4Evolution of Oversight of Emerging Clinical Research

Publication Details

The roles and responsibilities of the Recombinant DNA Advisory Committee (RAC) have evolved since its creation, providing a significant contribution to the general public and the scientific community. Today, the RAC no longer has a formal regulatory role in gene transfer clinical trials, but retains an advisory role to the National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), and research institutions' institutional review boards (IRBs) and institutional biosafety committees (IBCs) and provides a forum for public discussion to ensure that gene transfer research has the necessary public transparency. With increased knowledge about gene transfer technologies and their associated risks, as few as 20 percent of protocols submitted have been selected for public review and discussion by the RAC, leading to the question of whether the service the RAC provides is still necessary, given the involvement of other regulatory bodies whose approval is required for gene therapy protocols to be implemented. The charge for this independent review is to determine whether the RAC remains critical to the oversight of clinical gene transfer protocols and, if so, to provide criteria to guide when those protocols should be reviewed.


Today, gene transfer research has matured to a state that has reduced some of the early concerns and uncertainty regarding risks; much has been learned about these technologies' safety and possible adverse events. The committee found that although gene transfer research continues to raise important scientific, social, and ethical questions and the state of gene transfer research is constantly evolving, not all gene transfer research can still be considered a completely new scientific enterprise or novel technology. Individual protocol review by the RAC no longer offers unique benefits except in special circumstances. Although patient safety is always paramount, regulatory oversight should not be required unless it provides a benefit; regulation without benefit is unnecessary and burdensome and should be eased.

Therefore, the committee concluded that individual gene transfer protocols should not be subject to additional public review by the RAC except in exceptional circumstances, such as when human subjects research involves novel technologies and treatment strategies or when the protocols cannot be adequately performed by other oversight and regulatory bodies. The purpose of such public review should be to continue to inform the scientific community, IRBs and IBCs and other regulatory and oversight bodies, as well as the public. Going forward, the committee recommends new specific criteria that should guide selection of protocols that represent exceptional circumstances and thus public review.

Minimizing the Administrative Burden

To minimize the administrative burden to the applicant that the current RAC protocol review process entails, the committee concludes that the protocol review can be accomplished by the investigator's submission of FDA's investigational new drug (IND) protocol and does not require the additional information required in the current mechanisms. As is current practice and accounted for in the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (the NIH Guidelines), proprietary information can be redacted from INDs when reviewed by the RAC (NIH, 2013, p. 36). The committee notes that the European Union has developed streamlined oversight processes that decrease the regulatory burden. For example, the Gene Therapy Advisory Committee in the United Kingdom has been substantially streamlined, with duties largely transferred to and embedded in other review groups, thereby reducing the regulatory burden (NHS, 2013). Comments from those engaged in drug development attest to improved efficiencies and absence of impact on patient safety (NHS, 2013).

All clinical trials involving gene transfer should continue to be registered with the Office of the NIH Director. However, this registration process can be accomplished through the use of the FDA-approved IND application and IRB-approved protocol, which is sufficient to provide the context critical for subsequent adverse event review. Upon registration of a protocol, the Office of the NIH Director, in consultation with IRBs and IBCs, may request additional public review of individual protocols if one or more of the criteria described below are satisfied. The committee expects that allowing the NIH director, in consultation with IRBs and IBCs, to select protocols for review will eliminate the role of the RAC as a self-perpetuating body both selecting protocols to review and performing the review. The expertise and authority of the RAC is best utilized to provide additional oversight for exceptional circumstances, such as when human subjects research involves novel technologies and treatment strategies. RAC review should continue to be performed in an open and transparent manner.

Supporting Institutional Review

The committee recognizes that not all IRBs and IBCs will have the necessary expertise to properly review a particular gene transfer clinical trial. Therefore, inquiries to the Office of the NIH Director are intended to establish a dynamic process whereby the Office of the Director has the capacity to help provide IRBs with examples of precedent-setting protocol reviews, which may obviate the requirement for review beyond the IRB. In addition, there is significant potential for centralized IRBs to broadly disseminate more protocol-specific information in this dynamic process than would be possible with individual IRBs.

