Rethinking the Regulatory Infrastructure for Human Gene Transfer Clinical Trials
Authors: Christopher L Jenkins, Mark L Bagarazzi, Hans-Peter Kiem, Arnold J Levine, Dale Ando, Carl H June, Tony Reid, David W Emery
Journal: Molecular Therapy (2016)

The year 2015 marked the 40th anniversary of the Asilomar Conference leading to the first biosafety guidelines for research with recombinant DNA molecules,1Berg P Baltimore D Brenner S Roblin RO Singer MF Summary statement of the Asilomar conference on recombinant DNA molecules.Proc Natl Acad Sci USA. 1975; 92: 1981-1984Crossref Scopus (230) Google Scholar as well as the 25th anniversary of the first human gene transfer clinical trial approved by the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC).2Blaese RM Culver KW Miller D Carter CS Fleisher T Clerici M et al.T lymphocyte–directed gene therapy for ADA−SCID: initial trial results after 4 years.Science. 1995; 270: 475-480Crossref PubMed Scopus (1201) Google Scholar Since that time, the field has seen tremendous growth, with more than 1,500 human gene transfer (HGT) trials reviewed by the RAC to date. This has been accompanied by significant advances in the efficiency and efficacy of gene transfer tools, as well as our understanding of the biological risk profiles for these tools. The first therapeutic agent containing recombinant DNA was approved by the US Food and Drug Administration (FDA) in October 2015, joining three gene-based therapeutics recently approved in the European Union.3Greig SL Talimogene laherparepvec: first global approval.Drugs. 2015; 76: 147-154Crossref Scopus (83) Google Scholar As a result of the increasing experience and comfort level with this kind of clinical research, the “NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules” (hereafter, “NIH Guidelines”) have recently been revised to shift the primary responsibility for biosafety oversight of HGT clinical trials from the RAC to local oversight bodies.4Emery DW Big changes coming to biosafety oversight of clinical gene transfer.Mol Ther. 2014; 22: 1402Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar,5Federal Registry Announcement Final Action Under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) 81 2016 FR § 15931Google Scholar Aside from the recent changes to the process of RAC review, there have been relatively few changes in the regulatory framework for HGT clinical trials since their inception. To date, most organized efforts at reforms in this framework have focused on revisions to the NIH Guidelines4Emery DW Big changes coming to biosafety oversight of clinical gene transfer.Mol Ther. 2014; 22: 1402Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar,5Federal Registry Announcement Final Action Under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) 81 2016 FR § 15931Google Scholar and standardizing the preclinical regulatory process.6Kiem H-P Baum C Bushman FD Byrne BJ Carter BJ Cavagnaro J et al.Charting a clear path: The ASGCT Standardized Pathways Conference.Mol Ther. 2014; 22: 1235-1238Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar The WIRB-Copernicus Group (WCG) convened a panel of academic and biopharmaceutical industry leaders to provide advice on the major risks facing the field of HGT clinical trials. The Gene Therapy Working Group identified several areas of concern pertaining to the regulatory infrastructure of the field and offered several recommendations designed to address these areas. The authors believe that the independence of this working group from federal regulatory bodies and existing professional societies, combined with representation from both academia and industry, provides a unique perspective from which the field as a whole could benefit. We provide here an overview of the current regulatory infrastructure for HGT clinical trials in the United States, identify key areas in this framework needing improvement, and offer suggestions of the Gene Therapy Working Group for addressing these key areas. Four basic regulatory bodies oversee HGT clinical trials that are subject to the NIH Guidelines: (i) the FDA Center for Biologics Evaluation and Research (CBER), (ii) institutional review boards (IRBs), (iii) the RAC, and (iv) institutional biosafety committees (IBCs).7Institute of Medicine 2014 Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee RN Koehler BM Altevogt LO Gostin National Academies Press Washington, DC 134Google Scholar These entities in turn work with the clinical-trial sponsor (often from the biopharmaceutical industry) and with principal investigators for individual study sites. Oversight by the FDA and IRBs focuses on the integrity of the clinical-trial design and welfare of study subjects, and extends beyond HGT clinical trials. Only HGT trials covered by the NIH Guidelines are subject to possible review by the RAC. Included here are trials for which the sponsor or trial site receives funding from the NIH for research with recombinant or synthetic nucleic acid molecules, or for which the development of the study agent was supported by NIH funds. Although considered a regulatory body, the RAC does not actually have the authority to approve or disapprove individual clinical-trial proposals but instead provides a venue for public discussion of individual clinical trials and advice to the director of the NIH regarding biosafety policies. Review by local IBCs is also predicated on prior or current funding by the NIH.8Board on Health Sciences Policy, Institute of Medicine Committee on the Independent Review and Assessment of the Activities of the NIH Recombinant DNA Advisory Committee.in: Lenzi RN Altevogt BM Gostin LO Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. National Academies Press, Washington DC2014Google Scholar Trial sites are required to establish IBCs if they receive funding from the NIH for research with recombinant or synthetic nucleic acid molecules, or wish to conduct HGT clinical