Research Ethics Roundup: NIH moves to retire chimps, the “mouse hospital” approach, and more

by Maeve Luthin, JD, project coordinator

Take a few moments to catch up the latest news in research ethics! Whether you work in animal care and use or human subjects protections, this week’s edition has something for you!

Super Sugar Keeps Naked Mole Rats Cancer-Free: Researchers have discovered that naked mole rats do not contract cancer due to hyaluronan, a complex sugar, which exists in spaces between cells and prevents them from clumping together to form tumors. Scientists plan to continue their research by planting the hyaluronan into mice to see whether they too can remain cancer-free.

Tiny Patients, Major Goals: Some researchers are studying certain types of cancer using a “mouse hospital” approach, in which mice are genetically altered to develop cancer in their organs as opposed to under the skin. In this model, investigators observe these mice using tools such as ultrasounds and CT scans, which allow researchers to explore treatments that pinpoint the genetic roots of the disease.

Tight Budgets Put the Squeeze on Promising Medical Research: With National Institutes of Health (NIH) grant approvals at their lowest level ever, many promising scientists are leaving academic research. Those who are staying in the field are spending a majority of their time writing grants and securing funding instead of conducting research. While US federal grant money has declined, other countries are increasing their research budgets, leading commentators to warn of a “lost generation” of US-based scientists.

NIH to Significantly Reduce Use of Chimps in Research: NIH announced that it will be retiring 310 chimpanzees currently available for research purposes to the Federal Sanctuary System. The agency will keep but not breed up to 50 chimps for future biomedical research studies that meet the criteria and principles laid out by the Institute of Medicine (IOM). NIH plans to wind down all research projects using NIH-owned or supported chimps that do not meet IOM principles and criteria.

The Mystery of the Second Skeleton: The Atlantic traces the challenges of investigating rare diseases by profiling researchers and those with fibrodysplasia ossificans progressiva (FOP), a disorder in which patients grow new bones that stretch across their skeletons. Patients and their families banded together to raise money for the first lab dedicated to studying the disease and also volunteered blood and tissue samples to help propel research forward. In part due to this grassroots activism, NIH’s Therapeutics for Rare and Neglected Diseases program is now running preclinical tests on the first drug developed for the condition.

We live in one world: An interview with Henry Silverman

by Megan Frame, membership coordinator

Welcome to another installment of our featured member interviews where we will continue to introduce you to more of our members—individuals who work to advance ethical research on a daily basis. Please read on to learn more about their professional experiences, how membership helps connect them to a larger community, and what goes on behind-the-scenes in their lives!

Today we’d like to introduce you to Henry Silverman, MD, MA, professor of medicine at the University of Maryland School of Medicine in Baltimore, MD. 

Megan Frame (MF): When and why did you join the field? 
Henry Silverman (HS): My transition into the field of ethics has slowly evolved over the last 20 years, motivated initially by the difficult issues surrounding the end of life that I faced when I started working in an intensive care unit. My lack of knowledge of medical ethics prompted me to obtain a Master’s degree in bioethics which has provided me with the background necessary to analyze all types of ethical issues. Subsequently, I became very active in conducting critical care clinical trials, which led me into the research ethics field. All of this prepared me for obtaining a Fogarty/National Institutes of Health training grant  to enhance research ethics capacity of individuals in the Middle East.

MF: What skills are particularly helpful in a job like yours?  
HS: One major skill involved with my job is being able to conduct ethical analysis, which really requires a background in philosophy.

MF: Have there been any PRIM&R events or talks that you have attended that have significantly impacted your approach to your work? If so, what were they and how did they influence you?
HS: I can’t say there has been a single PRIM&R event or lecture that has influenced me, but rather simply attending PRIM&R conferences and being able to network with so many individuals at one time, in a short period of time, has been remarkable.

MF: How has membership in PRIM&R’s community of research ethics professionals helped you to advance in your career?
HS: The PRIM&R staff has been especially helpful in regards to the expanding international focus of our field. PRIM&R has taken a strong interest in providing opportunities to individuals from overseas. Many of my trainees in the Middle East Research Ethic Training Initiative (MERETI) have been recipients of PRIM&R’s conference scholarship program, and the PRIM&R experience has been extraordinary for them.  

MF: What is your proudest achievement? 
HS: Directing the MERETI program and developing professional and personal relationships with individuals from the Middle East.

MF: What is one thing you wish “the man/woman on the street” knew about your work? 
HS: We live in one world, and hence, the problems faced by individuals in the developing world do affect us, no matter how invisible they may appear to be.