An important feature of this new process is a collaborative relationship between the NIH director and oversight bodies. For example, in many cases, an IRB or IBC may believe that a protocol meets one of the below described criteria. However, it may be the case that the RAC, or another oversight body, has already reviewed a similar protocol. The NIH director can now serve as a resource, providing guidance based on precedence to the requesting oversight body to cite and reference the original protocol review—thereby ensuring that only protocols not previously addressed or outside the capacity of the oversight bodies get reviewed. The NIH director may also choose to organize workshops to promote greater expertise for reviews of emerging science issues versus reviews of individual protocols, which also help strengthen the capacity of local institutions.

Because this is a change from the status quo, the committee recognizes that not all IRBs and IBCs may currently have the capacity and capability to undertake all protocol reviews. However, with time and additional guidance from NIH, it is expected that this capacity will significantly increase in a short period of time. An example of how capacity can be increased is provided by the Embryonic Stem Cell Research Oversight Committees (ESCROs) (CIRM, 2013). Furthermore, the Genetic Modification Clinical Research Information System (GeMCRIS) provides the ability for accessing information on specific historical and ongoing protocols registered with the Office of Biotechnology Activities (OBA), which can and should be used to augment institutional capacity and convey previous RAC discussions and recommendations. For example, reviewers can search for a specific medical condition like arthritis and receive links to information on the investigators, vectors, cells and genes involved in the study, as well as to minutes of the public discussion.

Modified RAC Review Process

The protocol review process should also be modified to enable expeditious review to minimize delays in bringing sound and ethical protocols into human subjects trials. Investigators and their IRBs should be notified in a timely manner of either (1) the need for public review by the RAC, or (2) an exemption from RAC review because none of the criteria is met. When the RAC performs public reviews of gene transfer protocols, the goal will be to advise prospective research participants, the investigator, the Office of the NIH Director, FDA, IRBs, and the public.

If a protocol is judged exempt from public RAC review because none of the specific criteria for review is satisfied, the investigator and relevant IRBs and IBCs will be notified. Prior to subject enrollment, however, the final IND application approved by FDA (including the IRB-approved treatment protocol and consents) must be submitted to the Office of the NIH Director both to ensure that no amendments have occurred that would alter the prior determination of review exemption and to ensure future evaluations of adverse events. All protocol amendments must be submitted to the Office of the NIH Director. The protocol and protocol amendments will be abstracted and registered in GeMCRIS and made accessible to the public.


The committee established three specific criteria to guide which protocols should continue to receive additional RAC review. These criteria are intended to limit additional review to only exceptional circumstances. It is otherwise expected that the remainder of the oversight and regulatory system can address the protocol. The criteria sufficient for initiating public review and their rationales are as follows:

Areas of science that are novel, quickly evolving, and yielding scientifically complex materials and components should garner additional attention from oversight bodies. Novelty indicates an untested area of science, one that brings an additional layer of uncertainty as compared to research in areas of greater experience and one for which institutional review bodies typically do not have the requisite expertise. In gene therapy research, novelty encompasses such things as a new vector, gene, or route of administration. It does not include, however, a new clinical indication, testing in a vulnerable population, or use for the first time to produce a nontherapeutic benefit (e.g., enhancement). Therefore, these attributes of a protocol would not trigger the need for public review by the RAC. Although these may be important questions generally, with regard to the individual protocol, other agencies are well-equipped to evaluate these issues. Furthermore, it is possible that the Office of the NIH Director will provide a platform for general discussion, beyond a single protocol, of more wide-ranging issues, such as societal impact.

Although the use of new models is encouraged by the committee and may offer potential advantages, their use requires justification. In addition to assessing the value of these new models, a required public RAC review would provide benefits to the scientific community by disseminating data on new models and offering a forum for public discussion.