trials that are otherwise subject to the NIH Guidelines. Once established, IBCs have the responsibility and independent authority to review and approve all HGT clinical trials conducted at their institution as described in the NIH Guidelines, whether or not those clinical trials are subject to the NIH guidelines. Finally, it is important to recognize that the sponsors of HGT clinical trials also play an important role in the regulatory process. Both regulatory compliance and timely study startup depend on understanding the unique issues inherent in HGT trial design and training of the clinical-development team regarding the differences between HGT product development and conventional drug development. The working group noted the current paucity of trial design and clinical-development staff adequately trained in the regulatory framework for HGT clinical trials. The patchwork and overlapping nature of the biosafety review processes (combined with lack of adequate HGT expertise) potentiate delays in startup, increase costs, and entail increased risk to subjects, study staff, and the general public. Length of time associated with regulatory reviews. We have entered an era in which a large proportion of HGT clinical trials are sponsored by the biopharmaceutical industry rather than by academia. This transition reflects the field's maturity and is essential if the field is to reach its full potential. The biopharmaceutical industry is sensitive to clinical-trial startup times, with potentially millions of dollars lost for every week in delays. The working group noted that much effort has gone into staffing and processes to assure efficient review of HGT clinical trials by the FDA CBER. The IRB field has recognized the inefficiency of multiple reviews of the same protocol, and current trends are toward a process for centralized IRB reviews as evidenced by recent proposed federal rulemaking recommendations toward a central IRB review mechanism.10US Department of Health and Human Services, Office for Human Research Protections, Notice of Proposed Rulemaking: Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators, 80 2015 FR § 53931Google Scholar To satisfy the current requirements for NIH registration and possible RAC review, study sponsors must still commit time, effort, and expertise to prepare written responses to Appendix M of the NIH Guidelines, a cornerstone of the NIH registration and RAC review process. Although the newly revised NIH registration process can take 10 days or less, protocols selected for full review and public discussion by the RAC still face delays of at least two months, with the possibility of even more time for addressing questions and comments arising from the RAC review. Review by local IBCs can also add very significantly to HGT clinical-trial startup times. One survey from 2014 revealed that the average time for review of HGT clinical trials by IBCs at academic medical centers is longer than 17 weeks.11Jenkins CL Trends in United States biological materials oversight and institutional biosafety committees.J Res Admin. 2014; 45: 35-48Google Scholar The working group identified three general issues that delay the IBC review process. First, the paucity of committee members with adequate HGT expertise on some IBCs results in the need for additional research or the need for advice from ad hoc reviewers. Second, the lack of adequate information in some HGT study protocols or responses to Appendix M of the NIH Guidelines forces IBCs to request additional information from sponsors so as to conduct requisite risk assessments. Third, the process of vetting proposed facilities and operations by IBCs is often iterative in nature, because the study staff may not be aware of certain facility requirements under the NIH Guidelines until they begin to interact with the IBC during review. Delays arising from inadequate preparation for IBC reviews become especially problematic for later phase HGT clinical trials with multiple trial sites, because each individual trial site is obliged to undergo review by its local IBC. Variability in the IBC review process. In addition to issues of startup times, IBC review of HGT clinical trials is further complicated by the lack of clearly defined roles for IBCs in the review process. At the most basic level, IBCs are obliged to review HGT clinical trials as defined in the NIH Guidelines. However, applying the facility and operational requirements of the NIH Guidelines to the clinical setting can be difficult, since these requirements were written primarily for research laboratories. In addition, nearly two-thirds of institutions with IBCs have chosen to expand the scope of IBC oversight to include research with infectious agents that have not been modified with recombinant or synthetic nucleic acid molecules.11Jenkins CL Trends in United States biological materials oversight and institutional biosafety committees.J Res Admin. 2014; 45: 35-48Google Scholar This in turn typically entails the application of an additional set of regulations encompassed in the Centers for Disease Control and Prevention's Biosafety in Microbiological and Biomedical Laboratories. Ambiguities in the application of the NIH Guidelines to the clinical setting, and the use of an additional set of review standards at some, but not all, institutions, can lead to significant differences in requirements and determinations of individual IBCs at different study sites. This issue is compounded even further by the need for each IBC to undertake an independent risk assessment. Differences in the local sentiments, institutional cultures, and professional backgrounds of committee members can all influence the perceptions of risk and subsequent determinations regarding required biological containment levels and processes to address the identified risks. A lack of clear guidance as to the relative roles of IBCs and IRBs in assessing the risk of HGT study agents to