Celebrating a journey of family, hope, scientists and philanthropy: Triumph

Gala - Alison FraseLast month we left off the story of Joshua Frase, his sister Isabella, and their parents Paul and Alison with their determination to find a treatment for a faulty MTM1 gene, which results in the fatal and physically devastating neuromuscular disease, Myotubular Myopathy (MTM).

Just before Joshua’s first birthday, his parents launched The Joshua Frase Foundation to fund research with the hope of a cure.  There is none more devoted than a child’s parents to raise funds, advocate for research and persistently seek treatment and cures. With the help of Paul’s status as a former NFL defensive lineman (Jets 1988-1994, Jaguars 1995-1996, Packers 1997, Ravens 1998), and the family’s tenacity, the Foundation supports basic and preclinical gene therapy research for MTM.

Alison was inspired when she saw a video of a crippled mouse, soon restored to full mobility following gene therapy.  It was her “aha moment” to find a cure for Joshua.  The research process is often long and complex, but the Frases had a short timeline and high expectations to identify a starting point to move rapidly to a cure.  Myotubular Myopathy is a good candidate for gene therapy where a functional copy of the gene replaces the faulty one and is delivered to each cell in the body using a viral vector.

Through the counsel of researchers, she started searching for a large animal model by calling veterinarians throughout the US and Canada until—miraculously– they identified a female chocolate Labrador retriever who was a carrier of the MTM1 mutation.  This pup, Nibs, became part of the Frase family and the start of a colony of research animal heroes for preclinical research toward a gene therapy cure.  Dr. Martin Childers at the University of Washington leads this research; we honor him at our 2018 Gala.  The dogs bred for this research are born with the MTM1 mutation and untreated would live only about 18 weeks; with gene replacement, they are still alive after 5 years.

Joshua passed away on Christmas Eve at the age of fifteen.  To quote his dad, Joshua’s “story is far from over.”  Thanks to the Frases, their countless supporters, the lab animal heroes, the animal care and research teams, Dr. Martin Childers and his team….the hopeful cure for this disease has entered a phase I/II clinical trial.  The study drug is an AAV8 vector containing a functional copy of the human MTM1 (hMTM1) gene to replace the dysfunctional copy in people with MTM.  Enrollment began August 2017, about 10 years after Joshua’s death and 21 years after the Foundation began, to treat four boys under the age of five with MTM.

For their journey, we are honoring Paul and Alison Frase for their courage, persistence, advocacy and fundraising on behalf of their beautiful son and others affected by Myotubular Myopathy. We are also honoring Dr. Childers for his passionate, compassionate and brilliant research to understand and treat MTM.

 

In his blog as a young teenager, Joshua published intimate thoughts about his personal mission in life.  He wrote, “My ultimate goal is to have a career as a research scientist. I want to specialize in muscle gene therapy so that I will be able to find a cure for Myotubular Myopathy.” He also wrote of his goals to “gain confidence in speaking before a group of people” and to “continue to grow spiritually.”  These are remarkable goals for any person, let alone someone so young and with unusual health challenges.

Help carry on Joshua’s personal mission to cure Myotubuluar Myopathy.  By attending the NWABR Gala you celebrate Joshua, his family, Dr. Childers, and the lab animal heroes who have brought his mission into reach.

 

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A Reflection on Brain-computer interfaces: Ethical challenges and opportunities

brain_computer interfaceFacilitated by Kevin Measor, PhD, Gonzaga University, and Jen Wroblewski, MPH, NWABR on April 10, 2018

In a packed room at the back of a popular Spokane pub, we gathered not for a birthday party or alumni gathering. Undergrads, science-enthusiasts, medical students, business owners and professors wedged into a crowded pub to talk about the emerging technology of brain-computer interfaces (BCI). Dr. Kevin Measor, faculty at Gonzaga and founder of the Spokane Center for Public Neuroscience Education, led the discussion.

The ability to record brain activity and use this information to control devices like computers, wheelchairs, and brain stimulators is a goal of brain-computer interface (BCI) research. With this technology comes great promise to improve people’s lives, but will the introduction of BCI devices into medicine and beyond raise ethical concerns? What brain data is private? Will these devices lead to human enhancement? Who will have access to expensive BCI devices? Will this technology raise questions of identity and what makes us human?

We tackled three key scenarios that illustrate currently available technology: (1) Deep Brain Stimulation (used to treat tremor in patients with Parkinson’s Disease) to treat mental/behavioural health issues, (2) Neuroprosthetics capable of interacting with the brain and prosthetic limb and (3) Neurofeedback recordings used to measure states of awareness in long-haul truck drivers.

