The regulatory landscape for regenerative therapies is evolving, and this chapter explores relevant issues including approaches to developing standards and establishing and enforcing regulations that meet the needs of patients. The speakers in this session were Robert McBurney, the president and chief executive officer of Accelerated Cure Project for Multiple Sclerosis and co–principal investigator of the iConquerMS Patient-Powered Research Network; Steven Bauer, the chief of the cellular and tissue therapy branch in the Center for Biologics Evaluation and Research at FDA; and Katherine Tsokas, the senior director for global regulatory affairs at Johnson & Johnson.
Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system that causes damage to the myelin sheath that insulates the nerve fibers. This damage can lead to conduction failures and, ultimately, the death of nerve cells, McBurney said. People living with MS experience such symptoms as loss of mobility, loss of vision, cognitive problems, fatigue, sleep disorders, and mental health problems, he said. Over the past 25 years, there has been remarkable progress made in treating the symptoms of the disease, he said, with 15 FDA-approved therapies available today and 2 or 3 more that should be ready for regulatory review over the next couple of years. However, there is still no cure for MS. All of the
approved therapies, he said, address aspects of the immune system’s role in MS, but none address the fundamental cause of the disease.
The Accelerated Cure Project1—founded in 2001 by an engineer who was diagnosed with MS—has two main programs: a biorepository containing DNA, RNA, plasma, serum, and white blood cells from 3,200 consenting individuals collected at 10 MS clinics around the United States, and a people-powered research network called iConquerMS™ which was started in 2014 with funding from the Patient-Centered Outcomes Research Institute.
The biorepository, McBurney said, has supported more than 100 studies with a mandated return of data from any researcher who receives samples from the biorepository. This mandated data return, he said, has allowed for the creation of virtual collaborations among participating organizations. One advantage to these virtual collaborations, he said, is that they often do not require participating organizations to complete legal agreements, a feature which has accelerated collaborations. The iConquerMS network includes approximately 4,000 MS patients who are involved in the conception and conduct of research studies, the dissemination of information, and advocacy as a means of improving care for MS patients. iConquerMS currently has 36 individuals on its governing board, research committee, and engagement committee, 22 of whom are lawyers, scientists, neurologists, and biorepository experts who have MS.
Speaking about the regenerative medicine opportunities in MS, McBurney highlighted three areas in particular: rebooting the “confused” immune system with hematopoietic stem cells or MSCs; repairing the damaged myelin sheath with oligodendrocytes regenerated from MSCs or iPSCs; and regenerating lost nerve cells and reforming appropriate connections using MSCs or iPSCs. Currently, he said, there are approximately 50 clinical studies under way worldwide in these 3 areas. Of the 16 studies based in the United States, 12 academic studies are completed or are no longer recruiting, and 4 industry-sponsored trials, primarily using MSCs, are in the recruitment phase. However, McBurney said, he considers the four U.S. industry-sponsored trials that are patient-funded to not be traditional clinical trials. In fact, he said, while there are excellent academic and industry-sponsored studies going on outside of the United States, there is also a great deal of medical tourism aimed at MS patients.
One therapeutic approach uses autologous hematopoietic stem cell transplantation (aHSCT) to attempt to reach an endpoint known as “no evidence of disease activity,” or NEDA. NEDA is indicated by three measures of MS activity: no relapses, no progression to disability, and no new
or enlarging lesions upon magnetic resonance imaging. The multi-step process of aHSCT involves ablating the patient’s immune system and attempting to reconstitute it using hematopoietic stem cells. Preliminary results indicate that certain groups of patients have a higher likelihood of achieving NEDA with aHSCT than with other available disease-modifying therapies, although additional work is needed to verify these findings (Muraro et al., 2017a,b; Sormani et al., 2017). The regulatory environment needs to be in good shape, McBurney said, so that if future trials for aHSCT go well, then the therapies can reach the MS community as quickly as possible.