individual study subjects can also be problematic. Under the NIH Guidelines, local IBCs are expected to consider the risk of study agents to the study staff, close contacts of the research participant, members of the community, and the environment. IRBs are expected to consider the risk of HGT study agents to the well-being of study subjects. Distinguishing between risks to subjects and risks to others can be difficult, and local IRBs can be poorly equipped to adequately assess the risks associated with novel gene transfer agents or navigate their role in assuring that HGT trials are conducted in compliance with the NIH Guidelines. Limited expertise and experience of IBCs and IRBs. Historically, HGT clinical trials were conducted at the NIH and at large academic medical centers, where the IRBs and IBCs are assumed to have the background and experience to meet their regulatory obligations. As the field has expanded, HGT clinical trials are increasingly conducted at smaller clinics and regional medical centers, where IRBs and IBCs often lack the expertise and experience to conduct thorough and timely reviews. Even at academic medical centers, there may be a small number of experts capable of reviewing protocols involving HGT or risks of specific HGT products or technologies; furthermore, those same experts may be inappropriate to perform the review because they are involved in the study's conduct. This problem has been abated in part through the use of central IRBs, which offer scalability and product-specific expertise that is difficult to replicate at the institutional level. An increasing number of smaller institutions have also made use of externally administered IBCs, which likewise provide for scalability, product-specific expertise, and ease of administration. However, unlike central IRBs, externally administered IBCs are required to include local members of the public unaffiliated with the institution, as well as institutional staff, who can speak to local conditions and represent local sentiments when considering individual HGT proposals. As such, even this option brings with it the potential for variations in the standards applied, and determinations made, by IBCs at different institutions. Shortage of biopharmaceutical clinical-development teams familiar with the specific issues in HGT research. The biopharmaceutical industry has invested heavily in the training and development of individuals who can design clinical trials and manage the trials at individual study sites. Adequate training and development of these trial design and study staff is sufficiently critical to the success of the biopharmaceutical industry that an independent training and accreditation industry has evolved to meet the need. In general, training resources have not yet been adapted to train clinical development professionals in the nuances and specifics of clinical trials involving HGT. As a result, biopharmaceutical clinical teams may run into unexpected challenges in shepherding HGT clinical trials through the NIH registration process and reviews by IRBs and IBCs. When designed by teams not familiar with HGT, clinical-trial protocols may leave critical questions unaddressed that can result in the selection of a particular protocol for full review and public discussion at a convened meeting of the RAC. Study protocols and associated materials that do not include all the information required by regulations can also delay reviews by local IRBs and IBCs, as they need to request more information from the sponsor to determine whether the study plans meet the criteria for approval. Lack of specific knowledge about HGT study conduct can result in the selection of study sites that are ill-prepared to meet critical biosafety standards. Besides creating delays in the time to study startup, inadequately trained trial design and clinical-development staff also raise the potential risk for regulatory noncompliance and even overt accidents with biohazardous materials. Although individuals can gain practical expertise through experience, the value of this expertise is dependent on retention of individuals in a market characterized by turnover, and is not routinely or easily transmitted within individual companies. Public perception. With the death of Jesse Gelsinger in 1999 and the ensuing investigation and media coverage, the heightened interest of the media and public in the field of HGT led to that attention being shaded in a negative light.12Verma IM A tumultuous year for gene therapy.Mol Ther. 2000; 2: 415-416Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar The general public has become increasingly concerned with the presence of genetically modified organisms in the food chain; Hollywood has capitalized on public fears with apocalyptic disasters arising from human genetic experimentation; and political disputes have eroded public trust in the integrity of scientific experts. There have been no consistent voices in the public arena to assuage these fears through informed outreach and education, with the result that the general public remains ill-informed regarding the underlying technologies and real-world safety profiles associated with today's gene delivery tools. The field remains at risk of public backlash, well-founded or not, in the event of another highly publicized death or first-ever documented case of horizontal transmission of a recombinant study agent. The likelihood of such events is increasing, given the expanding investigation of HGT therapeutics in the field of oncology where the common occurrences of deaths from disease progression may be misattributed, as well as the expanding prevalence of gene transfer vectors based on live attenuated viruses that have a greater potential for horizontal transmission. The impact of such events will depend in large part on the context through which these events are viewed by the public. Oversight for studies and study sites not