In Safeguarding Children, the Bioethics Commission reaffirmed the conclusion reached in Moral Science that those “harmed in the course of human subjects research ought not individually bear the costs of care required to treat qualified harms resulting directly from that research.” The Bioethics Commission noted that the principles of justice—which requires that the benefits and burdens of research be distributed equitably—and beneficence and respect for persons—which together require that ameliorable risks to participants be minimized—support compensating injured research participants.

In the context of pediatric medical countermeasure (MCM) research, the ethical case for compensation is particularly acute. Children who enroll in pediatric MCM research cannot legally or ethically provide informed consent for participation. These children could also be asked to bear greater risk than ordinarily permitted in pediatric research—although no more than a minor increase over minimal risk—for the benefit of children exposed to a potential future attack. For these reasons, children injured as a result of their participation in pediatric MCM research should receive necessary medical care and appropriate compensation for their injuries. Reviewers of pediatric MCM research have a corresponding obligation to ensure that researchers have a plan to treat or compensate those participants who are injured.

As acknowledged by the Bioethics Commission in Moral Science, there is, as yet, no overarching federal policy to ensure that all injured research participants receive treatment or compensation. There are, however, two systems that provide some compensation for research-related injuries, although they do not provide sufficient protection in the pediatric MCM context. The first system is the National Vaccine Injury Compensation Program, a national system that compensates those injured by vaccines listed in the Vaccine Injury table (available here) or that are recommended by the U.S. Centers for Disease Control and Prevention for routine administration. Most MCM vaccines are not listed in the Vaccine Injury Table, and not all MCMs are vaccines. Injured pediatric MCM research participants would therefore not be eligible for compensation under this program.

A second, and potentially more suitable, alternative is the Public Readiness and Emergency Preparedness (PREP) Act, which provides limited access to compensation for those injured as a result of receiving an MCM. The PREP Act permits those who suffer “serious physical injury or death” to recover from the “Covered Countermeasure Process Fund,” a pool of funds that comes into existence once the Secretary of HHS declares an emergency. Those who suffer minor injuries, however, or those whose injuries arise after the expiration of the PREP Act’s one year statute of limitations, will be unable to receive compensation.

Ultimately, the Bioethics Commission concluded that, in both pre- and post-event pediatric MCM research, those conducting research must ensure that there is a sufficient treatment and compensation plan in place so that the costs of any resulting harm or injury do not fall on pediatric research participants or their families.

In their commentary, Gutmann and Wagner continue the public deliberation of the Bioethics Commission’s report, Privacy and Progress in Whole Genome Sequencing, in which the Bioethics Commission took a forward-looking approach to the privacy concerns raised by whole genome sequencing—issues that have come to the forefront of this important science.

Under current law, health information that is deidentified—information for which there is “no reasonable basis” to believe it can identify an individual or that has been stripped of traditional identifiers—is afforded different legal protections than identifiable health information. However, whole genome sequence data are unique to only one person, making them more vulnerable to reidentification.

Recent articles have cast doubt on the extent to which whole genome sequence data can be deidentified. For example, in Identifying Personal Genomes by Surname Inference, published in Science in January, Melissa Gymrek, et. al. successfully uncovered full identities of 50 individuals.

It is not always easy to control access to genomic data—indeed scientific progress in this area requires large-scale access for researchers. As Gutmann and Wagner argued, to contribute to such progress “the public must trust that the research community will guard their data zealously and use them in the most respectful and productive manner possible. Donor consent to whole genome sequencing is critical, but warning participants of risks in a consent document is not enough: such risks must also be prevented whenever and wherever possible.”

Current federal and state laws protect genomic data differently—some are tied to the collector of the data, others to where the data is collected. Therefore, a centerpiece of Privacy and Progress was Recommendation 1.2, which urged “federal and state governments to ensure a consistent floor of privacy protections covering whole genome sequence data…” Informed consent should be obtained, regardless of the future identifiability of the data (Recommendation 3.1), and this consent should make it clear that there are potential risks inherent in agreeing to share data (Recommendation 3.2). The Bioethics Commission also recognized that persons who have authorized access to genomic data “must be guided by professional ethical standards related to the privacy and confidentiality of whole genome sequence data and not intentionally, recklessly, or negligently access or misuse these data…” (Recommendation 2.1). Best practices must be implemented to keep genomic data secure (Recommendation 2.3).