Early results from using autologous hematopoietic stem cells to treat MS have spurred the development of another upcoming trial, called the BEAT-MS trial. McBurney said he hopes that the BEAT-MS trial will carefully develop analytical aspects so that the researchers can ensure that the cells are in the best possible state prior to transfusion. Ultimately, he said, the goal of clinical trials and successful treatment are the same for small molecules and cell therapy—to deliver a material with the right properties into the right patient at the right time in the right concentration.
Patients are an extremely valuable resource, McBurney said, because they can facilitate the conduct of clinical trials and product approvals through their involvement from the beginning of the process. Patients can be involved at many stages, from the development of a clinical trial protocol through to the end of the process when developers are seeking approvals and reimbursement. It is extremely important to educate the patients and caregivers, McBurney said, specifically regarding the characteristics of high-quality clinical trials and as a way to bridge the gap between expectation and reality which often develops because of the normal human tendency to hope.
Biorepositories play an important role in therapeutic development, McBurney said, because they allow for research on the properties of cells at various stages. Biorepositories can process, store, and distribute research materials and mandate data returns in an agnostic manner, he said. “We need neutral management and oversight of the activities of a biorepository,” he said, “including study approval, material distribution, and return of data.”
FDA sees product characterization as encompassing chemistry, manufacturing, and controls (CMC), Bauer said. The goals of characterization are to ensure product safety, ensure the consistency of the process and product, and, ideally, predict in vivo activity; the last of these three is a particular challenge for this field, he said. In his view, Bauer said, product
characterization also includes the identification of CQAs. The field will move forward rapidly if there is progress on developing better strategies for identifying and measuring CQAs, he said. The assessment of each of these aspects of CMC should be guided by a detailed understanding of the manufacturing process and the product.
Several years ago, when FDA conducted a survey of the investigational new drug (IND) applications submitted for MSC-based products, it found that, generally, MSCs are quite diverse in terms of their characterization, manufacturing, and sources (Mendicino et al., 2014). The issue of CQAs for MSCs is still an open question, Bauer said, and the understanding of their relationship to performance in clinical trials needs more work. The review from Mendicino et al. (2014) demonstrated that investigators working with MSCs define these cells by their characteristics of having immunomodulatory and anti-inflammatory activity; being capable of generating adipocytes, chondrocytes, and osteoblasts; and having the property that when manufactured in large number the cells will maintain the relatively few CQAs measured when the cells were harvested from the patient. Most research teams, he added, follow the MSC research community’s guidelines concerning how to define an MSC, though researchers often give themselves more latitude than what is in those guidelines.
To address the issue of identifying CQAs for MSCs and correlating them with in vivo and in vitro assays of safety and efficacy, FDA started a regulatory science program known as the MSC Consortium.2 While it is important to relate CQAs to performance in an in vivo model, Bauer said, there were some advantages of correlating measurements with in vitro bioassay outcomes in terms of improving the characterization in an iterative, stepwise approach. The raw materials for the consortium came from Bauer’s laboratory, which manufactured MSCs from eight different human bone marrow donors obtained from commercial sources. The consortium has subjected this material to a variety of analytical methodologies, including gene expression and epigenetic analyses and in vivo and in vitro models of immunosuppression and wound repair. For example, his group looked at in vitro quantitative differentiation assays that may be useful as in-process controls or surrogate potency assays. The consortium has not yet progressed to the stage of finding an animal model that is sensitive to differences among the cell lines from the eight different human donors, he noted.
One finding from these studies was that the current MSC surface markers being measured by researchers in the field do not reveal significant differences between donors, nor do they show significant differences with
2 More information about FDA’s research on MSCs can be found here: https://www.fda.gov/biologicsbloodvaccines/scienceresearch/biologicsresearchareas/ucm127182.htm (accessed August 16, 2017).
an increase in passage number (Lo Surdo et al., 2013). This finding was important, Bauer said, because the consensus MSC surface markers at the time of that study did not predict the observed functional biological heterogeneity of MSCs. His team also found that the adipogenic potential varied between cell lines obtained from different donors and that it decreased with passaging. “This theme of stem cell–like activity dropping with duration and tissue culture is something that we saw in this and other MSC biological assays,” Bauer said. The finding suggests that it should be possible to develop a molecular characterization scheme that would help identify the subpopulations of cells that define the activity of the entire mixture of cells, he said.