subject to the NIH Guidelines. HGT clinical trials that are not subject to the NIH Guidelines are not required to be reviewed by individual IBCs or registered with the NIH, and are not eligible for review by the RAC. This potentially creates an incentive for biopharmaceutical companies to avoid large academic medical centers and other institutions that receive funding from the NIH for research with recombinant and synthetic nucleic acid molecules when selecting clinical-study sites. As a result, these studies are not eligible for expert review and public discussion by the RAC, are never subjected to professional biosafety oversight at individual study sites, and may be conducted at institutions that are generally less able to recognize the hazards associated with recombinant and synthetic nucleic acid molecules. This arrangement has potentially huge implications for the field of HGT. First, it creates an uneven regulatory environment for biopharmaceutical sponsors that receive funding from the NIH, or are considering whether or not to participate in the clinical translation of novel HGT study agents that were developed with funding from the NIH. Second, it drives innovative clinical research away from academic medical centers. And third, it incorrectly characterizes biosafety oversight as optional rather than a necessary part of sound HGT clinical-trial risk management. This places the whole field at increased risk of biosafety mistakes that could cause real harm to trial subjects, research staff, and the general public. Such mishaps could also turn the public against the field to such a degree that federal regulators would be obliged to craft and institute additional and burdensome regulations, possibly halting or curtailing progress in the interim. Recent changes to the NIH Guidelines affecting biosafety oversight of HGT clinical trials. Effective 27 April 2016, the NIH Guidelines were revised with the goals of streamlining the registration and biosafety review of HGT clinical trials at the level of the NIH.4Emery DW Big changes coming to biosafety oversight of clinical gene transfer.Mol Ther. 2014; 22: 1402Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar,5Federal Registry Announcement Final Action Under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) 81 2016 FR § 15931Google Scholar,8Board on Health Sciences Policy, Institute of Medicine Committee on the Independent Review and Assessment of the Activities of the NIH Recombinant DNA Advisory Committee.in: Lenzi RN Altevogt BM Gostin LO Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. National Academies Press, Washington DC2014Google Scholar This was accomplished in large part through the efforts of the American Society of Gene and Cell Therapy (ASGCT) and the biopharmaceutical industry. In short, the revisions replace mandatory registration and review by the RAC with mandatory registration by the NIH, substantially reduce the documentation necessary for that registration process, and reserve RAC review for protocols that meet specific criteria. Although these processes will probably shorten the review time for later phase HGT clinical trials at the level of the NIH, they place two new burdens on local IBCs and IRBs that may extend the overall review time. First, the new protocol registration process requires that the protocol, Appendix M responses, and other study materials be reviewed by at least one local IRB and IBC before the first site registered, and those local oversight bodies must recommend whether or not the protocol would benefit from full review and public discussion by the RAC. Second, if RAC review is not performed, all local IRBs and IBCs that review the study will need to conduct their review in the absence of a RAC imprimatur to help support their own risk assessment. Both of these revisions will probably have little impact on the review of these trials at institutions with IRBs and IBCs that are adequately staffed and trained to carry out truly independent assessments. Many IRBs and IBCs currently rely on the RAC review process to supplement and to provide the basis for their own review, and thus may require additional time, effort, and expertise to conduct their assessments. This may also result in unwarranted requests for RAC reviews that add unnecessary delays to clinical-trial startup, or unwarranted RAC declinations that may subject institutions to additional scrutiny. Given the current and projected regulatory infrastructure for HGT clinical trials, the working group proposed the following recommendations. 1Revise the NIH Guidelines to allow for “central” IBC review of HGT clinical trials. An increasing number of clinical trials, including HGT clinical trials, undergo IRB review and oversight using a central review process. This process, in place for decades and becoming increasingly popular, separates the review of the protocol itself from the review of investigators and study teams, as well as their qualifications. A similar process could be established for a centralized IBC review model, such that the protocol and associated documents are reviewed and changes made if required; during this review, the risk assessment and necessary standards for sites to conduct the study would also be established. Then, each clinical site would be reviewed and the facilities, qualifications of the study team, and training to conduct the research would be assessed; preparation for this review may include an in-person site visit of the clinical-research site. This process provides for a single review of the protocol by a committee with appropriate expertise and experience, and the identification of key subject safety elements that can then be applied to all subsequent study sites as appropriate. This would entail either eliminating or modifying the current requirement for local IBC membership. The working group recommends that a similar process should be made available for the IBC review