Because adverse events of a specific vector, gene product, or mode of delivery may be realized only across protocols, adverse events may not be known by individual investigators or the public at a given time. Review of adverse events across protocols should be used to evaluate trends in adverse events that may lead to a greater awareness of safety concerns, necessitating public review and discussion in the context of the proposed protocol. This aggregation of protocol information and adverse events is a key function of the current GeMCRIS and should be maintained. This information should assist the investigator, IRB, IBC, and FDA in the development of a treatment plan that optimizes safety and assists the research participant in making an informed decision about whether to participate.

In addition, when considering which protocols are chosen for additional public review, the NIH director, in consultation with the other oversight and regulatory bodies, should consider broader societal issues that may warrant a public forum. Emerging technologies in gene transfer science, as presented in new clinical trials protocols (e.g., first-in-human trials), may present scientific or ethical concerns and represent a significant departure from familiar techniques, requiring additional oversight. Therefore, in considering which protocols are chosen for review, the NIH director, in consultation with an IRB, should consider broader societal issues that may warrant public concern.

Recommendation 4-1: Restrict individual gene transfer protocol reviews to exceptional cases that meet specified criteria.

The National Institutes of Health's (NIH's) Office of the Director should continue to register all gene transfer protocols and, in consultation with appropriate regulatory and/or oversight authorities, should identify protocols for additional public review only if both items 1 and 2 below are satisfied


Protocol review could not be adequately performed by other regulatory and oversight processes (for example, institutional review boards, institutional biosafety committees, the U.S. Food and Drug Administration);


One or more of the criteria below are satisfied:

  1. The protocol uses a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk.
  2. The protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value.
  3. The proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and that may render it difficult for local and federal regulatory bodies to evaluate the protocol rigorously.

Even if the protocol does not meet the foregoing criteria listed in items 1 and 2, the NIH director in consultation with appropriate regulatory and/or oversight authorities should have the flexibility to select protocols for review that may present significant societal or ethical concerns.

Illustrative Case Studies

In order to illustrate how the new criteria should be used to limit the number of protocol reviews that are selected by the Office of the NIH Director, three historical cases are provided below that compare the outcomes that could be reached by using the proposed framework versus the present-day RAC review (see Boxes 4-1, 4-2, and 4-3). The examples were selected from the 10 most recent protocols that have been chosen for public review by the current RAC as of August 2013. It is important to note that the committee did not single out any specific gene transfer research protocol or any particular area of investigation, but rather selected a few current examples for the purpose of illustration. In each case, the RAC briefly reviews the protocol and makes a determination of whether or not the protocol requires additional oversight—in the form of a public review—with the proposed new criteria. The proposed criteria are intended to streamline review and limit the additional review of individual gene transfer protocols to a smaller number. Individual gene transfer protocol review is intended for only exceptional cases like those described. The committee notes that the criteria should be interpreted as strictly as possible, as has been highlighted in its case studies. Furthermore, it is the committee's intent that these reviews serve to provide models to the public and oversight/regulatory bodies to enable reviews to be increasingly performed at institutional level.

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BOX 4-1

CASE STUDY 1. Phase I Ascending Dose Trial of the Safety and Tolerability of Toca 511, a Retroviral Replicating Vector, Administered Intravenously to Subjects Undergoing Subsequent Resection for Recurrent High Grade Glioma and Followed by Treatment with (more...)

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BOX 4-2

CASE STUDY 2. Phase I Study of Intrathecal Administration of scAAV9/JcT-GAN for the Treatment of Giant Axonal Neuropathy. This Phase I study proposes to evaluate an adeno-associated virus (AAV) vector to deliver the gigaxonin gene to subjects, including (more...)

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BOX 4-3

CASE STUDY 3. E10-A (Endostatin Adenovirus) for the Treatment of Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck. This Phase III study proposes to evaluate the benefit of the gene transfer product E10-A, a replication deficient adenovirus containing (more...)


