Exploring Novel Clinical Trial Designs for Gene-Based Therapies Proceedings of a Workshop (2020) / Chapter Skim
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3 Understanding the Complexities of Patient Selection, Enrollment, and the Consent Process
3 Understanding the Complexities of Patient Selection, Enrollment, and the Consent Process
Pages 23-40
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From page 23... ...
(Tisdale) • Newborn screening for severe combined immunodeficiency is critical because it provides an unbiased population-level ability to make an early diagnosis, which in turn promotes fair access to treatments, including clinical trials.
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The workshop's second session explored the ethical issues surrounding patient selection, enrollment, and consent for gene-based therapies and how those differ from conventional clinical trials. This session also identified resources that can help patients and providers accurately understand the potential risks and benefits of participating in a gene-based clinical trial and explored communication strategies aimed at helping patients make informed decisions about participating in trials for gene-based therapies.
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From page 25... ...
Following these four presentations, there were an additional three speakers who provided patient and family perspectives: Ronald Bartek, a co-founder and the president of the Friedreich's Ataxia Research Alliance; María José Contreras, a mother of two sons with DMD; and Tesha Samuels, who participated in a gene-based sickle cell disease clinical trial run by Tisdale in 2018. An open discussion with the panelists followed these presentations.
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From page 26... ...
The regimen also includes the drug sirolimus, a compound with immunosuppressive, antitumor, and antiviral properties, in an attempt to mitigate the risk of GVHD. A key difference between this regimen and the standard one with myeloablative chemotherapy is that this one does not completely replace the patient's bone marrow with that of the donor, and, indeed, Fitzhugh said, it is not necessary to replace all of the bone marrow to cure sickle cell disease.
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From page 27... ...
Although Fitzhugh did not discuss gene therapy approaches to treat sickle cell disease -- a topic that was covered by Tisdale, the following speaker -- Fitzhugh did describe what she and her colleagues tell patients about gene therapy. To start, she tells them, patients can serve as their own donors, which means that it should be available to all patients.
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Eleven of the patients had spoken to patients who had positive outcomes, five had spoken with patients who had negative outcomes, and seven of the patients had not spoken to other patients. THE COMPLEXITIES OF PATIENT SELECTION, ENROLLMENT, AND CONSENT IN THE CONTEXT OF GENE THERAPIES TO TREAT SICKLE CELL DISEASE Continuing on the theme of sickle cell disease, Tisdale said that both allogeneic bone marrow transplantation and autologous gene therapy work by either replacing or repairing bone marrow stem cells so that the body produces hemoglobin that will not polymerize and cause sickling (see Figure 3-1)
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From page 29... ...
His team now makes a point of going to patient advocacy meetings and holding meetings in their clinic to update patients on the results of ongoing clinical trials. "I think it is helpful to engage the patient population as real team members in this effort," he said.
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cities to FIGURE 3-2 Autologous bone marrow stem cell–targeted gene editing to treat sickle cell disease. NOTE: GVHD = graft-versus-host disease; SCD = sickle cell disease.
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. Focus groups were shown a short educational video on somatic genome editing and its potential use for sickle cell disease and then given a survey related to genome editing and participation in future clinical trials.
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. This form of SCID is the most difficult to treat with allogeneic bone marrow cell transplant, Puck said, and autologous gene therapy may be a better approach.
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When the protein product of dystrophin was identified in 1987, Furlong said, many investigators were confident that gene therapy for DMD would be straightforward. However, she continued, more than 30 years later clinical trials for a gene-based therapy for DMD are just beginning.
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From page 34... ...
The current informed consent process is not very informative, Furlong said, and families may not even realize that by agreeing to have their child participate in a gene therapy trial, they are opting out of every one of the other 27 active clinical trials taking place in the DMD space. Aside from worries about the muscle biopsies that are done under anesthesia and the doubling of the steroid doses that comes with getting the therapy, another common parental concern is whether the child is receiving the experimental treatment or is part of the control group that will eventually receive the active therapy once the trial is over.
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From page 35... ...
Other needs, Contreras said, include an expedited regulatory process and improved trial accessibility for patients in early and advanced phases of the disease, for international populations, for boys and girls, and for families that cannot afford to participate in clinical trials. Trial design could be improved by the development of innovative protocols that minimize placebo arms and use natural history studies, master protocols that may combine different therapeutic approaches, and the increased involvement of patients and families in protocol design.
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From page 36... ...
That persistence paid off, and she enrolled in the NHLBI trial using an autologous gene therapy transplant rather than requiring a matched donor bone marrow transplant. The gene therapy process that Tisdale and his colleagues laid out for her in great detail, both in writing and verbally, was almost too much to take in for her and her family, Samuels said.
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From page 37... ...
Turning to the family perspective on gene therapy clinical trials, Bartek said that safety is a concern, but given that there are no approved treatments for many of these diseases, families are often willing to take substantial risks. Perhaps the gravest concern of families is whether their loved ones will receive a therapeutic dose of the investigational agent.
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From page 38... ...
Tisdale answered that hydroxyurea also reduces the number of bone marrow stem cells that can be harvested from patients, which would reduce the likelihood of reaching the therapeutic target dose. Thus, in order to harvest sufficient quantities of bone marrow stem cells from patients, hydroxyurea treatments stop and exchange transfusions are used instead, Tisdale said, as a way to yield a better product that is less prone to downstream complications.
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From page 39... ...
Bartek said that the Friedreich's Ataxia Research Alliance has had tremendous access to the statistical community, including enlisting statisticians to help fortify and analyze the organization's natural history database. Recently, in collaboration with FDA and the National Organization for Rare Disorders, his organization has populated its natural history database by adding placebo arm data from clinical trials with help from statisticians.
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From page 40... ...
Panelists were asked if they had ever encountered cases where parents and children were at odds over signing the consent form. Furlong said that typically young boys with DMD do what their parents say, and Puck said that the children she has worked with and who are old enough cognitively to understand the process have been extremely enthusiastic about participating in a clinical trial, even after learning that the procedure may not work for them.
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