Recent studies highlight that whole genome sequence data thought to be deidentified can become identifiable to those with expertise; and the corresponding need to address privacy concerns through robust informed consent processes, data security and access provisions, and a consistent national floor of privacy protections. As Gutmann and Wagner concluded in Found Your DNA on the Web, “if we move the debate from identifiability to public beneficence and respecting persons, the real ethical focus must be on promoting progress while respecting privacy;” something to which all persons who work with whole genome sequence data can contribute.

“I view my main role here as reminding you, despite being research centered, we are humans…not to forget to pay attention to that human side.” – Sarah Hilgenberg, M.D., F.A.A.P., Department of Pediatrics, Stanford University.

“These relationships don’t come with a platonic ideal of what these relationships are or are not, they evolve due to policies, cultural understanding.” – Amy Gutmann, Ph.D., Chair of the Bioethics Commission, President of the University of Pennsylvania.

“There is still a primary duty in each domain that is different: research’s duty is to discover new knowledge, the company’s duty is to its shareholders, and the clinician’s duty is to patients.” – Alex John London, M.A., Ph.D., Professor of Philosophy at Carnegie Mellon University.

“The way that the technology is proceeding is that it may be cheaper to do whole genome sequencing than one or two tests at a time. When all these results are obtained, they will become part of the clinical record. So it is not possible to try and withhold any information, there is a very important case to be made that in those circumstances [where] there may be no incidental findings.” – Raju Kucherlapati, Ph.D., Professor in the Harvard Medical School Department of Genetics.

“In a clinical setting, that may not be the time when you want to hear [that piece of information], you may wish to hear that information later…we built a system where nothing is incidental.” – Joanna Mountain, Ph.D., Senior Director of Research, 23andMe.

“Real autonomy starts with information, people knowing what their options are.” Robert C. Green, M.D., M.P.H., Associate Professor of Medicine at Harvard Medical School.

In the case of incidental findings in direct-to-consumer testing, the ethical question becomes one of whether or not corporate responsibility extends beyond the contract between the customer and the corporation, and if so, how much. The dominant view among corporations right now, states Thomas Donaldson, Ph.D. Professor of Legal Studies at The Wharton School of the University of Pennsylvania, is “not very much.” The primary consideration for a corporation is to maximize profit for the shareholders. It may be up to regulation to determine how direct-to-consumer corporations handle incidental findings.

Currently, there is a “lack of clarity in the regulatory environment” states Gail Javitt, J.D. M.P.H., a research scholar at Johns Hopkins University. Javitt pointed out to the Bioethics Commission at today’s public meeting that this lack of clarity is particularly evident in direct-to-consumer testing. While the Centers for Medicare and Medicaid Services (CMS) is concerned with laboratory testing quality, the Food and Drug Administration (FDA) regulates medical devices, including in vitro diagnostic devices. In addition, while most direct-to-consumer testing legislation has been at the level of the federal government, states can regulate medical practice, and may, as in the case of New York, not even permit direct-to-consumer testing.

And this regulatory environment may become more important as the findings from direct-to-consumer testing proliferate. Joanna Mountain, Ph.D. a Senior Director of Research at 23andMe, described how the genetic findings of the company may proliferate over time, increasing the odds that people receive information they might not have wanted to know. From an initial group of only 40 findings, 23andMe now has well over 200 potential findings for each consumer, and the reports grow each year as the company acquires new information through research. 23andMe notes on their website that customers may receive information they may not like, and deliberately locks some information so that consumers have to “opt in” to receive information about some potentially frightening diseases, such as breast cancer.

In the context of direct-to-consumer testing, the panel discussion raises the question of what an incidental finding really is when corporations are conducting these large-scale screenings. If customers have voluntarily signed up to receive the information, and have agreed to continue to receive results from the initial screen, it may be that no finding in this context is really incidental.

Danielle Ofri, M.D., Ph.D., Associate Professor at the New York University School of Medicine, spoke of a patient with gastrointestinal pain. While Ofri, as her primary care physician, Ofri knew that the gastrointestinal pain was a common occurrence and probably nonthreatening. However, when her patient checked into the Emergency Room, the doctors, who did not know the patient’s history, performed a CT scan. The CT scan showed no cause of gastrointestinal pain. But it did turn up something else: “a 2 cm nodule in the right adrenal gland” or as Ofri wryly called it “The dreaded incidentaloma.”

