Berro, Marlene MS; Burnett, Bruce K. PhD; Fromell, Gregg J. MD; Hartman, Karen A. MSN; Rubinstein, Eric P. JD, MPH; Schuff, Kathryn G. MD; Speicher, Lisa A. PhD; on behalf of the IND/IDE Taskforce of the Clinical and Translational Science Award Consortium
Ms. Berro is program manager of regulatory support, Clinical and Translational Science Institute, University of California, San Francisco, San Francisco, California.
Dr. Burnett is director of regulatory affairs, Duke Translational Medicine Institute, Duke University School of Medicine, Durham, North Carolina.
Dr. Fromell is executive director, Office of Human Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, and Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania.
Ms. Hartman is operations manager, Office of Research Regulatory Support, Mayo Clinic, Rochester, Minnesota.
Mr. Rubinstein is director, Office of Regulatory Support, Clinical and Translational Science Institute, University of Rochester, Rochester, New York.
Dr. Schuff is director of regulatory support services, Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon.
Dr. Speicher is director, Clinical Trials Office, Office of Clinical and Translational Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Please see the end of this article for information about the authors.
Correspondence should be addressed to Dr. Schuff, Division of Endocrinology L-607, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098; telephone: (503) 494-1685; fax: (503) 494-6990; e-mail: firstname.lastname@example.org.
First published online December 16, 2010
Supplemental digital content for this article is available at http://links.lww.com/ACADMED/A33.
An important objective in the mission of academic health centers (AHCs) is advancing scientific knowledge for the benefit of patient care. Investigator-initiated clinical research is key in achieving this objective as an essential part of the research continuum of translating basic science discoveries into new human therapies. When investigator-initiated research involves an investigational drug or device, the investigator assumes responsibility for the regulatory management of the study in addition to his or her more commonly recognized scientific and safety responsibilities. Depending on the investigational drug or device used, a study may require submission of an Investigational New Drug (IND) application or an Investigational Device Exemption (IDE) to the Food and Drug Administration (FDA) for review. An overview of this process has been recently presented.1 In these cases, the investigator takes on the regulatory role of sponsor, a position of responsibility more traditionally held by biotechnology, pharmaceutical, or device companies.
When a researcher is both a regulatory sponsor and an investigator, this role is aptly termed sponsor–investigator and carries with it a broad set of regulatory responsibilities defined in the Code of Federal Regulations.2,3 Historically, there has been minimal institutional support within AHCs for faculty who are sponsor–investigators performing clinical research. Managing the complex set of regulatory requirements of a sponsor–investigator is a daunting task, which often slows the translational research process. Inadequate training and support can lead to gaps in research-participant protection programs and leave the investigator and the AHC vulnerable to regulatory risks. Further, the frustration of the experience may dissuade researchers from further pursuing such research.
In this report, we provide an overview of IND/IDE regulations and sponsor–investigator responsibilities, highlight issues about support and oversight of sponsor–investigators that AHCs should consider, present data on current support of sponsor–investigators in Clinical and Translational Science Award (CTSA) institutions, and, finally, discuss different models to support investigator-initiated clinical research. These recommendations are the product of the CTSA program, a partnership between the National Institutes of Health (NIH) and AHCs.
NIH/AHC partnership and the CTSA IND/IDE Taskforce
In 2004, the NIH launched a new initiative, the NIH Roadmap for Medical Research, “to address roadblocks to research and to transform the way biomedical research is conducted by overcoming specific hurdles or filling defined knowledge gaps.”4 One of the initiatives was to invigorate academic clinical research through the launch of the CTSA Consortium.5 The consortium began in 2006 with 12 AHCs and has since expanded to 55, with the potential to grow to 60. The objectives of this initiative include enhancing interinstitutional research collaboration and identifying and fostering best practices, policies, procedures, and other measures in order to advance and support clinical and translational research. As part of the CTSA Consortium's effort to enhance translational research, a variety of working groups and task forces were created. The IND/IDE Taskforce (whose members' names are presented in List 1) is part of the Regulatory Knowledge group of the Clinical Research Innovation Key Function Committee and focuses on enhancing CTSA capabilities at AHCs to support faculty who are sponsor–investigators. In the spring of 2008 the authors, as members of the IND/IDE Taskforce, conducted a survey of the 24 CTSA Consortium members in existence at the time to better understand the current configuration of institutional support of sponsor–investigators, either preexisting or developed as a result of the CTSA. The implementation and results of that survey, summarized below, provide context to the recommendations of the IND/IDE Taskforce for institutional considerations, approaches, and best practices for providing support to sponsor–investigators.