Scenario #1. Should deep brain stimulation be used to alter undesireable, non-pathologic behavior? What about mandated treatment for pathologic behavior? Most agreed that if the science is solid, DBS should be offered but that no treatments should be forced on people. People did perceive a difference in mandated mental health treatment using medication versus DBS because of concerns that DBS may not be irreversible or that it may have in intended consequences.
Scenario #2. People with neuroprosthetics use their new limbs to restore, as best they can, what they have lost. There is an argument that BCI prosthetics actually enhance, rather than simply restore, the health of a user. In the case of athletes we wondered whether individuals using BCI prosthetics might have an advantage if they could program their ‘robo-limb’to resist fatigue, improve reaction time, etc. Most thought it would be more fair to offer separate competitions for people with BCI prosthetics. We were concerned though that BCI prosthetics will be more costly than traditional prosthetics, which are already 20-40K each. Access to this technology will be tricky, as will repairs to the hardware when it needs refurbishing.
Scenario #3. By far people were most interested in this scenario where long haul truck drivers would be monitored for their state of consciousness/awareness using a hat embedded with EEG sensors. The sensors would send real time data to a control center to judge whether a driver is in a dangerous, sleepy state and would then order the driver to stop driving and rest. Similar technology may be useful for other professions such as soldiers and medical professionals working long shifts. As a group we were split on the legality and usefulness of BCI for this purpose. It raised more questions than answers. For example, who is legally responsible in the event of a truck accident or medical mistake? Isn’t this an invasion of the employee’s privacy? Others felt that BCI could provide useful tools for employees in sleep-deprived professions to self-assess their job safety and provide data to justify changes in company policies. In the end, we arrived at a universal bioethics dilemma: which is more important….individual rights (autonomy) or public safety?

BCI has the power to restore individual agency, reduce suffering and improve human performance. On the other hand it raises concerns about privacy, access and power. Like any good discussion all we could say was…..IT DEPENDS.

 

Celebrating a journey of family, hope, scientists and philanthropy to treat myotubular myopathy in Phase 1 clinical trials, Part 1

Dr. Martin ChildersIf you are a parent you already know the guts, fortitude, desire and village it takes to raise a child from milestone to milestone to adulthood.  Imagine your child is born with a fatal genetic disease affecting the function of all his skeletal muscles.  Meet Alison and Paul Frase, their daughter Isabella, and finally their son Joshua who was born with myotubular myopathy.  If you remember anything about their story, I want you to remember the power of passionate parents working with brilliant, dedicated scientists who tenaciously act and hope for a cure through biomedical research.

The genetic villain in the story is the MTM1 gene, where mutations cause total loss of function in the myotubularin gene.  This gene normally makes an enzyme, myotubularin, which is thought to create and maintain muscle cells.  Kind of important. So when the gene cannot make this enzyme, people (and animals like dogs) experience muscular “floppiness,” breathing issues, feeding issues and scoliosis to name a few.

If you are a scientist, like Dr. Martin Childers, you also know the guts, fortitude, desire and village it takes to conduct research…especially research you hope will treat devastating genetic diseases like the one that affected Joshua.

The Frases, Dr. Childers and other folks have partnered to do something about myotubular myopathy in animals and people.  NWABR is honoring their work at the Speak Up for Research Gala this year.  Want to know more?  Stay tuned for the May newsletter and register for the Gala on May 24th.

What’s in Our Water, Who Decides and Why? A Spokane Community Conversation

This Conversation was facilitated by Ms. Emily Firman, MPH, MSW (ARCORA Foundation) and Jen Wroblewski, MPH (NWABR) on January 16, 2018.

The question of community water fluoridation (CWF) has been long debated in Spokane, WA.  Citizens haveDrinking water voted three times on the matter and all times chosen not to introduce fluoride to the drinking water.  The most recent vote in 2000 failed by 1%.

Given this history, I expected our Conversation last night to include some significant voices of opposition. It turns out that our audience was either neutral or in favor of CWF.  Our attendees were mainly college or medical school students, public health officials and professors.  This demographic has traditionally supported CWF.  What WAS surprising was that many who attended did not know the historical opposition to CWF and did not understand why the benefits of CWF were even in question.  Prior to the Conversation both NWABR and our partners received letters or queries from known opponents to CWF from California and Colorado. I had hoped some would attend the Conversation.