process for multicenter trials. Central IRBs and IBCs, with experience assessing HGT clinical trials and history of interaction with NIH personnel, would complement the current NIH Guidelines efforts to streamline the RAC review process.2Collect data on HGT study-startup time so as to inform policy changes. The areas needing improvement identified by the working group are based on collected experience. As such, uncertainty remains about both the universality of these observations and the quantifiable impact of the identified areas on startup times. Accordingly, the working group recommends that an effort be undertaken to survey large academic medical centers, a selected number of smaller clinical centers, and biopharmaceutical sponsors for HGT clinical trials, regarding their individual experiences with the current regulatory infrastructure. This survey should include, at a minimum, real-world experiences with (i) turnaround times with reviews by the FDA, RAC, IRBs, and IBCs, (ii) registration of HGT clinical trials with the NIH, (iii) use of central vs. institution-specific IRBs for HGT protocol review, (iv) variations in determinations between individual IBCs, and (v) requests for identification of process areas that require improvement. These efforts would best be sponsored by the FDA, the NIH, professional societies such as ASGCT, and industry trade groups.3Develop educational programs for individuals involved in the regulatory framework for HGT clinical trials. The working group recommends education as a key area of need, including education not only for members of IRBs and IBCs, but also for clinical development teams and for the general public. Sponsors for such training programs could include the NIH (through joint efforts between the Office of Scientific Policy and Office of Human Research Protection) and professional societies such as the ASGCT, the Biotechnology Innovation Organization, the Society of Clinical Research Associates, Public Responsibility in Medicine and Research, and the American Biological Safety Association International. The ASGCT is in a particularly strong position for outreach to the general public, whereas the latter three groups already offer training courses and certification programs for clinical-research staff, IRB professionals, and biosafety professionals. Such courses and programs could be expanded to include similar offerings for HGT clinical trials.4Develop an accreditation body for IBCs. Independent accreditation bodies exist for IRBs, certified IRB professionals, institutional animal care and use committees, clinical-research professionals, registered biosafety professionals, and others. The working group recommends that a similar accreditation body be developed for IBCs. This would be one mechanism for benchmarking measures of proficiency, professionalism, and best practices for individual IBCs, and for certifying the credentials of individual IBCs for the oversight of HGT clinical trials. Such a program would need to be voluntary and not supersede the main function of IBCs in satisfying a condition of the NIH Guidelines.5Define the roles of IRBs and IBCs in the oversight of HGT clinical trials. The NIH Guidelines currently do not clearly distinguish the respective roles of IRBs and IBCs in the oversight of HGT clinical trials. The RAC has historically played an important role in bridging these two areas of risk assessment, but the changes to the RAC review process assure that fewer HGT clinical trials will benefit from this multifaceted review. The revised NIH Guidelines in particular expand the role of local IRBs in the initial assessment of HGT clinical trials but do not provide a clear directive as to the recommended content of such assessments. The working group recommends that the NIH consider providing additional guidance regarding the expected roles of IRBs and IBCs in the oversight of HGT clinical trials, with a special emphasis on the new RAC submission process.6Adapt the NIH Guidelines to the clinical setting. The NIH Guidelines—especially the standards to be applied for biosafety levels 1 and 2 containment—were generally written for laboratory settings and do not translate well to clinical settings. The working group recommends that the NIH provide additional guidance regarding the application of biosafety levels 1 and 2 containment to the clinical setting. This could go as far as revising the NIH Guidelines to include new categories of biocontainment for clinical research defined as “clinical-biosafety levels,” much as biosafety levels have been defined for research with animals and plants.7Provide for biosafety oversight of HGT clinical trials that are not subject to the NIH Guidelines. The working group recommends that a mechanism be developed to assure that HGT clinical trials not subject to the NIH Guidelines are nevertheless overseen by an independent review body for biosafety. Rather than identifying a specific mechanism for this purpose, the working group suggests that this issue could be best addressed through a collaborative effort of the NIH, the FDA, and the Centers for Disease Control and Prevention, with input from affiliated professional societies and biopharmaceutical industry interest groups.Although the Working Group assessment and recommendations are focused on the regulatory framework for HGT clinical trials within the United States, the members also recognize the international nature of the field and the need for efforts toward harmonizing similar regulations worldwide. We thank Lindsay McNair and Joan M. Robbins for their helpful discussions and critical reading of the manuscript. M.L.B., H.P.K., A.J.L., D.A., C.H.J., and T.R. received compensation from WCG for serving on the Gene Therapy Working Group. A.J.L. is on the board of a gene therapy company. D.W.E. and C.L.J. are employees of WCG, which provides independent IRB review services and externally administered local IBC services.