Drug and device regulations and institutional considerations
When an investigator submits an IND or IDE application to the FDA and thereby assumes the role of sponsor–investigator, that individual takes on a number of responsibilities above and beyond those normally associated with conducting a clinical research study. These responsibilities include quality assurance activities, routine and expedited submission of safety and other regulatory reports, and monitoring and auditing. These are briefly described in List 2 and in more detail in Supplemental Digital List 1 (see http://links.lww.com/ACADMED/A33). There are numerous factors for institutions to consider with regard to supporting and overseeing the work of AHC researchers who are also regulatory sponsors. These factors (detailed in Supplemental Digital List 2; see http://links.lww.com/ACADMED/A33) include points such as ensuring the qualifications of the research team (not only scientifically, but also their expertise and capacity to handle the burden of the regulatory requirements), the institutional policy for IND exemption determinations, and consideration of institutional risk and thereby the level of oversight of sponsor–investigators. Taking these factors into consideration will help ensure that sponsor–investigators and their research staff are appropriately equipped to manage all aspects of the regulatory responsibilities associated with conducting FDA-regulated research.
In addressing these issues, the IND/IDE Taskforce recommends that institutions take a combined approach of research oversight and sponsor–investigator support and training to achieve optimal research safety and data integrity, as well as to minimize administrative burden and avoid inefficiencies and unnecessary barriers in the research process. Three models of support and oversight are described later in this report.
IND/IDE Taskforce survey
To assess the question of how AHCs currently provide regulatory support and oversight for sponsor–investigators, the IND/IDE Taskforce conducted a survey of the 24 CTSA awardees in existence in 2008. Surveys were sent to the CTSA Regulatory Knowledge representative at each institution and completed by the person(s) deemed to have knowledge of the institutional configuration for IND/IDE oversight and support. Nonrespondents were requested to complete the survey on at least two additional occasions. Responses were analyzed by descriptive statistics. The survey did not collect any identifiable personal information and therefore was determined to be exempt from institutional review board (IRB) review and approval.
Responses were received from 19 of the 24 CTSA centers in existence at the time the survey was fielded (79% response rate), and also from one respondent from an affiliate CTSA institution, and are presented below and in Table 1. Of the total of 20 responses, 55% (11 of 20) reported having an IND/IDE support office compared with only 25% (5) who reported having a support office prior to receiving the CTSA grant. Of the 11 institutions with IND/IDE support offices, 9 reported that their office was located in a larger support office separate from the IRB, 1 office was part of the IRB, and 1 office was a stand-alone unit.
The 20 responding institutions reported a wide range of volume of investigator-initiated drug and/or device research:
* The number of sponsor–investigators ranged from 6 to 100 (17 respondents, a mean of 28 sponsor–investigators, a median of 21).
* The number of sponsor–investigator IND/IDE applications ranged from 8 to 110 (16 respondents, a mean of 37 sponsor–investigators, a median of 27).
* The number of studies conducted under those IND/IDEs ranged from 10 to 125 (16 respondents, a mean of 44 studies, a median of 38).
* In two instances, the institution acted as an IND/IDE sponsor.
* Half of the institutions (10 of 20) required electronic submission of protocols to the IRB.
Interestingly, 80% of the 20 respondents reported that a goal of their institution is to increase the number of sponsor–investigators, and 5 of the 20 reported some form of incentive to faculty members to be sponsor–investigators (e.g., lower institutional indirect costs; free or reduced pricing for the use of regulatory services).
Over half of the IND/IDE support offices (8 of 11) serve an oversight role, performing a variety of functions in this role (Table 1, sections 1 and 4). Eight support offices assisted investigators in making IND exemption determinations, and at two other AHCs the investigator was required to have the IND/IDE support office make the determination of IND exemption. Several offices were involved in tracking IND/IDEs for the institution as well as contributing to development of institutional policy in this area. About half of the IND/IDE support offices (6 of 11) had a process for supporting/ensuring regulatory compliance, but in only 2 of 11 offices was that a direct responsibility (Table 1, section 1). The majority of the institutions with an IND/IDE support office (9 of 11) provided assistance with external regulatory audits (Table 1, section 3). The level of assistance ranged from preparatory (preaudit inspection) to fully participatory (working directly with the outside regulatory auditor to manage the visit).
For the 11 institutions with an IND/IDE support office, the survey also assessed the type of services being provided (Table 1, section 2). Most institutions provided assistance with the preparation/review of IND/IDE applications and annual reports. Only a few provided assistance with electronic communications (secure e-mail or electronic submission) with the FDA, or planned to provide this service in the future.
About half (6 of 11) of the institutions provided advanced IND/IDE training for faculty. However, only 2 of the 11 institutions required researchers to take such training.
Discussion and Recommendations
Barriers to efficient clinical and translational research have been described in a number of publications and are summarized by Heller and de Melo-Martin.6 The lack of clinical and translational investigators who are fully qualified, by experience and training, to serve as sponsor–investigators is one significant barrier. The CTSA initiative provides a stimulus and forum for interinstitutional collaboration among AHCs to develop a variety of approaches to address such impediments, allowing each institution to develop a process tailored to its characteristics and needs.