Evolution of Oversight of Emerging Clinical Research

The RAC was established to respond to an emerging technology of great public interest and with risks and benefits only barely understood. The RAC has successfully provided oversight for a complex technology for almost 40 years, providing exceptional service to NIH, the scientific community, and the public. Its value has been immense in ensuring safe clinical protocols that benefited from input from diverse experts. By engaging the public in a focused discussion on the technology and its potential societal impacts, the RAC engendered trust and credibility. Over time, gene transfer research, although not entirely without areas of uncertainty or public concern, has become better understood, and many risks have been minimized. The committee recommends not only that the RAC's review of gene transfer oversight be narrowed to areas still in need of special review or expertise, but also that the necessity of a RAC model for other emerging technologies that might benefit from lessons learned and structures built for the responsible development of gene transfer science be explored.

Emerging areas of science within human clinical intervention (including but not limited to gene transfer) can be defined as areas of research that pose an uncertain risk, may pose harms to individuals' or the public's health, and which could not otherwise be adequately assessed by existing regulatory processes. Many emerging technologies represent groundbreaking advances and innovation in science and may provide tools to solve challenging problems. In the field of medicine, emerging technologies have the potential to lead to better health outcomes, lower health care costs, and earlier patient access to more effective treatments (Anatol et al., 2013). Currently, in addition to gene transfer research, there are many emerging technologies with clinical applications that present their own risks and uncertainties, including combination products (drugs and biologics), nanotechnology, and regenerative medicine (including cell- and tissue-based products). Also, gene transfer products, as noted in the FDA guidance discussed in Chapter 2, have many characteristics in common with cellular therapies, but also present additional concerns in the context of combination cell and gene transfer products. Nanomedicine, for example, presents additional concerns and uncertain risks related to the special properties of nanoparticles, such as their greater ability to penetrate and translocate across cell membranes or different parts of the body (Wolf et al., 2009). Furthermore, many nanotechnology techniques involve putting materials into humans that have not previously been used in any clinical intervention and present uncertain risks. However, different areas of emerging sciences are often at different stages of development, and therefore differ in their materials characterization and understanding, process development, understanding of uncertainties and establishment of safety to research participant, close contacts, community, and environment, in addition to raising different societal concerns. For example, technology creating chimeras raises different societal concerns than nanomedicine, and embryonic stem cell research raises still others. Because different areas of science are at different stages along this developmental trajectory, the committee stresses that this mechanism should only apply when a technology is at the level of science being used in clinical research.

The committee also notes that experience with gene transfer research may offer valuable lessons for how to proceed with human trials of other medical advances that depend on emerging technologies. For this reason, it recommends that NIH assess whether there are other areas of clinical research that might benefit from a venue for targeted, transparent oversight beyond that provided by existing regulatory mechanisms. If so, then consideration of an appropriate mechanism would be in order.

Future technologies, whether gene transfer–related or emerging from other areas of science, will be novel, may present significant risks and uncertainties, and could benefit from review such as that currently provided by the RAC. The RAC has served an important function and its contributions to gene transfer research not otherwise available from other bodies should continue, although these could be reframed and offered through an expanded process. The oversight of an emerging science should be triggered when it reaches the stage of human subjects research. Any review process should be sensitive to the fundamental understanding that different areas of science may be at different stages of development, as discussed previously. The committee recommends exploring an approach that considers, among other criteria, the uncertainty of risk posed by a research protocol.