TRUST

Attendees accepted that CWF has great benefit in strengthening tooth enamel and therefore reducing dental decay.  They trust the judgment of most health authorities, who have either conducted their own observational population research or reviewed the research of others, who state that CWF is a safe and effective way to prevent and treat tooth decay.

ECONOMIC FRAME

Based on available data and personal stories, attendees perceived that it is more economical to offer CWF than to pay for the subsequent oral health costs of increased decay. Some studies cite that every dollar spent on CWF saves $38 on future health costs.  The Spokesman Review cited in 2001 that installing CWF would cost about $1million with an additional $300,000 per year (Hansen, 2/12/2001).  One attendee shared that she has 11 crowns, several implants and other dental work.  She wondered, “maybe if I lived in an area with community water fluoridation this [amount of dental work] wouldn’t be the case.” She went on to say, “If I spent the money on my dental work, about $30,000, on fluoridation instead imagine the good I could have done!”

GREATEST GOOD VS. AUTONOMY

It’s a classic clash of two ethical principles in public health: maximizing good vs. autonomy (individual choice, determination). The clash fascinates me because it’s a natural dilemma at which groups of people arrive whether or not they have training in bioethics. “I don’t see why, if just a small percent of people are against it, the rest of the population shouldn’t have a voice when they want fluoridation.” While the attendees tonight strongly valued maximizing good, they also understood the argument for personal choice.

A medical student suggested that autonomy goes both ways.  “People should have a choice on whether to consume water with fluoride, but so should people have the right to smile with comfort and have a pain free mouth.” Poignant.

COMPROMISE POSITION…the THIRD WAY

Someone suggested that the ethics of autonomy and maximizing community good didn’t have to be in conflict.  She thought that perhaps the community water supply could remain nonfluoridated and people could have free access to fluoride drops or tablets.

Numerous comments unfolded about the success of this approach. A mother who moved to Spokane in 2000 just as the “no” vote emerged, said “I wanted fluoride for my kids in their water.  I thought, ‘What sort of backwater place have we moved to?’” She went on to tell the story about administering fluoride drops to her kids.  She thought that if some drops were good, more were better.  Her son is now grown and has cosmetic fluorosis—but no cavities!  When her kids were little the fluoride drops were a prescription and she had to provide a copay.  She acknowledges that the copay system may prevent some people from accessing fluoride drops.

A physician in the group noted that patient compliance is not as good as he’d like and worries that leaving the administration of fluoride up to parents might not be broadly successful. This is even more true when you consider than only 50% of kids in Spokane see a dentist regularly.  In addition, fluoride drops are not currently given to adults who would benefit from cavity reduction through remineralization of early cavities.

BENEFITS OF RESPECTFUL CONVERSATION

I was struck tonight by the impact of the information, stories and shared conversation among folks, even though they largely agreed with one another.  Evaluation comments indicate that people plan to take action on this issue.  Attendees want to build relationships with those who oppose CWF, talk to their city councilpeople, share what they learned with friends and colleagues and invest their time and energy in this issue.  They are eager to influence nuanced thinking about water fluoridation.

By together setting discussion ground rules, by presenting opposition perspectives and by encouraging any and all opinions, tonight’s Conversation had a strong impact. The secret?  Strong science.  Compassionate listening. Personal stories. Moving toward nuanced rather than binary thought.  Seeing one another as people first and opponents second. This Conversation was one of the best yet.

With gratitude,
Jen

The War on Drug Prices

Cost of Drugs_cartoon
Most Americans ask the question, is the price I pay for prescription medications FAIR? In other words, what is the true cost of developing, making and selling a medicine, AND how much profit seems reasonable? This is what we tackled last week during our Community Conversation with experts from the U of Washington’s International Society for Pharmacoeconomics and Outcomes Research (ISPOR).

KEY FACTS THAT INFORMED OUR DISCUSSION
Tufts estimates that it costs $2.6 billion to develop an FDA approved drug, a number that increases 9% per year.  People in the US pay more for drugs than people in other countries for a few reasons: 1) we use more medications because we have better access to new ones, 2) we have a higher burden of chronic disease like diabetes and obesity, and 3)  in the US, the government protects drug manufacturing monopolies and limits price negotiations while other countries have more price regulation.

Another reason people in the US (and in Canada and Europe) pay more for medications is simply because, on the whole, we can afford to. Picture a world map, and picture all the people who live on Earth.  At 326 million, the US population is 4.4% of the world’s 7.5 billion people, but the US accounts for 50% of all medication sales in the world. Mind blown.