Nodules in the adrenal glands are common, and while Ofri notes that 98% are entirely benign, in rare cases they can lead to problems such as the overproduction of hormones, or to cancer. “Nevertheless,” Ofri said, “once the incidental finding had been given life, so to speak, it was no longer incidental.”

Ofri had to refer to the standard-of-care for an adrenal incidentaloma, which involved a list of complicated tests. “As clinicians,” said Ofri, “we have a bias toward doing something, as opposed to doing nothing…Our patients, almost uniformly, want us to do something. Both doctor and patient are enthralled within this overwhelming medical imperative to act.” The tests would cost thousands of dollars, and also threatened to expend Dr. Ofri’s medical capital with her patient.

There was only so much time she had to spend with the patient, and with all of the information required to discuss the incidental finding, Ofri was obliged to skip over many other issues that the patient needed to have discussed, such as high blood pressure, cholesterol, and diabetes. These issues “…ended up with the short end of the clinical stick that day—an outcome” Ofri noted, “that is surely not incidental.”

Next, Carol Krucoff spoke of her experience as a patient who received an incidental diagnosis of a small acoustic neuroma. Even though her so-far benign neuroma has caused her significant anxiety, Krucoff stated that she would rather know about the presence of the neuroma than not. She recommended policies to help patients deal with incidental findings, including keeping patients informed in simple, direct language, training providers with communication skills to ensure both compassionate and clear communication, and to add a support person to the healthcare team, to help patients and their families process difficulty information.  And, she says “Unless it’s a necessity, don’t rush to treatment.”

Sarah Hilgenberg, M.D., tells her story.

During today’s meeting of the Presidential Commission for the Study of Bioethical Issues (the Bioethics Commission), a panel of experts discussed the ethical considerations associated with incidental findings that arise during research.

Alex John London, M.A., Ph.D., Professor of Philosophy at Carnegie Mellon began by noting “The researcher may have a duty to act in the best interest of the participant, and this may involve revealing findings to the patient that were outside the scope of the study and linking them up with clinicians, as well as keeping information confidential.”

In this case, the incidental finding may have saved a life. Peter Bendettini, Ph.D., chief of the section on functional imaging methods at the Laboratory of Brain and Cognition at the National Institute of Mental Health, noted that only 2% of brain scans have an incidental finding of clinical significance, but to those 2%, the incidental findings may have life-changing consequences.

For example, eleven years ago, Sarah Hilgenberg, now an M.D. in pediatrics, was just beginning a promising career in medicine. “I was high on life, feeling physically, emotionally and intellectually fulfilled,” she said. As she completed her orientation camping trip for the Stanford University School of Medicine, a friend asked her to participate in some research he was conducting on learning and memory. The research involved a functional magnetic resonance imaging (fMRI) scan.

Immediately after the test, her friend who was conducting the research appeared concerned. After consulting a neurologist, he revealed to Hilgenberg that she had an abnormality in her brain scan. She immediately received a diagnostic neurological evaluation, as well as a large dose of worry. While the doctors initially feared that she had a brain tumor, the final results revealed an arterio-venous malformation (AVM), a malformed connection between the arteries and veins which usually goes undetected, until it is found as an incidental finding. An AVM can be very dangerous, as increased blood pressure can cause them to bleed, with potentially fatal complications.

Hilgenberg underwent a long series of tests and surgeries, attending medical school at the same time. She said that the combination of medical school and her own medical condition was a powerful experience. “I was learning firsthand the material taught in class: the vulnerability of the body and, in particular, my brain”. However, due to the early intervention as a result of the incidental finding, Hilgenberg was cured of her AVM. She is now a successful physician, married, and the mother of a little girl.

Hilgenberg is grateful that she received information about the incidental finding. “A part of me thinks that he [the researcher] had no obligation to do this,” she told the Bioethics Commission. “But I am not sure that I would be here today to speak to you if he had not acted.” The chair of the Bioethics Commission, Amy Gutmann, Ph.D. agreed. “There is a kind of minimal standard for what human beings with a basic ethical sensibility will say to themselves ‘If I don’t do this, I won’t be able to sleep at night,’” Gutmann said.