The Use of the RAC Model in a New Process

The necessity of any new process that could both focus resources on a limited number of gene transfer protocols that meet the criteria described above and address other emerging technologies. Like the current RAC, a forum for emerging technologies in which investigators could discuss and disseminate new information and share best practices and where members of the public could express and discuss their concerns would serve as a public good and could be beneficial to the scientific and broader communities alike. The committee recommends exploration of the potential for a new process that would have ad hoc capacity to review the full breadth of emerging areas of research supporting human clinical intervention that may have special risks and that could not be adequately assessed under the existing regulatory processes for clinical research. To be clear, the criteria presented in Recommendation 4-1 are meant to be used to select gene transfer protocols that require an exceptional level of review and are not meant to apply in whole or in part to other technologies. Similar concepts may be considered, however, when developing any criteria to select protocols for review in other areas of emerging science.

The new review process may need to include a continuation and expansion of the current NIH processes of symposia and workshops that inform the larger gene transfer research community, broadening them to include emerging science and technologies. Symposia and public workshops provide opportunities for discussion about a broad array of issues at the forefront of emerging technologies, including gene transfer research, both as a response to and in anticipation of scientific, ethical, and societal concerns. As described in OBA's mission statement, one of its primary roles is to foster and enable public discussions of the science of gene transfer research and the public concerns it raises:

The NIH Office of Biotechnology Activities (OBA) promotes science, safety, and ethics in biotechnology through advancement of knowledge, enhancement of public understanding, and development of sound public policies. OBA accomplishes its mission through analysis, deliberation, and communication of scientific, medical, ethical, legal, and social issues.1

The committee believes that this role remains critical and could serve an important benefit if it were expanded to other areas of emerging, novel, or risky science. This function could be fulfilled through symposia and workshops focusing on two areas, which may take place in unison: (1) the state of the science, and (2) societal concerns and implications of the science. The identification of symposia and workshops topics should remain NIH's responsibility, with the process for identifying topics and timing responsive to and in consultation with the scientific community and other interested stakeholders, including the public.

Symposia and workshops that foster awareness in these two areas will be an important part of NIH's ongoing education and support of institutional review processes via IRBs and IBCs, which may lack expertise in specific areas, and will also assist state and federal regulatory bodies as increasingly complex sciences move forward. These forums will also aid regulatory oversight (via FDA). Finally, and importantly, the expanded process will contribute to maintaining public trust that new areas of potentially risky science will be responsibly managed.

The capacity to enable a public discussion of issues, concerns, and challenges in emerging gene transfer science and other technologies is of great value to the scientific and stakeholder communities and also serves the public's interest. This capacity must be maintained going forward. There are many options to be considered for implementation of an expanded process to evaluate and advise on new technologies that are anticipated for use in clinical interventions and which pose uncertain risk and consequences to individual and/or public health. The committee acknowledges that this process should leverage scientific knowledge sharing and commitment to advancing novel technologies.

The committee reviewed many of the proposals and assessments for the design of oversight for emerging technologies, which can be considered going forward. For example, Kuzma and colleagues (2008) developed a broad set of criteria to describe and assess relationships among features, outcomes, and tradeoffs of oversight systems. Others note that nanotechnology is challenging the capacity of current oversight systems and that using a nano-vector to deliver genetic material in gene transfer research in humans will involve multi-stakeholder concerns, including FDA, NIH, the Occupational Safety and Health Administration (OSHA), the National Institute for Occupational Safety and Health (NIOSH), and the Environmental Protection Agency (EPA) (Fatehi et al., 2012). As of yet, there is no coordinated framework to deal with issues related to nanotechnology, suggesting that the RAC should undertake ethical analysis of this challenging topic to provide adequate guidance and protections going forward (Fatehi et al., 2012).

Others suggest that RAC oversight of gene transfer therapies could serve as a model for other areas of emerging science, noting that the RAC's historical contribution has been its expertise and promise of producing generalizable guidance and drawing attention to questions that have broad applicability across clinical trials (King, 2002). Marchant and colleagues (2010) also notes that although many emerging technologies raise important ethical and social issues, there are implications unavoidable in any regulatory scheme. Marchant describes several proposals, including ethical impact statements and ethics review boards, both of which could be considered in Recommendation 4-2. Further efforts to analyze oversight indicate that for emerging technology governance to be effective, collaboration is required among scientists, the government, and the public (Wiek et al., 2007).

