Bero, B Djulbegovic, and O Clark, “Pharmaceutical industry sponsorship and research outcome and quality: systematic review,” Br Med J (2003), 326:1167-1170; HT Stelfox, G Chua, K O’Rourke, AS Detsky, “Conflict of interest in the debate over calcium-channel antagonists,” N Engl J Med (1998), 338:101-106; RA Davidson, “Source of funding and outcome of clinical trials,” J Gen Intern Med (1986), 1:155-158; LA Bero, D Rennie, “Influences on the quality of published drug studies,” Int J Technol Assess Health Care, (1996), 12:2009-2037; M Friedberg, B Saffran, TJ Stinson, W Nelson, CL Bennett, “Evaluation of conflict of interest in economic analyses of new drugs used in oncology,” JAMA 1999, 282:1453-1457, LL Kjaergard, B Als-Nielsen, “Association between competing interests and authors’ conclusions: Epidemiological study of randomized clinical trials published in the BMJ (2002), 325:249.

[8] Katz J, “Informed consent to medical entrepreneurialism,” in Spece RG, Shimm DS, Buchanan AE, eds., Conflicts of Interest in Clinical Practice and Research, (New York, NY: Oxford Univ Press, 1996), 286-299.

[9] For some examples, see Tereskerz P., “Developing a new model: Preserving scientific objectivity, trust, and the informed choices of human subjects,” in Riding the Green Wave. Financial Conflict of Interest in Industry-Sponsored Clinical Research, Chapter 10, (University Publishing Group, Hagerstown, MD, 2007), pgs. 153-168; or Moses III H, Martin JB, “Academic relationships with industry: a new model for biomedical research,” JAMA (2001), 285:933.

Fineberg was speaking at a presentation marking the release of a new report from the IOM on conflicts of interest in medical research, education, and practice. Among the many recommendations in the 353-page document is one that will make sense to advocates in the transparency community. The committee authors recommend that individuals at medical institutions should regularly disclose to those institutions financial relationships with drug and device makers and biotech companies—but significantly, the study says that national organizations should agree upon a standardized format for disclosure information so that it can be made accessible in appropriate databases. They go so far as to compare the necessary software with that available for formatting journal references and offer a list of potential fields to facilitate ready information sharing.

“Disclosure is a necessary first step, but it is a limited first step,” cautioned committee chair Bernard Lo of the University of California, San Francisco. And disclosure is a two-way street, as the authors call as well for Congressional action to mandate that pharmaceutical, medical device, and biotechnology companies and related foundations disclose not only their payments to physicians and researchers, but also professional societies, advocacy groups, and continuing medical education providers.

The committee does not claim that disclosure alone will remedy conflict of interest issues, but the presenters offer it as a way to establish a comprehensive system for managing them. “You can’t manage what you don’t know about,” said committee member Eric Campbell, of the Massachusetts General Hospital and Harvard Medical School.

Lo described an ecosystem built on disclosure in which organizations had the responsibility to help enforce rules that manage conflicts. He highlighted the need for institutional responsibility, not just individual responsibility. At the current moment, there are instances where current parameters go ignored, as in the field of research publications. “Many journals do not comply with the recommendations of their professional group,” he said.

Lo also underscored that fact that not all relationships between physicians and industry are problematic. Indeed, they have lead in many instances to productive collaboration. As Campbell pointed out, virtually all medical devices and drugs on the market today would not be available without such relationships.

This U.S. policy development is of special concern to Russians, as an increasing number of U.S. pharmaceutical companies conduct their drug trials in Russia, which currently lacks extensive regulations. Merrill Goozner is currently reporting on that country’s health care system, which he explains has the potential to become “ground zero” in the discussion over the FDA’s withdrawal from the Declaration.

Russian health care and longevity has fallen dramatically since the end of communism, and in some areas is just now starting to recover. In some of the most rural parts of Siberia, the first health clinics are just now being built. Even with the recent improvements, the lack of regulations regarding pharmaceutical companies conducting trials concerns Sergey V. Smirnov, the Russian director of the nongovernmental organization, Community of People Living with HIV. Goozner spoke with Smirnov for Scientific American about his activism on the regulation of pharmaceutical trials:

Two years ago, Smirnov joined an informal working group of scientists and bioethicists in drafting legislation designed to beef up clinical trial patient protections. Among backers: representatives of the Russian government’s Bioethics Commission, the Russian Academy of Sciences, and the local UNESCO office.