Incidental findings include information gathered in a clinical, research, or direct-to-consumer medical setting that is beyond their stated aims or goals. The discovery of incidental findings can have practical, legal, and ethical considerations for the doctor, researcher, business, and most importantly, the recipient of the incidental finding.

Executive Director Lisa M. Lee, Ph.D., M.S., addressed the Bioethics Commission with an introductory presentation on the ethical issues associated with incidental findings. First, there are questions that arise with the discovery of incidental findings in different modalities.

In imaging studies such as X-rays or ultrasounds, Lee informed the Bioethics Commission that the potential for incidental findings is extremely high, with over 40% of scans resulting in incidental findings. For example, in angiography, 50% of angiograms will reveal a non-calcified nodule, but 99% of these nodules will be benign. Follow-up on these findings can produce a great deal of patient anxiety, and is both costly and potentially dangerous. Finally, in the case of research, Lee noted that much of the imaging used in research is of lower quality, and may not provide definitive information.

In biological samples, such as metabolic panels, clinicians and researchers are aware that as the number of tests increase, so does the potential for incidental findings. While health providers and researchers can anticipate a certain set of possible findings, Lee stated that once abnormal findings are found, they are difficult to ignore.

Secondly, Lee informed the Bioethics Commission that incidental findings could give rise to different issues depending on the context in which they are discovered. In the clinic, doctors have a fiduciary duty to patients to act in their best interest, and the question becomes whether returning the incidental findings will provide more benefit than harm. Due to concerns about liability, defensive medicine may lead to over-testing, and the discovery of further incidental findings. Insurance issues could also come into play as some incidental findings may be treated as pre-existing conditions.

In research, ethical issues also arise, with the constraints of the researcher to return the findings, whether they have adequate expertise, and what obligations the researchers owe to the research participants.

Finally, Lee described the emerging field of direct to consumer testing, in which the ethical issues lie at the intersection of medical and business ethics. They raise questions of the obligation that companies have to return incidental results, whether consumers themselves should be involved in the decision making process, and how the autonomy of the customer can best be respected.

All of these questions, the different ethical factors involved in each modality and context, will be discussed today, to provide more information and guidance to the Bioethics Commission.

At this meeting the Bioethics Commission will begin work on its next project, the ethical implications of incidental findings. As the commission members recognized in their recent report Privacy and Progress in Whole Genome Sequencing, an important unsettled issue is the ethics of reporting incidental findings to individuals. The Bioethics Commission noted in Privacy and Progress that it planned to take up the issue of incidental findings and will do so now.

Incidental findings are information gleaned from medical procedures or laboratory tests beyond their stated aims or goals. They can be discovered in the context of clinical care, research, or commercial direct-to-consumer testing. Emerging medical technologies, changing cost structures, and evolving medical practice make the likelihood of discovering incidental findings a growing certainty in the clinic, research, and commercial direct-to-consumer contexts.

The Bioethics Commission has a full agenda today including looking at the ethical challenges of emerging technologies, as well as hearing from recipients of findings incidental to research and to clinical care.

To examine these issues, the Presidential Commission will bring together experts with experience of incidental findings in research, clinical practice, and direct-to-consumer testing, as well as experts on the ethical issues associated with incidental findings in science.

You can follow the proceedings of the Commission’s meeting here at this blog, or on the live webcast at the Commission’s website: www.bioethics.gov. All transcripts and webcasts will be archived and available following the meeting.

Although the regulatory provision for national-level review of pediatric research has been in place for more than 30 years, it has been used only 14 times, and experts convened to assist the Secretary in evaluating those protocols have consistently noted uncertainty in applying the regulatory criteria, which, in part, call for compliance with “sound ethical principles” without specifying what these are. The criteria for national-level review provide fundamental baseline protections for those children involved in approved protocols while permitting sufficient flexibility for the Secretary to exercise discretion in reviewing research, allowing her to tailor the review for a given context. This flexibility is important to ensure that essential research can go forward, but it leaves reviewers with few guidelines about what is otherwise a unique form of review.

