The emergence of efficacious human gene therapy for life-limiting genetic diseases such as spinal muscular atrophy type 11  has raised hopes among families of children with previously incurable genetic disorders. However, a number of concerns have surfaced regarding the gene therapy trial process. Two bereaved parents, both deeply engaged in their disease communities, collaborated with an experienced gene therapy researcher to create patient education materials to aid parents in critical decision-making. In this Family Partnerships article, we present a summary of the module, as well the reflections of each of the 3 contributors describing the impetus for the Courageous Parents Network (CPN) unit Evaluating the Clinical Trial Option, and their hopes for its impact, as captured in an interview conducted after completion of the educational module.

The Evaluating the Clinical Trial Option unit (https://courageousparentsnetwork.org/topics/clinical-trial) offers an overview of the fundamental elements of clinical trial participation, written for a nonmedical audience to help families understand and evaluate their options. It is disease and therapy agnostic and does not advocate for any particular path or decision. Content areas include a glossary of terms; informed consent; clinical trial basics, such as efficacy; trial design, including the phases; participation criteria; and the emotional impact of decision-making. Its elements include a variety of media types: 85 short videos (average 2–4 minutes each, a total of ∼240 minutes); downloadable guides in English and Spanish; 3 podcasts; 4 blog posts written by parents; and a curated educational digital experience (“Guided Pathway”) that, through videos and text, walks parents through the most fundamental aspects to consider in the decision-making process. The specific elements of the unit are presented in Table 1. The videos feature parents who are considering a clinical trial for their child or who have participated in one and are reflecting on the experience and professionals with experience in supporting families, including a gene therapy investigator, a patient advocate from the industry, and a clinical trial study coordinator. All of the resources, including the guides and Guided Pathway, were originated by contributing parents Jennifer Siedman and Blyth Lord and then reviewed by contributing physician Terence Flotte, as well as several outside advisors with professional experience in clinical trials and patient advocacy.

TABLE 1

Contents of the Educational Unit

Evaluating the Clinical Trial Option Unit Contents
Guides (English and Spanish) 
 Questions to consider 
 Understanding informed consent 
 Clinical trial terms 
 CPN resources 
Video topics 
 Clinical trial 
 Trial basics 
 Trial design 
 Qualifying 
 Decision-making 
 Emotions and questions 
 After participation 
Podcasts 
 Anticipating 
 Supporting families 
 Community 
Blogs 
 Rational hope 
 A terminal diagnosis and risk aversion 
 The cure we don’t want 
 What survivor’s guilt looks like in rare disease 
Guided Pathway 
 Evaluating the Clinical Trial Option 
Evaluating the Clinical Trial Option Unit Contents
Guides (English and Spanish) 
 Questions to consider 
 Understanding informed consent 
 Clinical trial terms 
 CPN resources 
Video topics 
 Clinical trial 
 Trial basics 
 Trial design 
 Qualifying 
 Decision-making 
 Emotions and questions 
 After participation 
Podcasts 
 Anticipating 
 Supporting families 
 Community 
Blogs 
 Rational hope 
 A terminal diagnosis and risk aversion 
 The cure we don’t want 
 What survivor’s guilt looks like in rare disease 
Guided Pathway 
 Evaluating the Clinical Trial Option 

The material is intended to be accessible to parents of children with a wide range of serious life-limiting diagnoses, with a particular emphasis on parents of children with rare genetic diseases. The bioethical framework for the discussion was entirely consistent with the basic elements covered in the Belmont report and the regulatory framework of the Food and Drug Administration Common Rule but framed in the tangible context of a conversation between a physician-investigator and parents to provide the information necessary for either an informed consent or a decision not to participate.2,3 

Our middle child, Benjamin, was diagnosed with mucopolysaccharidosis type IIIB (also known as Sanfilippo syndrome) in 1997 at the age of 15 months. At the time, this was a young age of diagnosis and, although devastated, we considered ourselves lucky. It seemed to us that with a fairly long runway, a breakout treatment would come in Ben’s lifetime.

Our coping strategy was to take action. We single-mindedly devoted ourselves to advocating and raising money for research. We became knowledgeable and invested in the science, connecting with each of the researchers working on Sanfilippo syndrome.