Bauer and his team also discovered that the size of the cells increased routinely with passaging, which led them to carry out a morphological characterization study. The study, which assessed 96 different morphological measures of cell and nuclear shape, found that morphological characterization 3 days after stimulating the cells with osteogenic media, predicted mineralization activity of the cells at day 35 (Marklein et al., 2016). “The morphological response of the MSCs to the stimuli seems to predict what is going to happen biologically,” Bauer said. In another study, the consortium demonstrated that changes in MSC morphology after stimulation with interferon-γ predicted the extent of the immunosuppressive activity of the cells (Klinker et al., 2017).
Assessing morphological changes can be automated and quantified, Bauer said, which implies that it may be possible to use this kind of assay to screen samples from different donors for the desired quantitative biological activity. This type of assay might also be useful for evaluating the impact of a manufacturing process, particularly tissue culture conditions, on desired biological activity. In fact, consortium researchers examined the effects of different manufacturing conditions on osteogenic activity, as predicted by morphological changes, finding differences according to the manufacturing conditions (Marklein et al., 2016).
FDA is hoping that the thorough examination of MSCs will improve researchers’ ability to use quantitative bioassays to identify CQAs that are indicative of potency and activity, Bauer said. The agency is also hoping to use multifaceted cell characterizations to gain a better understanding of the active subpopulations of cells and to identify markers that are correlated with bioassay outcomes as a means of guiding enrichment techniques. It is also possible, Bauer said, that such assays could be used to measure osteogenic, adipogenic, immunosuppressive, angiogenic, and wound repair potential, among other biological activities.
The Code of Federal Regulations (CFR), specifically Title 21, parts 12703 and 1271,4 are the regulations that sponsors must follow when developing a new therapeutic product, Tsokas said. There are also guidance documents from FDA and other regulatory authorities, such as the International Conference on Harmonization, and standards such as those issued by USP that industry can use when developing its manufacturing processes. The variability with which industry applies these standards and guidelines and with which it handles the different requirements creates challenges, she said.
As a detailed example of both the flexibility and specificity of the regulatory framework, Tsokas discussed how 21 CFR 1271 specifies the ways in which investigators must handle human cells, tissues, and cellular- and tissue-based products as well as the types of tests that should be conducted in in order to prevent the introduction, transmission, or spread of communicable diseases. One of the challenges is that the regulation applies to a broad range of products and must therefore be flexible, she said. FDA’s CMC guidance recommends that sponsors refer to USP sterility tests, which provide the details needed to conduct those assays. The challenge, she said, is to make sure the sponsor can apply that test to its particular product and follow the procedure exactly. Another issue, she added, is that the USP procedure is not designed to ensure that each product batch is sterile. “To do that, we as sponsors need to make sure that we validate the procedure for our particular process,” Tsokas said.
While it is easy to focus only on U.S. requirements and guidance, other countries may have different requirements and guidance to follow, Tsokas noted. “One of the challenges we face as sponsors is that there is information from multiple sources, and the information is all slightly different,” she said, referring to the various international regulatory bodies. “The earlier you try to make sure you are meeting all of those global requirements, the easier it will be for you.”
From a regulatory perspective, understanding a product’s CQAs provides the foundation with which to answer questions, deal with challenges, and think of innovative approaches to address those challenges, Tsokas
3 More information about the CFR Title 21 Part 1270 can be found here: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=1270 (accessed August 28, 2017).
4 More information about the CFR Title 12 Part 1271 can be found here: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=1271 (accessed August 17, 2017).
said. Understanding the basic science early on is important because it leads to informed decisions about how to handle various regulatory requirements. Having a deep understanding of the product, its mechanism of action, and its structure–function relationships is important for determining CQAs and developing potency assays as well as for understanding the effect of the manufacturing process on product attributes, she said. CQAs are also critical for ensuring comparability of a product throughout development, including when the manufacturing process inevitably undergoes changes, so that early results remain relevant to the final product’s performance.