The legislative draft would give the government power to require greater disclosure of sponsors of and participants in clinical trials. It also provides a framework for protecting the patient privacy and safety in the trials, including requiring that they give their (noncoerced) consent to participate.

Smirnov hopes that the bill will be voted on sometime this year, remedying the current lack of effective regulations for clinical trials.

The decision by the FDA to withdraw from the Declaration of Helsinki has evoked much criticism, both at home and abroad. In recent years, the FDA has noticed that even with the Declaration in effect, many international drug trials run by American pharmaceutical companies are not reported until after they are conducted, and as such, the FDA cannot regulate them. The new guidelines may be an attempt to reassert control over these pharmaceutical companies, rather than rely on international law. By relaxing the rules, the FDA may either encourage more international drug trials—and therefore increase the number of drug trials that go unreported and unregulated—or it may find that companies are more likely to adhere to the slightly lower testing standards.

The University of Virginia is home to a Johnson & Johnson-funded study on Topamax’s ability to treat alcoholism. The Health Blog describes claims from the Public Citizen’s Health Research Group, which says that the University of Virginia, where the study took place with funding from J&J, put out a press packet that encouraged doctors to prescribe the medication off-label. Doctors can prescribe drugs off-label for uses not formally approved by the Food and Drug Administration, but drug makers cannot advertise or promote these alternative uses. The Health Blog also notes that the scientist who led the study at UVA, Bankole Johnson, chairman of UVA’s Department of Psychiatric Medicine, has financial ties to J&J.

In their main article on the study (subscription), The Wall Street Journal relays Dr. Johnson’s comments about how the current drugs used to treat alcoholism are only prescribed after a person stops drinking or goes through detox. According to Johnson, a drug like Topamax is a welcome development because it can be introduced while a person is still drinking.

The Wall Street Journal also reports that a spokeswoman for Ortho-McNeil Neurologics, the J&J subsidiary that produces Topamax, says they have no intention of submitting the drug for FDA approval as a treatment for alcoholism. And in an article by MedPage Today, they quote a UVA spokeswoman:

“We are not suggesting a go-ahead for doctors, but we are stating a fact,” said a spokesperson. “Doctors who are interested are allowed to prescribe it. No off-label use is being proposed, advocated, or promoted.”

Looking a bit deeper into the specifics of the scientific methodology, Mark Willenbring, doctor at the National Institute on Alcohol Abuse and Alcoholism, commented in an editorial in The Journal of the American Medical Association that accompanied Johnson & Johnson’s paper on Topamax that alcoholic subjects who volunteer for a study such as this one are self-selecting, whereas many alcoholics who undergo specialty treatment are coerced by judges or employers. This self-selecting group mostly closely resembles patients likely to be seen in primary care where pharmacotherapy would be most appropriate.

The New Scientist goes into some detail about how much the patients actually improved and how the drug works by blocking the brain-chemical (or neurotransmitter) dopamine; the piece is more optimistic than The Wall Street Journal.

A letter to Food and Drug Administration Director Andrew von Eschenbach from Sidney Wolfe, MD of the Public Citizen’s Health Research Group, emphasizes the current FDA warnings that caution against taking the drug with alcohol and calls attention to the statistically significant increase in side effects mentioned in the study such as dizziness and trouble concentrating.

Although the results of the study look promising, the side effects seem substantial and even the authors admit that there was no follow-up to determine whether the patients relapsed.

The findings aren’t necessarily hype, but Public Citizen is right to call attention to the fact that FDA approval is more than red tape. Large studies must be done on diverse populations in order to ensure safety and effectiveness and assess the overall risk-benefit relationship. That’s why Topamax remains off-label for alcoholism treatment and should remain so until the FDA approves it. Although it may be worth asking whether news coverage of the study and controversy itself may spur more patients or doctors to consider off-label use.

Also in the podcast, Malcolm Dando of the University of Bradford responds by calling attention to the “dual-use dilemma,” the fact that new technologies can be used for malign purposes as well as benign ones. Oxford neuroscientist Russel Foster discusses the notion of sleepless soldiers and government oversight and his responsibility as a bench scientist to inform the government about how the military can apply scientific research.

For more discussion on Moreno’s book Mind Wars and military neuroscience research, there’s video from a recent Dana Foundation event with Moreno, Foster, Dando, and NYT columnist William Safire.