Therefore, the committee makes the following recommendation.

Recommendation 4-2: Consider integrating oversight for gene transfer and other applications of emerging technologies.

The National Institutes of Health (NIH) director should convene an ad hoc working group that will be responsible for considering whether additional oversight and a venue for public deliberation are indicated for other applications of emerging technologies, and if so, to explore procedural options, including the possibility of an integrated oversight body. In this task, the focus should be on those human clinical applications that may be of particular interest to the public, or that feature uncertain risk, may pose harms to individuals or to the public's health, and which could not otherwise be adequately assessed by existing regulatory and oversight processes. If additional oversight is deemed appropriate, the Recombinant DNA Advisory Committee (RAC) should be used as one possible model, particularly with regard to these functions:

  • Provide a public forum for the review and discussion of
  • emerging areas of science.
    • Include the capacity for a partnership to consult, inform, and educate institutional review boards (IRBs) and institutional biosafety committees (IBCs).
  • Provide a venue to foster scientific and public awareness regarding emerging science in order to address concerns about clinical investigation and future societal implications.
  • Integrate the capacity to surveil, aggregate, and analyze adverse events across related trials of emerging technologies.
  • Perform an additional level of review of individual protocols that are identified by the NIH director, in consultation with one or more IRBs and IBCs, on the basis of exceptional issues raised as articulated in the committee's gene-transfer protocol criteria.

For the present, however, the RAC should continue to review individual gene transfer protocols but use the criteria set forth in Recommendation 4-1 to help limit review and focus resources on exceptional cases.

This expanded process could take a number of forms. One option would be an Emerging Technologies Advisory Committee that would function much like the RAC, but with the expanded purview of any emerging science supporting human clinical intervention. However, effective processes that would not require the creation of another formal ongoing convening activity, but instead could be dynamic and performed on an ad hoc basis, could be established. For example, another option would be to retain a pool of subject-matter experts to consult on an ad hoc basis as warranted. There are certainly other options as well. Although there are many potential models, in considering the new process for oversight, NIH should pay special attention to the value that the public nature of the RAC process has played.

The decision to include new emerging technologies that warrant additional oversight in the expanded process would arise from IRBs, IBCs, and the Office of the NIH Director. The committee recommends that the newly established process retain the following key functions historically provided by the RAC. These include the capacity to

  • provide a public forum for the review and discussion of gene transfer science;
  • provide a venue to foster scientific and public awareness regarding emerging science in order to address concerns about clinical investigation and future societal implications;
  • integrate the capacity to monitor, aggregate information about, and analyze adverse events across related trials of emerging technologies; and
  • perform an additional level of review of individual protocols.

The committee recognizes that the current NIH Guidelines limit the function of some parts of the regulatory and oversight system, for example, the need for additional clarity about what standards IBCs should use for review of emerging sciences. Therefore, in the development of this process, it is expected that NIH will also have to review and assess the current NIH Guidelines to ensure that they are updated to provide consistent guidance to all parts of the regulatory and oversight system it oversees.

Understanding that the NIH director will need time to establish a new process for monitoring emerging technologies, the committee recommends that the Office of the NIH Director continue the RAC in its currently constituted form for a limited period of time until the new process is established. In the interim, all gene therapy protocols should continue to be registered with the NIH director, but should only be selected for public review according to the three criteria detailed above, in order to help make the process less burdensome and more efficient. The suggested continued registration and newly recommended criteria for review will maximize efficiency by removing duplication in the regulatory process and will optimize scientific advancement while providing rigorous human subjects protection. In addition, centralized IRBs may serve as an important mechanism to provide subject matter expertise for specific areas of emerging science that IRBs may not have the capacity and/or expertise to address.


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From the OBA website, http://oba​.od.nih.gov (accessed August 1, 2013).