Thank you for sharing your stories with us, Henry.  If you’d like to learn more about becoming a member, please visit our website today.

In Memoriam: Harry Rozmiarek, DVM, PhD

by Joan Rachlin, JD, MPH 

Photo courtesy of Harry’s son, Daniel.

It is with a profound sense of loss and deep sadness that I write to let our community know of the untimely death of Harry Rozmiarek, DVM, PhD, a cherished member of the PRIM&R Board of Directors since 1990, and a longtime leader in the wider laboratory medicine world. Harry died on June 15, 2013, in Boston. Alexander Capron, PRIM&R's board chair, expressed what all of us are feeling, noting: "We will remember and celebrate his warmth, humor, and dedication to the welfare of humans and animals, and we will always be grateful for his wise counsel and unswerving support of PRIM&R.” 

Harry was an active and valued member of PRIM&R’s executive, finance, and certification committees, served as PRIM&R's board treasurer and secretary, and taught at more of PRIM&R’s annual Institutional Animal Care and Use Committee (IACUC) Conferences than almost anyone else, all of which he did with great skill, prodigious energy, bottomless wisdom, and common sense. Just recently he was asked if he was willing to be re-nominated to the board as the end of his current term approached, and, in characteristic "Harry-fashion," he said, “I’m more than willing to run again because I still have so much I want to do." 

He was unfailingly helpful and collegial, and was admired, liked, and deeply respected by his PRIM&R colleagues. As former board chair Walter Straus wrote: “Within PRIM&R, Harry was both a colleague and a mentor. At board meetings, he could always be relied upon to offer his frank and well-considered thoughts, which invariably enriched our decision-making. He had a good head for finances, and provided generous mentoring to many. I am also sure that PRIM&R’s support for ethical protection in animal research would not be nearly so strong were it not for Harry’s advocacy."  

Other reactions from members of PRIM&R’s Board of Directors—past and present—similarly bespeak his colleagues' admiration and corresponding heartbreak, and I'd like to share a few of those comments with you:

• "Harry was very helpful in building bridges and it was always a great treat to have time to talk with him about his life and work, particularly his years of service to several presidential pets." – David Borasky, Jr., MPH, CIP


• "I am honored to have known and learned so much from Harry and will remember him most fondly." -  Susan Fish, PharmD, MPH


• "Harry was always so kind and supportive." - Cynthia Gomez, PhD


• "I am truly shocked and saddened. He was an amazing man." - Tanise Jackson, DVM, DACLAM


• "Harry was a gentleman and a scholar, and I will miss his wisdom and humor." - Moira Keane, MA, CIP


• "It is so devastating to lose such a dedicated, warm, and generous human being." Paula Knudson


• "Harry was such a wonderful, kind, and dedicated individual. His compassion, commitment, and diplomatic ways serve as a role model for many of us. PRIMR will certainly miss Harry." - Susan Kornetsky, MPH


• "Harry was one of the best people I know and a very fine colleague. I mourn this loss and will miss him greatly." - Robert Levine, MD


• "Harry was fearless. He was a healer, a peacemaker! He revolutionized the care of animals and brought reason and order wherever he worked. He was a highly competent professional, but first and foremost he was a family man!" - Charles McCarthy, PhD 


• "I had the fortune to work with Harry on the veterinary side on committees, boards, publications, and activities for over 30 years. He had a positive impact on many developing careers in lab animal medicine and science, and will be missed deeply. Harry’s enduring and pervasive commitment to the organizations of this field and to PRIM&R was a persistent feature of his life.” - Chris Newcomer, VMD, MS, DACLAM


• "Harry was the ultimate gentleman and perfect colleague. I am so thankful for having had the opportunity to share time, ideas, conversations, and laughs over the past many years." - Pearl O'Rourke, MD


• "Harry has set a high standard for us to follow." - Marky Pitts, CPIA


• "Harry was such a wonderful person. I have no words to express the sadness of this tragedy." - Ada Sue Selwitz, MA


• "Harry was simply one of a kind." - Barbara Stanley, PhD


• "It was only after a few years of knowing Harry that I began to grasp the breadth of his knowledge and  professional stature. He was that modest. He managed to make significant contributions in several different professional paths, ranging from military veterinary medicine, to academic research, to enhancing the profession of veterinary medicine and finally to the broader PRIM&R constituency.” - Walter Straus, MD, MPH

There are many more testimonials, but what I'd really like to share are a few favorite snapshots of Harry's overflowing life. He was born on a dairy farm in Wisconsin to hard-working parents who did not have an opportunity to obtain a formal education. His mother had desperately wanted to go to high school, but her father insisted that she instead stay home and learn to cook, bake, and otherwise care for a family. To demonstrate her thirst for education, she offered to walk to and from school, but her father said that would wear out her shoes, whereupon she said that she would hold them in her hands and walk to school barefooted. Her father never relented, but her drive is symbolic of the thirst for education that was instilled in Harry by his parents, which he more than quenched over his long and illustrious career.