One of the biggest challenges faced by sponsors, Tsokas said, is the need to interpret information from multiple sources and to develop a comprehensive strategy to comply with the regulations and implement them in a quality system. Regulations in the United States, Europe, and Asia all contain the same concepts but apply them differently. The earlier a group can focus on international guidelines and try to meet those requirements, the easier it will be, she said. Regulations do give sponsors flexibility as to how they build their manufacturing control strategy, but once a sponsor implements its strategy, the regulations require strict adherence to GMP, good tissue practice, and good documentation practices.
The use of non-standardized tests can increase costs and inefficiency because of the need to validate the tests, Tsokas said; it is much easier to use an accepted, standardized test whenever possible. Additionally, the information required for an IND application may not include all regulatory requirements from a quality system perspective. For example, an IND application might specify the specific sterility test the sponsor plans to use, but an FDA inspection prior to the start of a Phase III trial may require sampling plans with additional details such as when the test will be conducted and the sample volume that will be tested. It is important to pay attention to all of the details that go into the manufacturing process and be prepared to document and answer questions about those details, Tsokas said.
One way to stay ahead of regulatory requirements is for sponsors to define their quality systems, or plans for managing the quality of manufactured products, in a way that ensures compliance with all applicable regulations. Quality systems, Tsokas explained, provide a framework for sponsors to feel comfortable that they are heading down the right development path for their products. One way that regulators could help sponsors during the development of a product is by providing additional feedback or assessment tools, Tsokas said, noting that such information would help sponsors understand whether they are implementing regulations and guidance appropriately. Another helpful approach, she said, would be to increase the number of USP monographs and specific checklists for standardized platform activities in order to help sponsors have confidence they are meeting regulatory requirements. Examples of potential standardized platform activities
include rapid mycoplasma and microbial testing for non-cryopreserved cell therapies; potency assays for CD19 CAR T cell products; testing for residual process-related impurities, such as bovine serum albumin, proteases, and foreign DNA; adenovirus, lentivirus, and adeno-associated virus vector quality; and monitoring for replication-competent viruses.
Regulatory guidance should allow for flexibility in the development process and should recognize and emphasize the iterative nature of the development process, the need for a risk-based approach to development, and differences in product type, Tsokas said. To facilitate the global development of advanced therapeutics, regulatory agencies should encourage the convergence of regulations, guidance, and regulatory processes across regions in order to create consistency in the regulatory approval process, she said. Getting to a state of harmonization and convergence requires an understanding of where the gaps are in the global regulatory institutions and identifying the most promising and valuable areas for harmonization, convergence, and making use of standards, Tsokas said. It also requires regulators, industry, and academia communicating with one another and working together to determine where to make improvements that will help industry develop advanced therapies for the benefit of patients worldwide.
Increasing Collaboration Among Stakeholders
FDA, NIST, and various standards determining organizations such as ASTM International, the American Type Culture Collection, the Standards Coordinating Body, and the National Institute for Innovation in Manufacturing Biopharmaceuticals are working together to determine where standards for regenerative medicine product manufacturing can be developed. FDA has active research collaborations with NIST in areas such as the standardization of cell counting and flow cytometry and also has internal regulatory research aimed at helping people better understand and characterize their products in cell therapy and regenerative medicine. FDA is also part of the International Pharmaceutical Regulators Forum,5 which has cell therapy and gene therapy working groups that are collaborating with regulators in 13 countries, some of which do not have regulatory frameworks for cell and gene therapy. The International Pharmaceutical Regulators Forum is also working on the convergence of regulatory approaches, which are surprisingly more alike than many people would realize, a workshop participant said.
