Critical Path Workshop on the Development of Cellular and Gene Therapy Products
Authors: Eda T. Bloom, Suzanne L. Epstein, Stephanie L. Simek
Journal: Molecular Therapy (2005)

The U.S. FDA recently announced an initiative known as The Critical Path to New Medical Products (http://www.fda.gov/oc/initiatives/criticalpath/), intended to address a “recent slowdown in innovative medical technologies submitted to FDA for approval,” as described in the FDA white paper, “Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products,” (http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html). The view of the FDA is that increased attention to certain hurdles is needed to provide more rapid public access to the new technologies that have emerged during the past two decades. FDA thinks new products development methods are needed “to improve predictability and efficiency along the critical path from laboratory concept to commercial product.” As an agency making science-based decisions, FDA is in the position to help identify problems and develop solutions, and it is essential that stakeholders be involved at each step. Toward this end, on 7 October 2004, Center for Biologics Evaluation and Research (CBER) of the FDA held a workshop entitled “From Concept to Consumer: Center for Biologics Evaluation and Research Working with Stakeholders on Scientific Opportunities for Facilitating the Development of Vaccines, Blood and Blood Products, and Cellular, Tissue and Gene Therapies.” The aim of this workshop was to share information between FDA and stakeholders and to gain insight into what scientific opportunities and approaches can be developed to shepherd innovative products along the critical path from discovery to clinical testing and then to market and broad public access. This report emphasizes the results of the CBER workshop applicable to cellular and gene therapies and related products. These products are among the most innovative on the medical horizon, including, but not limited to, gene therapies, cellular therapies, xenotransplantation, and cancer vaccines. They hold potential to provide new therapeutic approaches to diseases ranging from rare genetic disorders and cancer to replacement of failed organs and tissues. Several also pose serious risks that could adversely affect others in the general population (e.g., risk of novel infectious diseases as a consequence of xenotransplantation) or future generations (e.g., intentional or inadvertent germline alternation as a consequence of gene therapy). We believe that the information obtained from the workshop and similar interactions with stakeholders will be important for establishing what scientific information is needed to advance effective products safely along the critical path to the consumer. The morning session of the workshop provided overviews of activities within different CBER offices. Emphasis was placed on those activities related to advancing products through the development process to marketing, and presentations highlighted the scientific knowledge needed for progress along the critical path. These overviews were presented by leadership within each office. Dr. Joyce Frey, as Acting Director, Office of Cellular, Tissue and Gene Therapies (OCTGT), presented a summary of ongoing or planned OCTGT activities. Regulatory responsibilities include many novel biologics, such as cellular and gene therapies, xenotransplantation, tumor vaccines, related combination products and devices used in the manufacture of these products, and human tissues and human tissue-based products. Ongoing research in OCTGT includes virology (retroviruses, adenovirus, herpesviruses), immunology (host-vector interactions, transplantation rejection), developmental biology (control pathways in animal models and stem cell biology), and novel assay technology (genomics, proteomics and flow cytometry). Dr. Frey provided examples of how research programs have been used to investigate product safety and product characterization, and have led to development of assays and reference materials. For example, OCTGT scientists investigated (1) whether pre-existing liver disease increases the risks of using adenoviral vectors, (2) possible contamination of certain biological products with HIV and HCV, (3) assays for the detection of porcine endogenous retrovirus (PERV), thought to be a risk in xenotransplantation, and (4) development of adenovirus and retrovirus reference materials, and (5) standards for flow cytometry. Ongoing projects are determining ways to assess product-host interactions for products including gene therapy vectors, cellular therapies and xenotransplantation products. Other projects are aimed at identifying key control points and molecules crucial in cellular differentiation and development, as indicators of what biomarkers may be used to characterize safety, identity and potency of cellular products, including stem cells. Finally, Dr. Frey summarized OCTGT's future challenges as 1) identifying the scientific barriers to ushering promising products forward through the whole span of development, 2) leveraging stakeholder expertise to address these challenges, 3) identifying guidance, standards and assays that would be useful, and 4) preparing for the next generation of products. During the afternoon sessions, representatives of academia, industry, other government agencies, and patient advocacy groups were invited to be panelists in each of the workshop's breakout sessions. The Cell and Gene Therapy panel members included Katherine High, (Children's Hospital of Philadelphia), Alexander Kuta (Genzyme Corporation), Sonia Skarlatos (NIH), and Patrick Terry (Genetic Alliance). In addition, Dr. Nicholas Obiri represented the Office of Compliance and