To list Harry's accomplishments would take hours, but even a quick look at his CV tells the tale of a man who embraced life, learning, research, teaching, a career as a laboratory animal veterinarian, organizational work for at least a dozen nonprofits, and service on a remarkable number of high level committees and commissions. Those professional achievements are only part of the story, though, as no CV can describe or measure Harry's devotion to his family, friends, colleagues, mentees, and to the many who met him in the course of his near non-stop travel.  

By his own admission, Harry loved excitement, and the nearly endless travel opportunities life brought him provided him with enough excitement for many lifetimes. He made regular trips to China and other parts of Asia, South America, Europe, and Africa, and had, in fact, just returned from Spain prior to his passing. His passion for travel was not limited to international excursions, though. While serving as an attending veterinarian for the US Army in New York City from 1965-1967, Harry and his wife, Jane, went to 35 Broadway shows in an effort to pack in as much culture as they could before their family began expanding.

Another very unique source of excitement for Harry was his service as the Army veterinarian in charge of many presidential pets. He cared for President Lyndon B. Johnson’s dogs, Caroline Kennedy's pony, "Macaroni," and several deer that had been given to the Kennedy family by the President of Ireland. He was also responsible for the horses that pulled the caissons for President Harry S. Truman, General Douglas MacArthur, and President John F. Kennedy, and had a treasure trove of stories from those years.

During another Army stint, this time in Bangkok, Harry and Jane accumulated a large and beloved menagerie of animals that ranged from chicks to ducks to geese to dogs to baby otters to a one-day old black sheep; Jane nursed both the otters and sheep through their infancy. This barnyard assortment gave rise to many touching and funny stories, including the time Harry had to "introduce" one of the dogs to the gardener, lest he disturb the ducklings who were under the dog's protection. When the Rozmiareks decamped for the United States, they painstakingly found homes for each of their animals. This, and all of Harry's experiences, demonstrated his unwavering compassion and innate capacity for and commitment to nurturing whatever was under his care.

Harry Rozmiarek's embrace of education, hard work, volunteerism, and his family, combine to compose a life that defies sufficient description or adequate tribute. He was someone who had a prodigious appetite for adventure, and everything Harry embraced became an adventure. There are many ways to measure a life, but living with a whole heart and with kindness and respect for all creatures is surely one of the most recognized. Harry was a pure of heart man whose thoughts, beliefs, and actions were aligned.

As Bishop Beckwaith wrote in 1885...

“Plant a thought and reap a word;

plant a word and reap an action;

plant an action and reap a habit;

plant a habit and reap a character;

plant a character and reap a destiny.”

Rest in peace, Harry. You will be missed, but our lives have been so enriched by your presence among us and we will never forget you.

Research Ethics Roundup: Classifying chimps as an endangered species, gene patents, and more!

by Maeve Luthin, JD, Project Coordinator

It’s your favorite time of the week again! Take a few minutes to catch up with the research ethics world by reading through this edition of our Research Ethics Roundup.

US  Regulator Plans to Declare Research Chimps Endangered: The US Fish and Wildlife Service announced a proposal to classify captive chimpanzees as endangered species. The Service will work closely with the National Institutes of Health and the biomedical research community to examine the implications of the proposed rule.

An Experimental Drug’s Bitter End: The New York Times profiles individuals affected by Seaside Therapeutics’ decision to stop production of arbaclofen, a drug that failed a phase II clinical trial for fragile X syndrome and autism. Families and advocates of former research subjects are petitioning the company, as well as the US government, to continue to make the drug available.

Hospitals Want to Test Drug with No Consent: A Boston-based research team is looking to join a multisite study that provides emergency treatment for brain trauma patients. If approved, it would be the first study at a Boston hospital to use the Food and Drug Administration’s exemption from the informed consent requirement for studies conducted in emergency settings.