Recognizing these difficulties, the Bioethics Commission developed a rigorous ethical framework to guide national-level review of pre-event pediatric MCM research. Of note, the Bioethics Commission found certain conditions in the context of pre-event pediatric MCM research merited stricter research limitations than otherwise permitted by the regulatory criteria for national-level review. For pre-event pediatric MCM research, the proposed framework requires that any approved protocol present no greater than a minor increase over minimal risk, despite the absence of a risk limitation for national-level review in other circumstances.

Other considerations outlined by the Bioethics Commission derive from the circumstances requiring national-level review more generally, rather than solely the considerations of MCM-related pediatric research. For instance, the Bioethics Commission concluded that, given that children in research meriting national-level review (i.e. greater than minimal risk with no prospect of direct benefit) participate primarily for the benefit of other children and society more broadly, justice requires that care and compensation be guaranteed for any research-related injury to a child participant. In addition, the Bioethics Commission concluded that equitable and appropriate access to any successfully tested intervention must also be guaranteed prior to the initiation of research.

The ethical framework, laid out below, provides additional specification of national-level review criteria, clarifying, specifying, and emphasizing the three regulatory criteria that govern national-level review. The Bioethics Commission clarified when a protocol offers a “reasonable opportunity” to address a “serious problem” affecting the health and welfare of children, stating that the research ”must present an opportunity to learn about a specific MCM candidate that might be useful in protecting or treating children exposed to a serious threat,” defined by consequences of exposure that are “life-threatening, permanently disabling, debilitating, or similarly grave” from an event that is “relatively likely, as opposed to remote.” The Bioethics Commission also specified a rigorous set of conditions to determine if research would be conducted in accordance with “sound ethical principles.” These conditions limit the degree of risk that may be posed by any protocol, account for essential concerns in research design, establish requirements for post-research distribution, treatment and compensation for research-related injury, and call for community engagement and transparency and accountability. Finally, the Bioethics Commission emphasized that researchers and persons independent of the research must communicate the heightened risks and uncertainties involved in MCM research so parents can provide informed permission and children can provide meaningful and developmentally appropriate assent.

Although the framework was developed to assess pediatric MCM research, it encompasses many of the considerations required for any national-level review. Expert panels might find that it presents useful guidance as they evaluate non-MCM pediatric protocols.

What is AVA?

AVA is a vaccine used to prevent anthrax disease. Currently, AVA is the only anthrax vaccine licensed by FDA.

First licensed in the United States in 1970, AVA is approved for use in persons 18 through 65 years of age who are at high risk of exposure to B. anthracis spores. The vaccine is approved for use before exposure has occurred, though FDA has authorized adminis¬tration of AVA to adults to prevent infection after exposure under certain emergency circumstances. AVA given before potential exposure to B. anthracis is administered in five doses over 18 months, followed by an annual booster.

What do we know about AVA?

Although few in the civilian population have received AVA, it has been widely distributed to members of the military. Since 1998, over 1.5 million military personnel have been vaccinated with AVA.

Evaluations of AVA indicate that its safety profile is comparable to other vaccines. Testing in both animals and human adults has revealed that the most common reactions to AVA include tenderness and redness near the injection site. Other mild reactions near the injection site—such as itching, development of a lump, and bruising—have also been reported, but they are less common. Even more rare are systemic events, such as fever, malaise, and myalgia.

The immunogenicity of AVA, that is, the ability of AVA to produce an immune response, has also been evaluated in both adult humans and animals, and data from these studies demonstrate AVA’s ability to produce a meaningful immune response to combat anthrax infection. However, although the mechanism of immunogenicity is understood, the precise level of antibody that confers protection against anthrax is unknown.

Although human challenge studies (research in which individuals are exposed to a disease or pathogen to test a drug or biologic’s ability to prevent infection) would be unethical in the case of anthrax, studies in animals suggest that AVA is effective, and that it is most effective when combined with antibiotics. Observational studies conducted when individuals are naturally exposed to B. anthracis also suggest that the vaccine is efficacious in adults. Data from a 1962 study evaluating an early anthrax vaccine (not AVA), indicated that the vaccine provided protection against the development of cutaneous anthrax disease.

What is left to learn about AVA?

Research on AVA is ongoing. The Centers for Disease Control and Prevention and the Institute of Medicine have stated that future research on AVA should include studies on long-term side effects, alternative dosing methods, and quantitative correlates of immunity in animal models.