In this session, speakers explored objective metrics and reliable approaches to interpreting the outcomes of clinical trials for regenerative engineering therapies. Speakers also considered how variability in regenerative engineering products can affect the regulatory approval pathway. Karen Christman, the scientific co-founder of Ventrix, discussed the clinical studies and regulatory pathway of VentriGel, an injectable myocardial extracellular matrix hydrogel. Peter Marks, the director of the Center for Biologics Evaluation and Research (CBER) at FDA, discussed some of the agency’s expedited programs for regenerative medicine therapies and other resources that are available to product developers. The session was moderated by Kathy Tsokas, the regulatory head of regenerative medicine and advanced therapy at Johnson & Johnson.
As a case example, Christman described the process of taking VentriGel through the regulatory pathway. VentriGel is an injectable myocardial extracellular matrix hydrogel for treating ischemic cardiomyopathy. Following damage to the myocardium, VentriGel is used to provide a scaffold environment like the native extracellular matrix in order to facilitate cardiac repair and function at the site of a collagen scar. The product is derived from decellularized porcine myocardium, Christman said, and after decellularization the matrix is lyophilized, milled into a fine powder, and partially enzymatically digested so that it can flow through a catheter for delivery. When the liquid matrix is injected into recipient tissue, it reassembles into a porous and fibrous scaffold, creating a new microenvironment (Singelyn et al., 2009).
Variability across source tissue was mitigated by combining pig hearts in batches for product manufacturing, Christman said. In addition, the starting material was harvested from food hogs, which she explained are bred to be consistent. However, she said, there is some level of variability encountered with regard to the characterization assays. The assays for example, can vary by up to 30 percent. This can make defining the product
challenging, and Christman said that the limits of the biological assays lead to broad product specifications.
VentriGel was initially tested in a rat model of myocardial infarction, followed by testing in a porcine myocardial infarction model. Christman showed data from the porcine model, in which the animals received a transendocardial injection of VentriGel 2 weeks after being given an infarct. After 3 months, the ejection fraction, end-diastolic volume, and end-systolic volume were evaluated. Animals receiving VentriGel showed increases in ejection fraction and decreases in volumes, Christman said. Increases in contractility were also observed. The end result, she said, was increased cardiac muscle and reduced fibrosis (Seif-Narahgi et al., 2013; Wassenaar et al., 2016).
Because Christman’s early animal studies showed cell invasion into the area where the VentriGel was injected, a workshop participant asked whether VentriGel and cells administered together might lead to faster tissue regeneration. Christman confirmed that there is endogenous infiltration and increased cardiac muscle, but she said that the type of study proposed by the participant has not been done for the heart. An analogous material derived from porcine skeletal muscle was studied in a mouse model for its ability to deliver askeletal myoblasts, she said, and the data from it suggested that the material increased cell survival over simply injecting cells in liquid suspension. Christman said that several cell companies have expressed interest in her work. She added that most cell companies have their cells well characterized and that adding a biomaterial complicates the regulatory pathway, so partnering with cell researchers may come with additional regulatory challenges.
A phase I safety study is under way of VentriGel in 15 patients with early and late post-myocardial infarction (MI).1 Patients were between 60 days and 3 years post-infarction. Ideally, Christman said, interventions to repair the heart would be done early in the heart failure cascade. From a business perspective, however, there is a greater market for the treatment of later-stage heart failure patients. As such, a broad range of patients was included in the study, adding to the variability.
The study found that VentriGel was well tolerated, Christman said. Adverse events were of the type expected in this patient population. There were also “encouraging efficacy signals” from the secondary endpoints, she said; these included significant improvements in 6-minute walk test results, a symptom score trending toward improvement, and a magnetic resonance
imaging evaluation that showed decreases in end-systolic volume and end-diastolic volume (volumes expand as patients go into heart failure).
As discussed above, the phase I trial included both early and late post-MI patients. About half of those enrolled were within their first year post-MI. Interestingly, Christman said, there were some differences between those patients and the patients who were more than 1 year post-MI. During the initial development, she said, it was expected that treating sooner after MI would provide a more active repair environment. However, that was not necessarily seen in this study, she said, and she suggested that this may have been related to patient variability, as the “baseline is very noisy” in early post-MI patients. So, she said, although early treatment may offer benefits, this high level of variability can make it difficult to demonstrate the levels of efficacy that are necessary for regulatory approval. As a result, the phase II study will enroll heart failure patients in the later stages post-MI.
Disease severity can also result in variability, Christman said. As discussed, it can be difficult to demonstrate treatment effects in patients who exhibit mild disease. On the other end of the spectrum, though, patients may be too sick and have too much damage for regenerative therapy to be successful, Christman said.
Variability and the Regulatory Approval Pathway
VentriGel has a complex mechanism of action, Christman said, which may contribute to some of the variability observed in patients. A whole-transcriptome gene array revealed that there were significant shifts in global gene expression in animals receiving VentriGel as compared with controls (Wassenaar et al., 2016). The affected pathways included cell death, hypertrophy, immunomodulatory response, metabolic processes, blood vessel development, and heart development. Christman commented that this complex mechanism of action includes the immune response, as had been discussed earlier by Elisseeff (see Chapter 3).
Christman identified several specific challenges along the regulatory approval pathway. The first is the need for an activity assay for the phase III study and for approval. A key issue, she said, is developing a potency assay when the product under development has a complex mechanism of action, especially when that mechanism involves the immune response, and a mechanism that cannot be modeled meaningfully in vitro. Another challenge for complex products is developing antibody assays for the clinic, she said. Lastly, the per-patient costs of these trials are high, she said, and including the traditional endpoints of hospitalization and mortality would
require huge trials. Given the good safety profiles of these kinds of technologies, she suggested allowing more leeway in defining approvable clinical endpoints and then incorporating post-market monitoring to expand the data on efficacy in a larger, more variable population.