Supreme Court Rules Human Genes May Not Be Patented: In a unanimous decision that will have a far reaching impact on scientific research, the Supreme Court ruled that isolated human genes are not patentable, thus invalidating patent claims by Myriad Genetics’ on DNA codes found in the BRCA1 and BRCA2 genes. The Court held, however, that composite, or synthetic, DNA is patentable, as it is not a product of nature.

Geneticists Push for Global Data-Sharing: The Global Alliance, a consortium of 69 institutions in 13 countries, will convene to develop standards and policies regarding data-sharing of personal DNA sequences combined with clinical information. The group also plans to address privacy and informed consent issues that might inhibit the use of such data.

Additional developments in ongoing SUPPORT study controversy

by Elisa Hurley, PRIM&R Education Director

Since our post last Thursday, there have been some additional, noteworthy developments around the SUPPORT trial and the Office for Human Research Protections’ (OHRPs’) latest actions that we thought were worth sharing. One day after the publication of OHRP’s letter stating it was putting on hold all compliance actions against the lead SUPPORT site, the New England Journal of Medicine (NEJM) posted a letter to the editor, signed by nearly 50 prominent bioethicists, calling for OHRP to retract its determination that the institutions involved in SUPPORT failed to meet regulatory informed-consent requirements. "We believe this conclusion was a substantive error and will have adverse implications for future research," the letter authors write. Not only is OHRP’s conclusion that the study exposed subjects to additional risk "not supported by the evidence," but, the letter continues, "the conclusion of the OHRP that the SUPPORT investigators violated federal regulations in failing to include specific information elements regarding risks of the study interventions in the parental permission documents is without substantive merit and overreaches."

The criticism of OHRP did not end there, however. That same day, NEJM also posted a “Perspective” piece from the National Institutes of Health (NIH), which is housed, as is OHRP, within the Department of Health Human Services. Authored by NIH Director Francis Collins, NIH Deputy Director for Science, Outreach, and Policy Kathy Hudson, and National Institute of Child Health and Human Development Director Alan Guttmacher, the piece makes clear that NIH "respectfully disagree[s] with the conclusions of the OHRP," and suggests that OHRP’s conclusions resulted from a "fundamental difference in interpretations of how the regulations should apply to the state of scientific understanding when the SUPPORT study commenced." The letter laments that the controversy swirling around the SUPPORT study over the last several months has alarmed parents and confused the biomedical research and oversight communities, but goes on to suggest the debate has "set the stage for a substantive national dialogue with the research, advocacy, and ethics communities on how best to respect and protect participation in research studies conducted within the standard of care and how to define 'reasonably foreseeable risks' within this setting." Finally, the letter calls for OHRP to be more transparent regarding the process it follows for investigating complaints of noncompliance.

Has your IRB or HRPP been following the SUPPORT study controversy? If so, what is your take on these latest developments? Share your thoughts with the community!

The SUPPORT study and the future of Comparative Effectiveness Research

by Elisa Hurley, PRIM&R Education Director, and Avery Avrakotos, PRIM&R Education and Policy Coordinator

In a letter dated June 4, 2013, the Department of Health and Human Services (DHHS) Office for Human Research Protections (OHRP) took the unprecedented step of suspending all compliance actions against the University of Alabama at Birmingham (UAB) relating to its participation in the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) study.

Let’s review the events leading up to this development.

The SUPPORT study, which ran from 2005 to 2009, was a multi-site, randomized clinical trial investigating, in part, optimal oxygen-saturation levels for severely premature infants. When the study was conceived in 2003, the American Academy of Pediatrics recommended that premature infants receive supplemental oxygen levels anywhere between 85% and 95%, with the exact percentage left to the discretion of the treating physician.

What remained unknown, and what the SUPPORT study was designed to determine, was exactly how much oxygen within that range to provide to extremely low birth weight infants in order to minimize retinopathy (a long-known risk of the prolonged use of supplemental oxygen, which can cause blindness) without increasing the likelihood of other serious outcomes, such as brain damage or death. In 2004, 1,316 premature neonates aged 24-27 weeks were recruited at 23 study sites and were randomized into one of two groups: 85-89% oxygen saturation (low range) or 91-95% oxygen saturation (high range). Both ranges were within the standard of care provided at the participating institutions. The hypothesis being tested was whether, relative to infants managed with the high range of oxygen, the low range would result in an increase in survival without the occurrence of retinopathy. Thus, the two measured outcomes were retinopathy and mortality.