When Ben was 4, the first actionable treatment, a stem cell replacement trial, began. The instinct to do anything to save our son, combined with pressure from the research team, was intense. Our own knowledge of the science convinced us of the greater potential of emerging gene and enzyme replacement therapies. And although no medical profession confirmed this, we believed that enrolling Ben in the stem cell trial would likely exclude him from later trials. We decided not to enroll him, the first of a set of pivotal moments.

Ten years later, a researcher announced that her mice subjects had lived longer than ever before. We mobilized, e-connecting to our disease community and uniting foundations worldwide. Together, we initiated a natural history study and worked to support fledgling biotech companies that would later license the research.

Yet now there was an essential difference. We had to absorb the fact that Ben was too far progressed to benefit. He died in 2014, at 17. Two years later, a child with Sanfilippo syndrome received the first gene therapy. Her parents were naturally hopeful but indicated that they clearly understood the realities and risks of participating in an early stage, low-dose clinical trial.

The question of risk tolerance needs to be conveyed with more intention. When your child is a potential candidate for a clinical trial, you must consider the following: Is this the best option? How do you know? What do you “owe” to medical research, if anything? Some specialists are helpful, others are not. Industry is eager to have you. A disease community, always supportive overall, may present a mixed bag of opinions and emotions. It was not my personal experience, but I have seen that resentment and envy can affect long-standing, valued relationships. This can be isolating and disturbing for families. Decisional regret can be the source of angst for many families, particularly when their child dies. My husband and I escaped this pitfall because we were, by nature, strong-willed, knowledge-seeking individuals. However, I know that our choices, particularly the choice not to participate in a trial, would have benefited from the guidance of medical professionals and the wisdom of other families that had faced a similar decision.

Through our palliative care specialist and others, I connected with Blyth Taylor Lord. Blyth’s daughter Cameron and nephew Hayden had been diagnosed with infantile Tay-Sachs disease in the late 1990s and died within months of each other around the time of their second birthdays. Blyth was creating CPN, a digital platform designed to help orient and support families caring for children with serious illness. CPN’s media assets include short video interviews featuring families and providers, downloadable guides, podcasts, a blog, and Guided Pathways (subject-specific, curated collections of CPN content). I lobbied for a unit on consideration of a clinical trial. We could help parents learn the language. We could encourage them to consider their tolerance. We could normalize the messy mix of emotions. We would use the perspectives of families who have chosen to participate and who have declined, as well as providers, to tell that story.

A unit devoted to clinical trials resonated with me on a lot of levels. My family also raises funds for research. Indeed, funding research and driving toward a clinical trial is one of the ways that families find meaning and hope during their child’s illness journey (and, for some, in the years that follow their child’s death). I am also connected to our patient disease community as an active member, former president, and board member of the National Tay-Sachs and Allied Diseases Association. Now, >20 years after our daughter’s fatal diagnosis, the first clinical trials for infantile Tay-Sachs are on the horizon and the landscape for newly diagnosed families is so changed. I, like Jennifer, am watching with a combination of exhilaration and concern. I hear firsthand from parents hoping that their child will stay well enough to meet the criteria for the trial, and I have seen how this hope for the future impacts decision-making in the present. It is complicated, thus making an unimaginable situation all the more fraught with chances for regret.

We know that not everyone will be accepted into the trials, that some patients will respond and others will not, and that the trials may or may not be successful. Because there were no such trials available for our children, Jennifer and I have not had to struggle or deal with the decisions and outcomes that these parents may face. But with the participation of families and providers in the CPN, we can offer real-life reflections from others who actually have been there.

Although we do not advocate any particular path, there are some universal elements to this journey. We can reassure parents that there is no “right” answer (there is only what works for them) by telling stories of families who elected trials and families who did not. We hope to empower every family to truly participate in, and own, their decision with confidence. Those are CPN’s goals.

All CPN content is professionally reviewed. We asked University of Massachusetts Medical School’s Dean and Celia and Isaac Haidak Professor Terence Flotte, MD, to contribute content and advise the project overall.

I welcomed this project as an opportunity to convey the process of grappling with the uncertainty of participating in an investigational study. It is a process that revolves around understanding risks and benefits and making an informed choice. However, we can only determine what the risks and benefits truly are through conducting the study.

Researchers may feel that participating in a clinical trial is a reasonable choice because we have tried to mitigate the risks and maximize the benefits. But there are many unknowns. We always have to understand the perspective of the patient and family. We are dealing with diseases for which there is a grave prognosis if not treated, and it is impossible for some parents to not pin their hopes on the trial, whatever the unknowns may be.