Biologics Quality, Division of Manufacturing and Product Quality. Dr. Eda Bloom, who moderated the session, represented the OCTGT, Division of Cellular and Gene Therapies. Approximately one hundred attendees and discussants were present. The audience also included many CBER staff members who were present to listen to the concepts and ideas discussed by stakeholders, as well as to participate in the discussions. The purpose of the breakout session was to gain input on opportunities and initiatives to facilitate the development of cellular and gene therapy products. This review summarizes the concepts and ideas that FDA/CBER heard at this session, and therefore does not necessarily represent the views of the agency or the U.S. government. To start the discussion, the non-FDA panelists each provided comments. Dr. High summarized findings of a survey of ASGT members in which they were asked questions about interactions with FDA. Respondents emphasized the importance of retaining experienced reviewers and of continued access to reviewers. The value of pre-IND meetings and of guidance documents was mentioned. Respondents pointed out the novelty of gene therapy products, and the resulting need for a science-based regulatory process rather than rigid rules. Respondents said their interactions with FDA benefit from access to, and discussions with scientifically active reviewers who themselves perform research. They mentioned that the new OCTGT is clearly understaffed. Regarding scientific and technical problems, responding ASGT members mentioned the need for vector reference standards, improvements in vector production, ways to minimize vector integration such as insulating elements, methods for estimating frequency of integration for “nonintegrating” vectors, ways of regulating transgene expression (“molecular switches”), and information about immune responses to vectors and transgene products. Useful initiatives were deemed to be guidance documents, bridging studies to reduce testing necessary for additional serotypes of vectors already in use, assessment of germline risk, an FDA initiative on toxicology in rare disease systems, and participation by CBER staff in workshops on preclinical testing and long-term follow up and in training courses. The Biological Response Modifiers Advisory Committee, the CBER Advisory Committee that has been concerned with cellular and gene therapy products, was praised as very useful. Dr. Skarlatos spoke about the Programs of Excellence in Gene Therapy for Heart, Lung, and Blood Diseases intended to facilitate progress from the bench to the clinic. NHLBI has established core facilities for vector production for preclinical and clinical use. The use of core facilities should prove more cost-effective than vector production by individual investigators. Core Directors and investigators identified the following issues or problems: 1) deficiency in understanding how current Good Manufacturing Practices (cGMPs) apply to vector production, 2) a disconnect in communication between the core facilities and sponsors, which could be addressed by inviting core facility staff to pre-IND meetings, and 3) a need for a list of cell lines that may be appropriate for vector production, indicating regulatory challenges and hurdles for each. Dr. Skarlatos discussed the importance of seizing opportunities that arise for sharing data. For example, the National Gene Vector Labs (NGVL) of the National Center for Research Resources (NCRR) is currently entering toxicology data into a database that would allow core facilities to share data on vector production and cell banks. NHLBI is now collaborating with the NGVL for vector production. Mr. Terry provided insight from the patient/patient advocacy perspective about what is necessary to make progress in developing novel products. He said innovation is iterative and mistake-filled, requiring leadership. It takes place on the fringes, not in centralized, consensus-building environments: innovation happens at the point of contention. His comments, while they apply to all innovative medical products, apply especially well to cellular and gene therapy products. He said that government agencies are not good at coordinating and partnering with other agencies. He also cautioned that FDA should be careful about unintentionally raising expectations among consumers. For example, he thinks there is irrational exuberance about microarray technology when there is no actionable information that can currently be made available to patients. Mr. Terry emphasized the need to maintain focus by addressing the most pressing cell and gene therapy development problems and those with greatest potential public health benefit. He mentioned that developing reference standards and guidance documents are important and useful goals. He emphasized that attention should be paid to measures that can advance incremental change, for example identification of intermediate phenotypes and surrogate markers to use in characterizing phenotypes of genetic diseases. Mr. Terry also asserted that patient advocacy leaders need more dialogue with decision makers in FDA, saying that current contact with patient advocacy groups is essentially tokenism. In discussing patient concerns, he mentioned that proxies often speak for patients (ethicists, lawyers), but that it is also important to discuss and address actual patient views of risk-benefit and risk-tolerance. Dr. Kuta discussed the use of model systems and asked the participants to consider at what point data generated by novel models, not yet fully understood and/or not accurately reflecting the true biological state, actually retard rather than enhance product development because of theoretical concerns. He discussed surrogate