Exploring Novel Clinical Trial Designs for Gene-Based Therapies Proceedings of a Workshop (2020) / Chapter Skim
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5 Integrating Gene-Based Therapies into Clinical Practice: Exploring Long-Term Clinical Follow-Up of Patients
5 Integrating Gene-Based Therapies into Clinical Practice: Exploring Long-Term Clinical Follow-Up of Patients
Pages 55-68
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From page 55... ...
(Purohit-Sheth) • Products that FDA considers to have a greater risk of delayed adverse events include those that use integrating viruses, viruses capable of latency reactivation, and genome-editing products.
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From page 56... ...
The Cystic Fibrosis Foundation has been successful in this area in large part due to strong business relationships with pharma ceutical sponsors and credibility with regulatory agencies with regard to the patient registry. (Marshall)
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From page 57... ...
FDA may require long-term follow-up for gene therapy products because they are intended to achieve a prolonged or permanent therapeutic effect and, as such, long-term exposure may produce unpredictable or unexpected delayed risks for a patient receiving that therapy. Delayed risks can include malignancy, impaired gene function, autoimmune-like reactions, a reactivation after latency and infection, and resistant infections.
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From page 58... ...
Biodistribution studies should use the maximum feasible or clinical dose, and preclinical work should also include kinetic studies. FDA recommends that animal sacrifice should occur at the peak of FIGURE 5-1 Framework to assess the risk of gene therapy–related delayed adverse events.
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From page 59... ...
All follow-up studies should proceed using a dedicated clinical protocol with prespecified patient visit schedules, a prespecified sampling plan, the methodology that will be used to assess the persistence of vector sequences, the clinical events that will be monitored, a means of collecting accurate case histories, and a health care provider template for non-investigator caregivers. The protocol should also specify how adverse events will be reported to FDA, how they will be discussed in annual reports, and the procedure for submitting any necessary protocol amendments, such as the need to assess a new risk.
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From page 60... ...
Over the subsequent 10 years, FDA recommends contacting subjects at least yearly by phone, office visit, or questionnaire. Informed consent should explain the purpose of the long-term followup study, the expected participation and procedures, foreseeable risks, scheduled study visits, and tissue and data collection procedures as well as the basic elements required for any clinical study.
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From page 61... ...
assessment, self-report, reports, NDI med. record, NDI Collection of germline DNA >60% >95% NOTE: CCSS = Childhood Cancer Survivor Study; CNS = central nervous system; Dx = diagnosis; HL = Hodgkin lymphoma; NDI = National Death Index; NHL = non-Hodgkin lymphoma; SJLIFE = St.
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From page 62... ...
One of the strengths of assembling a cohort of survivors, Robison said, is that it is possible to look at multiple outcomes, which is important, given that pediatric cancer survivors are at risk for many different types of adverse outcomes. Data from the SJLIFE cohort revealed that the prevalence of a variety of adverse events, such as the occurrence of abnormal pulmonary function, hearing loss, heart valve disorder, and breast cancer in female survivors, increased over time and that, when assessed in the clinic, survivors were found to be experiencing multiple health issues (Bhakta et al., 2017)
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From page 63... ...
LONG-TERM FOLLOW-UP FOR GENE AND CELLULAR THERAPIES Long-term follow-up for cellular therapies, Chonzi said, should include monitoring for adverse events such as secondary malignancies, autoimmune disorders, new persistent hematological disorders, and other issues such as hypogammaglobulinemia and infections. Following persistence is also important because it is not yet known if all cellular products have the same persistence characteristics in humans.
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From page 64... ...
Some groups have done so, he said, but more data are needed on secondary malignancies, autoimmune disorders, and persistent hematological disorders. The field of cellular therapy is growing considerably, and more studies will be coming, he said, adding that "it is even more important for us at this moment in time to try and harmonize how we are collecting the data so that it becomes easier and easier." ROLE OF THE CYSTIC FIBROSIS FOUNDATION IN ADDRESSING POST-APPROVAL REGULATORY OBLIGATIONS Tracking patient outcomes after a gene therapy clinical trial may be improved through access to a patient registry.
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From page 65... ...
He added that FDA approvals of drugs to treat cystic fibrosis have come with post-approval requirements and commitments, which have included • a 10-year prospective observational study to assess the risk of fibrosing colonopathy3 for reformulated pancreatic enzymes; • a 5-year prospective observational study to assess the risk of anti biotic resistance to a new inhaled antibiotic; and • a 5-year prospective observational study to assess the safety of a new modulator of the cystic fibrosis transmembrane conductance regulator (CFTR)
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From page 66... ...
They knew of our Care Center Network, and they knew of our registry, so, it was easy to develop a business relationship with them," he said. "We also had credibility with the FDA in terms of our registry." A PATIENT'S PERSPECTIVE ON LONG TERM FOLLOW-UP STUDIES As the fourth patient to receive CAR T therapy for CLL at Penn Medicine in 2013 and one of the first to receive a second round of CAR T therapy in 2017, Levis provided a patient's perspective of what it is like to participate in a clinical trial -- and as he put it, be genetically modified.
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From page 67... ...
DISCUSSION The presentations in the session were followed by a moderated panel discussion, which served as an opportunity for workshop participants to ask questions of the speakers. The panel discussion explored the length of time patients are followed after a gene therapy clinical trial, motivating factors for participation in follow-up studies, and costs for tracking patients over several years.
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From page 68... ...
DeBaun, the session moderator, noted that a large percentage of children and adults in the United States receive health insurance from the government through Medicare or Medicaid. The likelihood of an adult or child with sickle cell disease participating in long-term follow-up with a knowledgeable provider after receiving a curative therapy is less than 1 percent, he said.
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