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Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop (2019)

Chapter: 5 Meaningful Engagement of Patients and Families

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Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
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5

Meaningful Engagement of Patients and Families

Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
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Zeal and enthusiasm underlie some of the ethical dilemmas raised by gene therapy, according to Holly Tabor, associate professor of medicine at the Stanford University School of Medicine and associate director for clinical ethics and education at the Stanford Center for Biomedical Ethics. She cited the case of 18-year-old Jesse Gelsinger, who died in 1999 from a severe immune reaction to the gene therapy treatment he received as part of a Phase 1 clinical trial for the metabolic disorder ornithine transcarbomylase deficiency (Sibbald, 2001). Tabor quoted Robert Steinbrook, M.D., who wrote,

In their zeal to help patients with a life-threatening disease, leading researchers at one of the premier academic medical centers in the United States lost their focus. They overlooked warning signals suggesting that the experimental intervention was not safe, with tragic, fatal consequences. (Steinbrook, 2008, p. 117)

The case provides lessons that resonate with other emerging and innovative treatments, said Tabor. These lessons relate to inclusion criteria, recruitment, therapeutic misconception, informed consent, transparency, conflict of interest, and institutional oversight, she said. The Gelsinger case also highlighted the need to strengthen and improve regulatory structures, maximize safety, and consider carefully who should be in a Phase 1 trial; create systems that prevent conflicts of interest; and increase transparency around all stages of clinical trials, said Tabor. She suggested that these challenges can be addressed by conducting empirical analysis of informed consent procedures for gene therapy trials, interviewing participants and researchers about their views on some of these ethical issues, and developing and testing shareable tools to mitigate therapeutic misconception and optimism.

Cristina Sampaio agreed that participants’ expectations resulting from therapeutic misconception need to be carefully managed. Therapeutic misconception can be defined as existing

when individuals do not understand that the defining purpose of clinical research is to produce generalizable knowledge, regardless of whether the

Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×

[participants] enrolled in the trial may potentially benefit from the intervention under study or from other aspects of the clinical trial. (Henderson et al., 2007, p. 1736)

As treatments become more complex and invasive and as more hype is generated for a treatment, participants and families may convince themselves that a cure is possible only if they do everything possible, including disrupting their lives, to gain access to a trial. She noted that strategies have been identified that can reduce therapeutic misconception (Christopher et al., 2017).

One way to avoid therapeutic misconception, said Petra Kaufmann, is to communicate transparently with patients and patient groups. Frank Bennett echoed her comment, adding that it is important for parents to recognize that this is a team effort in which their participation is essential. His team has found that when parents are more proactive in caring for their children and dealing with the complications of spinal muscular atrophy (SMA), the children actually do better.

FACILITATING PATIENT AND FAMILY ENGAGEMENT

Meaningful engagement and shared governance with patients and families is important, said Tabor, and requires more than including them on advisory boards. Rather, it requires learning about their lived experiences with their conditions without assuming they all have the same perspective and attitudes. Timothy Coetzee, chief advocacy, services, and research officer at the National Multiple Sclerosis Society, agreed, noting that patient perspectives and attitudes are evolving with regard to participation in placebo-controlled trials, sharing data with others and gaining access to their own data, and switching treatments. Patients are moving from passive to fully activated, he said, and dealing with the consequences of that activation requires moving from a recruitment mindset to an engagement mindset.

Sampaio said that in the United Kingdom, sponsors are required to submit their clinical trial protocols to a formal committee populated only by patients with different types of diseases in order to get approval. The committee comments on the protocol and may recommend changes. She added that a voluntary international committee called the HD Coalition for Patient Engagement (HD-COPE) is also available to review and make recommendations regarding Huntington’s disease (HD) protocols and research plans.1

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1 For more information about HD-COPE, see https://ehma.org/2018/05/14/multi-act-kicks-off-today-bringing-research-closer-patients-society (accessed June 10, 2019).

Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×

Coetzee noted that the European Union has funded the MULTI-ACT project2—with leadership provided by the Italian Multiple Sclerosis Society—with a broad spectrum of partners to advance the science of patient input and foster engagement of all stakeholders in the development of new tools to assess, from multiple perspectives, the value and impact of research and innovation on people with brain diseases. He observed that MULTI-ACT has developed a particularly useful construct for patient engagement involving four domains: inform, involve, consult, and co-design. While the end goal is to develop safe and effective treatments, Coetzee said it is also important to ensure affordable access, which will require embracing all stakeholders and not simply leaving decision making to policy makers.

Tabor said the Patient-Centered Outcomes Research Institute is another model of how funding agencies have tried to mandate and facilitate patient engagement. The old models of patient engagement through patient and advocacy groups have strengths to build on, she said, but new approaches such as those that incorporate social media are also needed. Jill Morris, a program director at the National Institute of Neurological Disorders and Stroke (NINDS), added that the National Center for Advancing Translational Sciences requires data coordinating centers in the Rare Diseases Clinical Research Network to have an engagement and dissemination core to promote better engagement of industry and advocacy groups.

