Abstract
The growth of gene therapy trials and the Food and Drug Administration (FDA) approval of six gene therapies has only been possible because of the voluntary participation of patients and, in the case of pediatric patients, their caregivers. The majority of these patients suffer from rare or ultrarare diseases. Relatively little is known about the perspective of such patients and families as they are under investigational or newly approved gene therapies. The systematic review by Kimberly et al., in this issue, 1 seeks to summarize the existing literature on the lived experience of gene therapy by patients and families and to define gaps in our knowledge to guide future research.
This article systematically reviewed the literature and ultimately found that only 10 articles reported primary data on the perspective of the patients and patient-caregivers who underwent gene therapy. Even with this limited amount of data, some clear patterns emerged. The most significant common experiences of gene therapy patients related to weighing of risks and benefits, decisions on timing of when to participate in gene therapy trials, the value of clear communication, and quality-of-life considerations. Each of these aspects warrants further investigation.
The weighty responsibility that parents bear to make the right decisions about whether and when to participate in gene therapy trials has not previously been dealt with in detail. Prior literature has cited the concept of “therapeutic misconception,” meaning an unrealistic expectation that the investigational gene therapy will result in a dramatic cure. In contrast, Kimberly's team points out that families generally have realistic views about the potential benefits of gene therapy. Many parents maintain that they are able to distinguish “hope” from “expectation.”
This means that they do not have exaggerated expectations about the power of gene therapy, but still are motivated by the hope that gene therapy could provide some benefits. Parents are often willing to take on significant risks even with a realistic view of the potential benefit. Most parents understand that there are significant risks that the therapy could result in harm to their child.
One additional issue, which could present a significant burden on families, is the decision about when to participate in a gene therapy clinical trial. Parents are aware that participating early in the course of product development could present a greater possibility of risk. The dose-escalation feature of phase 1 clinical trial design means that a child enrolled early in a trial will receive a lower dose of the treatment than those enrolled later in the trial. Some trials also have a placebo control. The progressive nature of many severe genetic diseases magnifies the difficulty of this decision. Parents and patients with progressive diseases face a very limited time window during which their child may receive the benefit of the gene therapy treatment or else lose the opportunity to participate forever.
The numerous difficult decisions for patients and families demand a highly skilled clear communication between gene therapy principal investigators and families. Relatively little literature is available to inform the communication strategies for clinical investigators in gene therapy or for patients and families themselves. Dr. Kimberly's group points out one resource that we can also strongly endorse. The multimedia module, “Evaluating the Clinical Research Option,” which is offered free-of-charge on the Courageous Parents Network (CPN) website, provides perspectives from both clinical researchers and parents of children with severe monogenic disorders. 2
As one of the contributors to that CPN module, I can attest that the CPN offering is unique in that there are numerous videos in the voice of the parents themselves. The parents who volunteered to participate in the development of this educational material are very articulate in relating their own experiences. This perspective is extremely valuable to clinical researchers trying to communicate clearly in a setting where many unknowns remain.
Many of the core concepts that investigators must strive to communicate revolve around the concept of probabilities (rather than certainties) of risk and benefit. Although we never know the benefit for any individual patient, we can communicate how and why a gene therapy vector has been designed and intended to benefit. It is also helpful, in my experience, to point out that although the degree of benefit is unknown, the probable outcomes will still entail some residual aspects of the underlying disease, that is, that there will not be a total cure. As the trial progresses and more data are generated regarding the range of potential benefit, it is helpful if the communication includes examples of functional outcomes that the parents may see in the course of the child's disease.
The risk of adverse effects is also difficult to communicate clearly. At the beginning of the consenting process, the investigators should state clearly that they do not currently know the exact extent of the risk. Indeed, that lack of knowledge is the primary reason that the therapy remains investigational. Stated another way, that is the reason we must do the trial. The researcher should state that the completion of the trial process will provide substantial additional information about the risks. One should note that several additional unforeseen toxicities of high-dose adeno-associated virus gene therapy have only been observed in the past few years. 3,4 Some of these toxicities were not accurately predicted in the preclinical studies.
Further research is clearly needed to further improve communication regarding informed consent for patients and families of children with life-limiting illnesses. Investigators should keep in mind that the effectiveness of communication can only be assessed by assessing what messages were actually received by patients and families.
Thus, research on the patients' and families' knowledge and lived experiences should continue to progress in tandem with progress on the dissemination of gene therapy to larger number of patients. As with other forms of health communication, it will be necessary to understand effectiveness across different cultural and linguistic groups. As many in the field strive to expand access to gene therapy outside of North America and Europe, the ability to effectively communicate risks and benefits should also expand. The full benefit of gene therapy will only be realized if both access and communication develop in parallel.