endpoints, and the need for Agency agreement on defining the term “reasonably represents clinical benefit,” while acknowledging the difficulty in knowing what endpoints will reasonably predict patient benefit. He praised the efforts outlined by FDA to convene experts to consider appropriate surrogate markers for disease states, but cautioned that this effort must include orphan diseases as these are often more difficult to characterize due to the limited information on disease natural history. He mentioned that post-approval commitments are important if surrogate endpoints are used. However, discussion of these commitments should begin between FDA and sponsors early in development (pre-phase III). He mentioned that it is important to think outside traditional clinical trial designs, i.e., the double-blind, randomized, placebo-controlled trial, especially in rare diseases with small populations which are often the focus of gene therapy trials. He agreed that FDA is uniquely positioned to see data that indicate which clinical trial designs work and which fail, and suggested that a formal mechanism be put in place within the Agency to allow the sharing of these experiences so that all staff (thus sponsors) may benefit. He suggested that the Agency use this information to assemble issues for public discussion at advisory committee meetings. He said standard reagents (“standards”) do provide some value, citing the replication competent retroviral and adenoviral standards. However, he cautioned that their utility needs to be clearly addressed; for example, the adenoviral “standard” represents only one serotype of adenovirus. Dr. Kuta mentioned that in the case of cellular products, a major issue is the short shelf-life of the product and stressed the resulting need for rapid testing. Meaningful assays for purity, potency, and identity also need to be considered. He stated that in the future the field will only get more complicated, e.g., products that incorporate gene-modified cells in a biomaterial matrix. He mentioned that while potency assays may not necessarily correlate directly with clinical benefit, they can indicate whether the cells are functioning and whether they do so consistently. A number of themes emerged from ensuing discussions regarding what kinds of science are needed to move cellular and gene therapy products forward. As an overriding principle, it was articulated that science cannot merely react to tragedy. Rather, research needs to be carefully supported and planned and remain “ahead of the curve.” Representatives of industry suggested that while reference standards exist for certain gene therapy vectors (e.g., type 5 adenovirus), multiple serotypes of adenovirus are in clinical use, and development of additional standards would be useful. The audience also discussed the need for more research to define informative preclinical animal studies. It was stated that there should be better-designed studies using more appropriate animal models for clinical indications such as rare diseases or genetic defects. Thus, while one member of the audience questioned whether preclinical work in any animal model is appropriate, because even very extensive studies in animals may not predict adverse events in humans, another responded that the scientific approach to drug development would be enhanced by development of animal models for systems in which none exist. Generation of additional data relevant to immunity and immunogenicity were identified as useful for the progress of cell and gene therapy products. For example, the impact of immunity to vectors, products of transgenes, and cell therapies needs a firm scientific basis to predict safety and efficacy better. Immunity should be investigated in preclinical models to help choose endpoints as means to monitor patients' responses to treatment. Vector integration was identified as another area needing more research. A better understanding of the frequency of vector integration would enable FDA to make science-based decisions on vector safety, particularly for so-called non-integrating vectors. It was also noted that research on product characterization and stability is needed, including improved and appropriate assays/bioassays for potency. One contributor observed that overall, improved understanding of the manufacturing and product systems would allow science-based decisions rather than decisions based on “sometimes unproven rules.” Participants emphasized that flexibility is prized in CBER's regulatory oversight of these novel products, and crucial for enabling them to progress through product development. Participants discussed what scientific advances would be useful for initiating and conducting clinical trials. Some comments reinforced previously identified needs for preclinical research to support trials or improve monitoring of clinical trials. There was discussion of why the number of clinical trials seems to be declining. Participants observed that developing cellular and gene therapy products is more challenging than originally expected, and that the early optimism resulted from simplistic views. The resulting uncertainty has discouraged some from sponsoring trials. One participant suggested that the clinical field of gene therapy has been inhibited, and sponsors discouraged from entering the field, as a consequence of the death of a patient in a gene therapy trial in 1999. He maintained that the death led to a reevaluation of risk tolerance and informed consent, which had been carried to an extreme by FDA, the Institutional review Boards (IRBs) and Institutional Biosafety Committees (IBCs). Participants mentioned that additional information should be obtained to develop surrogate endpoints or biomarkers that could be used