Defining the Role of Patient Advocates in Shaping Regulatory Policy
The National Patient-Centered Clinical Research Network and Genetic Alliance are examples of umbrella organizations that facilitate patient contributions to the regulatory process. Genetic Alliance currently includes approximately 2,000 advocacy organizations; two other umbrella patient groups involved in this effort are the National Organization for Rare Disorders and the National Health Council.
When communicating with patient advocates regarding regulatory policies, FDA tries to engage actively by including the advocates in some of the agency’s advisory panels. FDA is at the intersection of many different interests, Bauer said, but its interaction with patient advocacy groups is very highly valued. Johnson & Johnson also connects with patients in the specific therapeutic areas in which it works and shares data with advocacy organizations, Tsokas said. Regarding “right to try” legislation, which is a concern for some patients, Tsokas said that Johnson & Johnson supports the idea that products should be made available if possible, but the company firmly believes it is important to make sure such products are safe before they can be used for additional indications.
Biorepositories and Data Sharing
The Accelerated Cure Project for MS and other patient-focused groups, such as Genetic Alliance, have written resources on establishing a biorepository, but in general, McBurney said, he prefers to speak directly with groups who are interested in starting a biorepository about their needs because one approach does not necessarily work for another. His organization found it was beneficial to pay for sample collection and on-site study coordinators as a means of avoiding the involvement of the provider systems with regard to sample access. While it cost $15 million to do that, he said, “it is an important part of a model like this because it does provide flexibility to support research in different contexts.” The management of this process is fairly straightforward, McBurney said. “It is not without work, but the ability to create these virtual collaborations and return data to a central source is something that does accelerate progress,” he said. These data, he explained, have not been used for regulatory purposes, and the system was not set up to do so.
In the field of regenerative medicine, biorepositories and data sharing may be easier in the pre-competitive space, Tsokas said, noting that careful consideration should go into determining the best approaches for sharing resources. It has sometimes been easier to get companies than academics to return data generated from biorepository samples, McBurney said. Industry has conducted one-third of the studies from his organization’s bioreposi-
tory, and in each case those companies have returned their data once they completed those studies. McBurney said that his organization does not have the resources or time to retrieve all of the data from academics who do not return them.
Unregulated Therapies and Medical Tourism
Clinics offering unproven stem cell–based therapies are becoming more prominent in the United States (Turner and Knoepfler, 2016). There may be opportunities for patient advocacy groups and regulators to provide education to the public on what elements they should look for concerning a clinic offering cellular therapies. The issue of unproven stem cell therapies came up at a recent public workshop held by FDA in September 2016, Bauer said. The workshop focused on the scientific considerations and challenges to informing the development of human cells, tissues, and cellular- and tissue-based products subject to premarket approval and included speakers who discussed approaches to educating consumers about clinics offering unproven therapies.
Medical tourism is most likely driven by many factors. According to one workshop participant, patients with serious unmet needs can see promising and reputable data from an early MS trial, and if they do not have access to that therapy through conventional approaches in the United States, they may seek alternatives. While there are reputable clinics abroad offering therapies for MS, those clinics are not publishing any definitive data, McBurney said. The upcoming BEAT-MS trial will examine the autologous hematopoietic stem cell therapy, he said, and those running the trial plan to compare the results of that treatment to the best available therapy, he said. Early evidence has demonstrated a large amount of variance in the response of MS patients to the autologous hematopoietic stem cell therapy, McBurney said, but that may be due to the small number of patients in the early trials. Furthermore, the benefits of these hematopoietic stem cells seem to wane after 4 years for reasons not yet known.
Japan’s revised Pharmaceutical Affairs Law is a regulated accelerated or conditional approval pathway, as opposed to medical tourism, which is not regulated, Tsokas said. Sponsors still need to meet with Japanese regulators and review their manufacturing processes, she said. “You can, with safety data and minimal efficacy data, get conditional approval,” and then a confirmatory trial is needed in 7 to 10 years. It is still too early to tell if this approach has helped reduce medical tourism or increased the speed with which products can obtain full approval, she said.
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