We are looking for VALUE in our medications.  We want medications that are novel and offer leaps of improved quality of life.  We are willing to pay more for medications that achieve this high bar, but there is a point for every person where price will exceed our ability to purchase a medication.

Finally, we learned about the trade-off between innovation and access.  Monopoly protection funds innovation. In turn, industry creates more new drugs in the long run that cost more money in the short run and poorer access. “But if new medicines aren’t invented, then no one can access them in the long term.” (ISPOR)  How can the market incentivize innovation if not through the almighty dollar?

DISCUSSION THEMES
Many in the room were for the first time faced with the reality that the US foots HALF the bill of medications in the world.  I don’t think anyone, besides the facilitators, was prepared for this data.  As the discussion dug deeper, we realized that our drug costs fund innovation of new medications and devices.  Despite the relationship between US drug prices and world drug innovation, many participants still did not think it FAIR that people in the US pay more than those in other countries.

Some held high the banner of altruism and seemed happy having the US play this role.  Others felt perhaps that even within the US that medication prices should be on a sliding scale based on what a household could afford.  Some shared personal stories about themselves or people they know who have had to choose between paying for their medications and paying other bills.

Yet others remained firm that prices could drop while maintaining innovation if pharmaceutical companies could lower their profits to reasonable margins.  Some attendees implied that companies could reduce their expenses by accelerating the clinical research process, a point that was strongly opposed by a former industry employee.  Pharmaceutical companies have no interest in accelerating clinical research in this manner because it would cause less confidence in drug safety.

As we were wrapping up our Conversation, we faced the question of whether or not the way we finance medications is sustainable.  Our vocal attendees had faith in the free market to correct anything that was broken.  Others remarked that the balance of medications on and off patent would also help with price competition once medications go off patent.

Our ISPOR facilitators emphasized that drug pricing is a complex ecosystem.  They recommended that consumers, scientists, policy-makers and health care providers and administrators continue to learn and share their perspectives, in venues such as Community Conversations, as much as possible in order to find a stable and sustainable relationship between medication access and innovation.

To read some excellent resources on the topic, visit the Community Conversation archive and scroll until you find the “war on drug prices” topic.

~JenWroblewski

NWABR conference sits at the intersection of technology, ethics, and policy

The “Ethics and Regulation in the Digital Age” conference, co-presented by NWABR and Quorum Review, brought together researchers, regulators, and IRB professionals to discuss the challenges and potential benefits of emerging digital and mobile health (“mHealth”) technologies for biomedical research. Conference presenters represented a range of topics and perspectives, including on-the-ground researchers, federal regulators, and institutional officials. Max Little (MIT) and Joaquin Anguera (UCSF) presented primary research using mobile health technologies as recruitment tools, data collectors, and interventions. Cheryl Grandinetti (FDA) and Misti Anderson (OHRP) gave overviews of what federal agencies are doing to stay up to speed with digital and health technologies, including human subjects protection. Malia Fullerton (UW) provided insight into the ethical dimensions of the Precision Medicine Initiative, including participant consent and return of results. Eric Mah (UCSD) and Jeremy Block (Sloane-Kettering) discussed ways for IRBs and researchers to communicate risks and benefits of research with mHealth technology. Finally, Catherine Hammack and Kathleen Brelsford (Duke) presented ongoing research aimed at better describing risks and protections to participants involved in genomic research.

 

A few weeks has passed since this stimulating day of talks and networking. Many themes have stuck with me. First, we should all keep our sights on ensuring that emerging technologies don’t widen or exacerbate existing inequalities (e.g., health disparities and access to research and care). Dr. Anguera’s targeted expansion of his “Neuroracer” video game intervention to Hispanic/Latino populations is an excellent example. Second, policies need to balance patients’ and participants’ privacy with the collective benefit of leveraging their data for research. Dr. Fullerton’s presentation underscored how challenging this balancing act can be, specifically with the imminent recruitment of a 1M+ US citizens to the Precision Medicine Initiative Cohort. Third, the rapid pace of innovation means we will inevitably put technologies into use — in research, clinical, and everyday contexts — before we fully understand them. Despite the unease of “building the plane as we fly it,” so to speak, the alternative of holding back the technology may be even more problematic. As keynote speaker Dr. Little put it, waiting for the perfect technology may be unethical, akin to “withholding treatment,” and instead we should utilize what we have now despite the imperfections.