There are many reasons why families may resist enrolling in trials, such as fear of invasive procedures or side effects, a lack of knowledge or trust in researchers or biomedical research, certain cultural issues, or concerns about trials in which there is a placebo control. Some have a fear of their genes being manipulating, although this is becoming less common, as people have become accustomed to hearing about gene therapies.

It is critically important that we listen to our lay partners. Patients, parents, and other representatives in disease communities are closer to what our families really need. The members of the clinical trial unit use their voices to describe concepts that I and other researchers have been trying to explain for years. I hope that the clinical trial unit will reach a broad audience of patient families.

I hope it will also reach a broader audience of providers to explain what we do. The motivations of those engaged in clinical research are aligned with those of frontline providers. We are trying to accomplish the same goals in patient care. The researcher role is to provide good solutions where they do not currently exist.

The Evaluating the Clinical Trial Option unit was introduced in February 2020 (right before the coronavirus disease 2019 pandemic slowed progress on the launching of multiple clinical trials). In the 11 months since its launch (at the time of writing), there have been 9640 video views, the downloadable guides have been viewed 226 times, and the Guided Pathway has been visited 356 times. The CPN staff has since presented its content to numerous gatherings of providers, patient disease groups, and industry professionals to overwhelmingly positive feedback.

Since learning of the Evaluating the Clinical Trial Option unit, professionals who serve the rare disease community, especially patient advocates at biotech companies and patient disease groups, have reached out to CPN for resources from the Evaluating the Clinical Trial Option unit to meet particular needs. For example, content about informed consent helped a family feeling isolated understand the restrictions around posting to social media, and content about inclusion criteria, including a parent’s hope to “train” toward meeting the criteria, as well as the potential for parents to feel they have failed if their child does not meet that criteria, helped a parent navigate their stress and worry about coronavirus disease 2019–induced disruptions to their child’s physical therapy before seeking participation in a trial. Several companies have reported valuing the Evaluating the Clinical Trial Option unit as a therapy- and industry-neutral, unbiased source of information for families. A biotech company links to it in their patient support portal and another has used the videos in an in-service training. The patient disease group National Tay-Sachs and Allied Diseases Association, anticipating multiple clinical trials for its affected families in 2021, links to the Evaluating the Clinical Trial Option unit on its Web site and will send families considering enrollment links to it in e-mail communications. The American Society of Gene and Cell Therapy has recognized the Evaluating the Clinical Trial Option unit for covering the emotional aspects of trial participation that are not covered in their resources and has embedded links to it in their patient- and provider-facing Web sites. It is our hope that Evaluating the Clinical Trial Option, although designed as a resource to share with families and for their self-service, will also continue to be employed as a tool for provider self-education and as a resource for educating colleagues and peers striving to better understand the lived family experience. Creating and compiling the resources that are in the module to date has been a significant effort, but we know that there are areas where we can improve and add to it. We plan to continuously add new information that will help families navigate this decision, such as discussion of the diversity gap in clinical trials.

We thank the families and providers whose wisdom and perspectives inspired and fueled the creation of the Evaluating the Clinical Trial Option unit, Carol Trager, CPN director of communications, who interviewed the authors and edited our transcript, and Thomas Gallagher, PhD, for helpful comments and edits.

The project was initially conceived by Ms Lord and Ms Siedman; Dr Flotte then contributed to the conception and execution of the project; and all authors contributed to the composition of the article, take full responsibility for all of its contents, and approved the final manuscript as submitted.

FUNDING: Supported by the Courageous Parents Network, a nonprofit 501(c)(3). The Evaluating the Clinical Trial Option unit creation was funded in part with grants to Courageous Parents Network from Sanofi Genzyme, Bridgebio, Aspa Therapeutics, Novartis Gene Therapies (formally AveXis), BioMarin, bluebird bio, REGENXBIO, and Amicus Therapeutics.

     
  • CPN

    Courageous Parents Network

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: Dr Flotte is a paid consultant for Trizell Holding, SA; and Ms Lord and Ms Siedman have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Flotte has been elected to the Courageous Parents Network governing board. Ms Lord (founder and executive director) and Ms Siedman (director of family engagement) are employed by Courageous Parents Network, a nonprofit organization founded by parents for families and providers caring for children with serious illness.