For regulators working to understand what the predictors of efficacy might be, Christman said that indicators would be disease- or tissue-specific. For heart tissue, for example, the key quality would be functionality (e.g., contractility, increase in viable tissue, reduction in scar size).
A broad variety of regenerative medicine products exist, Marks said, from bioengineered skin, blood vessels, and bladders to CAR T cells. Across these many products there will be some commonalities in critical quality attributes, but there will also be many differences. As had been discussed throughout the workshop, he said that there are many sources of variability that could potentially affect the regulatory approval of regenerative medicine products. These include, for example, donor pretreatment, the characteristics of the harvested tissue or cells, manufacturing steps, the preparative regimen for the recipient, clinical trial inclusion and exclusion criteria, the endpoint assessment, and the disease outcome. In some cases these sources of variability are common in drug development, and in other cases they are unique to cellular therapy products. The task, Marks said, is to “control what you can control” and then deal with the rest. Responding to a point made by Christman, Marks suggested that if there are multiple mechanisms of action for a given therapy, then it makes sense to pick one mechanism of action to use to develop a potency assay and move it forward.
Expedited Programs for Regenerative Medicine Therapies
There is a great deal of interest in regenerative medicine as a way to bring new treatments and cures to address unmet medical needs, Marks said. Congress has taken notice of this and has provided the Regenerative Medicine Advanced Therapy (RMAT) designation to expedite product development and review. The RMAT designation is for products that are intended for serious or life-threatening diseases or conditions and for which preliminary clinical evidence indicates a potential to address unmet medical needs. Marks said that FDA has applied this designation fairly broadly to cell therapies, therapeutic tissue engineering products, human and cell tissue products, and combination products. Genetically modified cell therapies and gene therapies that lead to durable modifications have also been included, he said. Marks said that the bar for the RMAT designation is
slightly different than that for a breakthrough therapy designation, which requires clinical evidence showing a substantial improvement over existing therapies.
FDA will reply to submitted RMAT designation requests within 60 days, Marks said, and designated products are eligible for all of FDA’s priority review and accelerated approval programs. If a product is approved through RMAT accelerated approval provisions, there will be post-approval requirements, he said. These can be fulfilled through the submission of additional clinical evidence from clinical studies, patient registries, or electronic health records, for example, or through post-approval monitoring of treated patients. For example, Marks said, a product sponsor might also seek traditional approval by collecting larger datasets, perhaps from a protocol already under way.
From December 2016 until the time of the workshop, Marks said, FDA had received 81 requests for RMAT designations. There have been 27 designations issued thus far, and 17 also have orphan product designation. He added that most of the requests that have not been granted have not provided sufficient clinical evidence.
Challenges for the Development of Regenerative Medicine Products
Marks discussed some of the challenges facing developers of regenerative medicine products. First, he said, there is a need for standards for reproducibility in the production of regenerative medicine products. He mentioned the Standards Coordinating Body (also mentioned in Chapter 5) as well as a collaboration with the National Institute of Standards and Technology to develop standards for regenerative medicine.
Another challenge is the transition from pilot scale to commercial manufacturing. One of the areas that needs to be addressed will be distributed versus centralized manufacturing, Marks said, especially as semi-automated cell processing devices become more readily available. If a product will be manufactured in a central location, its developers should consider the scalability of the manufacturing process from the start. As an example of a distributed manufacturing challenge, Marks said that CAR T cells are being manufactured at many different centers for several hundred ongoing clinical trials. He said that much of the downstream time and effort could be saved if everyone manufacturing CAR T cells at academic institutions could agree on “early phase manufacturing processes that were commensurate with being transferred to commercial scale processes.” Referring to the molecular cloning laboratory manual first published in 1982 by Tom Maniatis, he suggested that a similar core resource is needed for regenerative medicine.
There are also challenges in the clinical development of complex therapies and in working with small patient populations. Marks said it is
important to create integrated development plans at the start that span the pathway from first-in-human trials to licensure. When working with small patient populations, he said, collaborative clinical development programs are sometimes possible. Each site manufactures the product according to an identical protocol, with controls in place to ensure that the product will be considered “the same” from a regulatory perspective. Data are then pooled for the biologics license application, and approval would be awarded to each site for its product. Marks noted that there are pilot programs under way that are testing this concept (discussed in Marks and Gottlieb, 2018).
Resources for Product Development
From a regulatory perspective, Marks said, early dialogue with the agency is encouraged. Sponsors of regenerative medicine products can contact the Office of Tissues and Advanced Therapies early on through the INTERACT program (INitial Targeted Engagement for Regulatory Advice on CBER producTs) to discuss their plans for development.2 This is a nonbinding, early interaction regarding a specific product in which developers can ask questions about pre-clinical or clinical studies, for example, or about chemistry, manufacturing, and controls.
In closing, Marks said, “FDA is committed to advancing the development and evaluation of regenerative medicine products.” The agency wants to help developers move through the process as quickly as possible, while still ensuring safety and efficacy, he said, and he encouraged product developers to reach out to the agency for early discussions about their products. FDA can, for example, help individualize product development, overcome manufacturing limitations, and provide input on novel endpoints and innovative trial designs.
2 See https://www.fda.gov/BiologicsBloodVaccines/ResourcesforYou/Industry/ucm611501.htm (accessed December 16, 2018).
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