In light of these concerns, I have been wondering how much of this is new versus existing controversies and tensions wrapped up in shinier, newer technology? A set of comments by Dr. Block sparked this question in my mind, when he articulated different “tiers” of technology use in research. In some instances we are using mobile or digital technology to do the same research activities as before, just on a different platform (e.g., a web survey versus pen and paper). In such cases, the technology may be distracting us into thinking that the ethical or policy dimensions of these activities have shifted. In many cases perhaps they actually haven’t. The first step when considering any technology use in research is to parse what is new versus old and differentiate between aspects of the platform (e.g., smart phone) versus the research activity (e.g., recording steps taken).

I don’t envy the job of IRBs having to fit cutting-edge research proposals into potentially outdated regulatory frameworks. But at the same time I wonder how much technological novelty may be blinding us to the similarities with what we already know and recognize as ethical and regulatory concerns. Patient privacy, data sharing, informed consent, potential misinformation, etc. Granted the pace and scale of these problems is increasing with our new mobile and digital tech. But as we move forward, let’s make sure we’re taking with us decades of bioethics and policy thought leadership and knowledge.

Sarah Nelson is a PhD candidate in Public Health Genetics at the University of Washington. Follow her blog at myopenreadingframe.com or on Twitter at @blueyedgenes.

Conflict of interest: Ms. Nelson received discounted access to the conference in return for writing a blog post.

Agreement Doesn’t Mean Consent at NWABR and Quorum Review IRB Conference

by Marie-Térèse Little, PhD

The ultimate purpose of the informed consent process in research involving human participants (subjects), is to provide information to the participants about the purpose of the research, its procedures, and the risks, potential benefits, and alternatives so that the individual understands this information and can make voluntary decisions whether to enroll and continue to participate in a given clinical trial. This informed consent process should allow for rational decision making and foster self-determination and an expression of autonomy. It should include information that is reasonably expected; not only a document of consent but an opportunity for a meaningful and intuitive discussion between the researcher and the potential participants with sufficient time allowed for questions and concerns. Participants should ultimately be given the opportunity to obtain, understand, and to act on the information.

At the Revolutionizing Informed Consent conference, there was a general consensus from all the speakers that our current approach to the informed consent process is troubling at best and it is clearly not serving our participants well.

Poignantly acknowledged by every speaker, the audience was reminded that the current models employed to “obtain consent” involve static, long (often over 20 pages), complex documents that are filled with dense, scientific and medical language and confusing regulatory and legalistic jargon. The informed consent document (ICD) is often a defensive deed designed to protect the institutions and the sponsors rather than protecting the participants in a proactive manner. Emphasis is on disclosure rather than learning. The complexity and length of the ICD results in poor readability. Furthermore, the needs of the participants vary greatly and the inflexible templates of the ICD often involve over explanations of the worst-case scenario. This is compounded by the short windows of time allotted to convey the overall message and the difficulty in quantifying what the participant really understands about the study and what they have consented to. Agreement without understanding is not consent. – JLWilbanks.

These difficulties encountered by participants, researchers and the ethics review community in the informed consent process were unambiguously acknowledged and openly demonstrated in the Keynote address titled “Informing the Research Participant: Emerging Models, Trends, and Regulatory Requirements” delivered by Mr. Kevin Hudziak, Emergent Strategy Consultant and leader of the Informed Consent Transformation project at Eli Lily and Company. Mr. Hudziak also questioned the current approaches and suggested that we, as Institutional Review Board (IRB) or Research Ethics Board (REB) members and staff, researchers and investigators, regulatory personnel and sponsors, need to uncouple Informed/Consent and treat it not as a single incident but an ongoing process that informs first and consents second. The Keynote address also served to introduce the trends in informed consent including e-consent and tiered, progressive, remote, and dynamic consent and the concept that innovation and technology can be leveraged to revolutionize the informed consent process.

 

Marie-Térèse Little, PhD is a volunteer member of Island Health clinical research ethics board on Vancouver Island, B.C. She worked at the Fred Hutch developing novel strategies for reduced intensity bone marrow transplants and she now lives in Victoria, BC with her family. Marie-Térèse is the founder and chief consultant at 4th Dimension Biomedical Research Communications (www.4Dbrc.com) where complex bio-medical and scientific information is distilled into clear, meaningful and comprehensible communications. This is her last entry for this conference. We thank her for her time and talent in serving her regional biomedical community, and the Western IRB for providing supplementary funding for her and other participants in 2015.