for monitoring clinical effectiveness. Panelists and participants agreed that investigation of treatment for rare disorders should be encouraged. Stakeholders expressed that successful therapies will be developed in systems with the best scientific underpinnings, from investigators who are intimately familiar with the diseases they are trying to treat, and who are informed about, and take advantage of, the incremental advances in technology. Such systems may be rare diseases. Advances in therapy for rare disorders would likely provide insight into treatment of other, more prevalent diseases. However, treatment of diseases caused by single-gene defects should not be considered simple. Even these can be multifactorial and appropriate science is necessary to understand molecular pathways and identify key control points and targets. One audience participant suggested that cancer is the disease most frequently addressed because it has good potential for financial benefit, whereas treatments for all monogenic disorders combined would not produce the same level of profit for manufacturers. The profit factor raised by this participant could affect development of new therapies despite FDA efforts to remove critical path hurdles. The long-term follow-up (LTFU) of patients treated with gene therapy was an area of discussion. Most participants would like FDA to expedite issuance of explicit guidance regarding the duration of LTFU needed. While participants declined to comment regarding what kind of science is necessary to generate this guidance, some mentioned that they believed that LTFU is not needed for plasmid vectors. It was acknowledged that LTFU issues do not apply solely to patients treated with gene therapy products. Discussion also addressed a number of regulatory review issues. Although the focus of this workshop was not on regulatory policy, the concerns raised are relevant to bridging the gap between recent scientific developments and application of this science to facilitate delivery of safe and effective products. Collaboration and cooperation within the US government and between the US government and international bodies was discussed. A number of participants emphasized the importance of interaction among FDA Centers, as well as between FDA and other agencies such as NIH and CDC. It was also noted that FDA should interact with other national and international regulatory bodies, and standards/guidelines development groups such as ISO. A need for disclosure or sharing of information was identified within the context of interactions with other regulatory entities. Disclosure was also discussed in the context of communication with stakeholders. It was pointed out that FDA has a body of information nobody else has, and that it would be valuable for that information to reach the public, as much as possible. One panel member mentioned that advisory committee meetings are one way to bring information into the public domain. Sponsors who are asked to present their data at advisory committee meetings usually agree to do so in open public session. Participants noted a “disconnect” between NIH funding levels for work that results in product identification and FDA funding levels to actually bring those products along the development pathway to the consumer. Reviewer experience and expertise and stability of review assignments was highly valued by workshop participants. One participant emphasized that “reorganizations make things worse.” In addition, the accessibility and willingness of cell and gene therapy reviewers to provide advice was highly regarded. Issuance of two Guidance documents was specifically requested: 1) for long-term follow-up of patients in gene therapy clinical trials (as mentioned above), and 2) for how current cGMPs should be applied to cellular and gene therapy and related products. One stakeholder noted that the NGVL would be helped by a guidance document that addresses use of cGMPs. One participant suggested that stakeholders participate in drafting guidance documents. Participants also pointed out that it is not yet clear how to develop cellular, gene therapy and related products, and that CBER needs more flexibility for regulating them than for reviewing classical drugs. An FDA participant mentioned that premature guidance may be less useful than workshops and advisory committee meetings, which can foster discussion of issues that are not yet resolved. It was also suggested that FDA continue to offer training courses and workshops to aid in the development of cellular and gene therapies, similar to those that CBER has held on toxicology for phase III clinical trials. Final discussion reiterated the importance of a flexible, science-based decision-making process rather than using only rigid rules in the regulation of cellular and gene therapy and related products. The cellular and gene therapy breakout session of the workshop was well attended by stakeholders from industry, academia, consumer groups and other government agencies, and discussion was active and enthusiastic. The session was informative, providing CBER, in particular the Division of Cellular and Gene Therapies within the OCTGT, with thoughts and opinions on various approaches to facilitate development of cellular and gene therapy and related products. Areas of comment and discussion included methods and standards development, product characterization research, biomarker and preclinical research, clinical endpoints and conduct of clinical trials, and the regulatory-science interface. This session is not intended to be the final forum for discussion of these subjects. It provided an excellent beginning for proposing science-based opportunities that can facilitate getting novel and effective cellular and