Characterizing and understanding patients’ and caregivers’ values around treatment decisions can help providers communicate more effectively about benefits, risks, side effects, and eligibility criteria for a trial, according to Tabor. She recommended that clinicians engage patients in explicit discussions about their awareness, knowledge, and potential misinformation about the natural history of the disease as well as their values and goals. For example, when she and her colleagues interviewed adults and parents of children with SMA about pursuing treatment with nusinersen, they found that patients and parents were trading off values and priorities when they assessed risks and benefits (Pacione et al., 2019). While one parent believed the potential benefits were insufficient to balance against the predicted continual decline in quality of life, an adult with SMA believed the drug would help her maintain a certain level of independence despite the barriers and challenges she faced. One mother believed the repeated intrathecal injections and a life focused around hospitals would conflict with their family’s goal to help their child to not feel disabled.

Patient inclusion is important at all levels, not just for clinical trials and treatment decisions, said Story Landis. She recalled that when NINDS

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2 For more information about MULTI-ACT, see https://ehma.org/2018/05/14/multi-act-kicks-off-today-bringing-research-closer-patients-society (accessed June 10, 2019).

Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×

was planning programs for Parkinson’s disease that required better metrics and initiatives, patients and families were more satisfied with the initiatives and efforts once they were brought into the discussions. Registries and natural history studies can promote engagement as well as enable clinical trials, added Daniel Burch. However, maintaining registries so they remain relevant for clinical trials can be challenging, said Sampaio, because diseases progress as participants age. For ENROLL-HD, mentioned in Chapter 4, a complex mathematical model has been created to guide future enrollment in the registry so that in 5 years, they will continue to have trial-ready participants, she said. The problem of multiple competing registries, which Akshay Vaishnaw mentioned in Chapter 4, also exists for non-rare diseases. Coetzee said there are 20 multiple sclerosis registries with some 60,000 participants, all started by various investigators. Although federating the data might be possible, the value of doing so is unclear because it would probably cost tens of millions of dollars, he said.

Patients’ Views on Data and Information Sharing

Data sharing is an additional challenge and one in which registry and clinical trial participants want to play a more active role, said Tabor. Although many patients are willing to share data in order to advance science, they want complete information about risks and to be informed about their individual results when the trial ends, rather than having to wait until the Food and Drug Administration (FDA) has approved a treatment, she said. She added that trial participants should be more engaged in decisions companies make about sharing placebo and non-placebo arm data with the field, which may require building new strategies for getting informed consent. Michael Panzara mentioned that neutral parties such as the Critical Path Institute can provide the infrastructure for data sharing in a manner that protects the interests of companies and academic researchers as well as the confidentiality of patients.

Patients and parents are increasingly getting their information through social media rather than from their physicians, said Tabor. Trial participants who post online about the process of getting injections and other aspects of a trial have in some cases unblinded themselves, she said. Tabor and colleagues found that patients and families found this information to be more reliable, useful, and up to date than the information obtained from other sources. From these social media groups, they also obtained useful information about insurance coverage, social support, reducing social isolation, obtaining medical equipment, and other important issues, she said.

Tabor suggested that new frameworks are needed to identify and address ethical challenges associated with gene-targeted therapies, rather

Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×

than addressing ethical issues on a case-by-case basis. Lessons from systems set up in California for governance of stem cell research could provide a model pathway, she said. These lessons include making room for laypeople in governance structures, promoting transparency, minimizing secrecy, creating opportunities for learning and innovation, and building alliances and collaboration among stakeholders, said Tabor (Mintrom and Bollard, 2009).

ACCESS, COST, AND EQUITY

The high costs of gene-targeted therapies pose additional ethical challenges related to access and allocation of scarce resources, said Tabor, noting that many of these challenges are neither new nor unique to gene-targeted therapies. Indeed, she said, in the early 1960s, perhaps the first-ever bioethics committee was established at a Seattle hospital to help determine who would get the very limited slots for dialysis (Jonsen, 2007). The high cost of admission to intensive care units has also been investigated for many years, said Tabor, yet there are few processes for deciding where, when, and how patients should be admitted. She suggested that if all or even a few of the gene therapies currently in the pipeline are approved, issues of costs and access will become even more critical.