The study was approved by institutional review boards (IRBs) at each participating study site. Written informed consent was obtained from the parents of each neonate in the study. However, on March 7, 2013, after two years of investigation, OHRP sent a letter to the lead study site at UAB detailing its finding that “the conduct of this study was in violation of the regulatory requirements for informed consent, stemming from the failure to describe the reasonably foreseeable risks of blindness, neurological damage and death.” More specifically, the letter stated that the consent forms did not contain information in the “possible risks” section about risk of death or the risk of retinopathy. One month later, Public Citizen, a consumer advocacy organization, brought OHRP’s determination, and the study, to the attention of the media with an open letter to DHHS Secretary Kathleen Sebelius supporting OHRP’s finding and further condemning the SUPPORT study design itself as unethical.

That letter set off two months of heated public debate touching on a number of central issues in research ethics: the notion of clinical equipoise and ethical study design; the proper understanding of standard of care and when research presents novel risk; how to evaluate whether the balance between the benefits of research and the risks to vulnerable subjects is reasonable; and what comprises appropriate informed consent in randomized studies of standard of care. Researchers, clinicians, and bioethicists have come out on either side of the conflict, some in support of OHRP or Public Citizen’s analysis that the informed consent form, or the study design itself, were unethical or even inexcusable; some critical of these positions and in support of the study design and the investigators carrying it out.

The implications of the SUPPORT trial, the subsequent disagreement within the research community, and, ultimately, the unprecedented move of OHRP point to growing pains around a dynamic shift in the way clinical research is being conceived and conducted across healthcare settings. Traditionally, randomized clinical trials have been a tool to discover new treatments for a given ailment. But in the face of a proliferation of treatment options, healthcare consumers, practitioners, and sponsors are seeking systematic ways to gain more information about the best and most cost-effective treatments currently available for particular conditions. This trend, and a recent call from the Institute of Medicine (IOM) to develop learning healthcare systems that encompass much of what we currently think of as clinical practice, suggest that comparative effectiveness research (CER) is gaining traction.

CER has the potential to dramatically improve health outcomes while reducing costs. This type of research can be fraught with complications, however, as it raises questions about, or even upsets, the boundaries between research and clinical practice. This is arguably the case with the SUPPORT Trial: as OHRP wrote in its most recent letter, “Ultimately, the issues in this case come down to a fundamental difference between the obligations of clinicians and those of researchers.”

If the healthcare community is to continue to undertake efforts to examine existing treatments in a systematic fashion, one thing is certain—clearer guidance is needed. OHRP acknowledged as much in its June 4 letter, admitting that “there is justification for an incomplete understanding of how [the rules around disclosing risk] might apply” to studies such as SUPPORT. It goes on to “recognize OHRP’s obligation to provide clear guidance on what the rules are with regard to disclosure of risks in randomized studies whose treatments fall within the range of standard of care,” and promises greater than usual public participation in the development of such guidelines.

This latest letter will not end the disagreements around the ethics of the SUPPORT study. But if it injects new urgency and energy into the discussions around the need for safe and respectful comparative effectiveness research, then surely everybody wins.

Research Ethics Roundup: The SUPPORT trial debate continues, avian flu makes news, and more

by Maeve Luthin, JD, Project Coordinator

It’s been a busy two weeks in the research ethics world! Grab some iced coffee and take some time to catch up with current events.

Dirty Medicine: Earlier this month, generic drug manufacturer Ranbaxy pled guilty to federal criminal charges of selling adulterated drugs with the intent to defraud, failing to report that its drugs didn’t meet specifications, and making intentionally false statements to the government. In this piece, Fortune investigates the company’s long-term fraud and misconduct, as well as subsequent steps taken by the Food and Drug Administration (FDA) in response to the company’s noncompliance with federal regulations.

Drug Shortages: Washingtonian explores the realities of drug shortages by profiling the practical effects of the current parenteral nutrition shortage. Parenteral nutrition, made up of some 20 nutrients, is a form of intravenous nutrition often given to premature infants. It is also one of more than 300 drugs, vitamins, and trace-elements in short supply in the US.

Avian Flu in Animal Models: Animal research on the H7N9 avian influenza strain shows that the virus is transmissible between ferrets. Learning about how the flu spreads among mammals allows researchers to predict the possibility of future human-to-human transmission of the virus.

SUPPORT Trial Debate: On the Bioethics Forum, the blog of the Hastings Center, John Lantos, MD, argues that the consent forms used in the controversial SUPPORT trial were adequate as they conveyed all reasonably foreseeable risks. In a response blog, Michael Carome, MD, and Sidney Wolfe, MD, reject Dr. Lantos’ conclusions, and outline inconsistencies between the consent form and the study protocol.