The approvals of Glybera, Spinraza, and Zolgensma illustrate many of these challenges, said Tabor. In 2012, after a very long development and approval process, Glybera was approved in Europe as a treatment for lipoprotein lipase deficiency with a requirement for post-marketing surveillance. At a cost of about $1 million per patient, 60 people were dosed in European trials, but only 1 patient paid for the treatment. The drug was withdrawn in the United States and not pursued in Europe, said Tabor. Spinraza was approved by FDA in 2016 at an estimated cost of $750,000 for the first year and $350,000 annually for the rest of the patient’s life. Tabor said that insurance coverage has been variable, and although Biogen offers financial assistance for Spinraza, there are many reports in the media of patients having difficulty with access. Zolgensma is predicted to cost more than $2 million, but will only require one treatment. All three of these drugs treat rare diseases, which somewhat mitigates the impact of the high costs at least at a societal level, but gene-targeted therapies are on the near-term horizon for many more common diseases such as hemophilia, sickle cell anemia, and macular degeneration, said Tabor. If 20 to 25 new gene therapies are approved each year over the next few years, as Peter Marks and others anticipate, the costs could overwhelm the health care system. Moreover, said Tabor, the costs related to gene-targeted therapies are occurring in a landscape of societal concerns about increased overall costs of drugs and medical care.

Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×

An independent, nonprofit research institution, the Institute for Clinical and Economic Research (ICER),3 produces reports analyzing the effectiveness and value of drugs and other medical services and shares their findings with the public, payers, and industry in an attempt to stimulate informed public discourse on the topic, said Tabor. She noted, however, that ICER has been criticized by patient groups and others because they are partially funded by industry and for how they assess cost effectiveness. These groups claim that payers use ICER’s findings to deny patients access to drugs, said Tabor.

Referring to a recent article about value-based pricing for emerging gene therapies (Garrison et al., 2019), Tabor suggested that there are elements of value that are not well assessed for rare, debilitating, or life-threatening diseases. These elements include the severity of the disease, equity, and the value of hope. While ICER and other groups typically assess value based on cost per quality-adjusted life-year (QALY), survey research suggests that people view QALY gains differently for different subpopulations, said Tabor. For example, people generally give priority to subpopulations with poor baseline health, including those at the end of life, she said. In response to public criticism, ICER issued a statement in December 2018 saying they would no longer depend solely on QALYs, but would also include a measure called “equal value of life years gained” (evLYG), which incorporates incremental gains in length of life regardless of changes in quality of life. Thus, a treatment that adds 1 year of life for the most severely affected patients would receive the same evLYG as one that adds 1 year of life for healthier people.

ICER also published an evidence report on the effectiveness and value of Spinraza and Zolgensma for the treatment of SMA (ICER, 2019). According to Tabor, ICER concluded that while both treatments improve the lives of patients and families, the cost of Spinraza far exceeds the threshold that would make it cost effective. They called for Novartis/AveXis to set a lower launch price for Zolgensma than the hypothetical $4–$5 million price that had initially been floated.

Several innovative approaches to pricing for these very expensive therapies have been proposed, said Tabor (Kaltenboeck and Bach, 2018). Value-based pricing, for example, sets the price based on the magnitude of benefit. Another approach treats the price like a mortgage, where the insurer agrees to pay the cost over time. Yet another requires the manufacturer to refund the cost of the treatment when an agreed-on outcome is not met. Tabor said that while these approaches may not have the kinds of effects needed, they demonstrate that efforts are being made to address the difficult issue

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3 For more information about the Institute for Clinical and Economic Review, go to https://icer-review.org (accessed June 14, 2019).

Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×

of pricing. However, her research suggests that more attention also needs to be paid to the impact of costs on the person who is experiencing the condition. Access and equity are key, she said. She asserted that scientists, policy makers, and clinicians have a moral and ethical responsibility to make sure that gene therapy and other innovative approaches are not only available to the very wealthy or highly insured. Patient and stakeholder engagement will be key to ensuring that issues of equity are considered, she said.

Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page 37
Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page 38
Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page 39
Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page 40
Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page 41
Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page 42
Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page 43
Suggested Citation:"5 Meaningful Engagement of Patients and Families." National Academies of Sciences, Engineering, and Medicine. 2019. Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25529.
×
Page 44
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On April 23 and 24, 2019 the Forum on Neuroscience and Nervous System Disorders convened a workshop titled "Advancing Gene-Targeted Therapies for Central Nervous System Disorders" in Washington, DC. This public workshop brought together experts and key stakeholders from academia, government, industry, philanthropic foundations, and disease/patient-focused nonprofit organizations to explore approaches for advancing the development of gene-targeted therapies for central nervous system (CNS) disorders, and implications of developing these therapies. Participants explored lessons learned from both successful and unsuccessful clinical development programs; new knowledge about the genetic underpinnings of brain disorders; the current status and future potential of gene-targeted therapies for CNS disorders; challenges and potential solutions for translating preclinical findings to approved therapies; and patient and caregiver perspectives. They also discussed what will be needed to develop these therapies for common disorders such as Alzheimer's and Parkinson's disease, as well as neuropsychiatric and neurodevelopmental disorders such as schizophrenia and autism. The workshop included approaches that target both DNA and RNA, as well as gene products using viral vectors, antisense oligonucleotides, and RNA interference. This publication summarizes the presentations and discussion of the workshop.

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