The CTSA IND/IDE Taskforce has considered this particular barrier and offers critical points for AHCs to consider when identifying how they can best provide support and oversight to their sponsor–investigators. We feel it is critical for AHCs to have programs that ensure adequate training of their sponsor–investigators, provide assistance with IND exemption determinations, and provide support for IND/IDE applications and oversight for sponsor–investigator activities.
Education about the regulatory requirements for FDA-regulated research is typically provided by either the sponsor or the investigator's institution. When investigators assume the dual role of sponsor–investigator, they may have to ensure staff training themselves. In addition, they must understand the additional responsibilities they have assumed in their sponsor role. As noted from the survey, only 2 of the 11 responding institutions had mandatory training for their faculty who chose to become sponsor–investigators. Training may involve online “just in time” training for those researchers who are submitting their first IND/IDE application, or one-on-one training from staff within the regulatory support office. However the training is accomplished, the critical component is ensuring that investigators are aware of the additional responsibilities and duties they are assuming in this role.
IND exemption determination
There are five criteria for exemption of a clinical study from IND regulations:
* is not intended to support a new indication,
* is not intended to support a change in labeling or advertising,
* does not involve a route of administration or dosage level or use in a patient population that significantly increases the risk or decreases the acceptability of the risks associated with the use of the drug product,
* is conducted under IRB oversight, and
* is within requirements regarding promotion and sale.
Of these criteria, typically the greatest challenge to AHCs in making the determination of exemption is deciding whether the investigation significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the investigational agent. The assertion that the research use of a drug does not increase research participants' risk requires scientific data. Simply citing the investigator's clinical experience with off-label use of the drug is not adequate.
In 2004, the FDA finalized a guidance document to assist sponsors in determining whether research use of marketed drugs or biologics for the treatment of cancer met the regulatory requirements for exemption from the IND regulations7 and also provided a document giving draft guidance for noncancer drugs.8 This latter guidance document provides examples of studies that are generally considered exempt from IND regulations and those that are not. Although the first document specifically pertains to studies using marketed cancer therapies, it still provides a useful framework for assessing whether other types of studies meet the IND exemption requirements. The FDA maintains that “because the assessment of risks involved in a therapeutic procedure is an everyday part of the practice of medicine, the individual investigator should usually be able to determine the applicability of the exemption,” meaning that a formal FDA determination of exemption is not required. However, even though this guidance indicates that investigators “should usually be able” to assess the applicability of exemption requirements, AHCs should carefully consider whether their investigators are truly adequately trained to do this independently with high accuracy. Assessment of this at one AHC indicates that this is generally not done accurately.*
Many AHCs struggle with the design of the optimal approach to managing the IND exemption determination process for research involving marketed drugs. Reponses to the IND/IDE Taskforce survey demonstrate that very few institutions (2 of the 20) have a centralized approach to managing this decision process. Given the potential for variability in interpreting IND exemption criteria and examples of the inaccuracy of investigators to do this independently, the task force recommends that institutions consider either a central determination process or consultative services to ensure consistency and accuracy in determining the exemption status of studies with marketed drugs.
Support for IND/IDE application submissions
Of the 20 respondents to the survey, 17 were able to determine the number of IND/IDE sponsors at their institutions, although for most institutions, this was not tracked prior to receiving the CTSA grant. Even though respondents to the survey reported projects of this nature, fewer than half provided any centralized support at the time of the survey. Of those institutions that did provide support, most assisted with either writing or reviewing the IND applications prior to submission to the FDA.
Support provided to investigators may involve providing guidance and direction for identifying outstanding issues to be clarified through optional pre-IND/IDE discussions with the FDA, as well as providing templates for IND or IDE applications, standard formats for protocol documents, and final application review prior to submission to the FDA. Table 1, section 1 identifies additional support activities that AHCs may provide, including assistance with meetings with FDA representatives. Providing regulatory support early may actually speed up the process for sponsor–investigators, allowing them more time to focus on the scientific aspects of the research project.
Models of institutional oversight and support of sponsor–investigators
We identified at least three potential institutional models for overseeing and supporting sponsor–investigators. These models, described below and assessed in Table 2, are defined by the range of services provided and the level of institutional oversight, and each has strengths and weaknesses.
* In the first model, seen in many AHCs, the investigator operates essentially independently, and the primary interaction with the institution regarding the IND/IDE is the general research oversight provided by the IRB. This likely does not provide sufficient assistance to enable and ensure that the investigator fully meets the requirements of the IND/IDE regulations.
* A second possible model has a central office that is consultative, providing education and services, but limited oversight.
* The final model provides robust support and full oversight. This includes activities such as requiring IND exemptions to be made by the centralized office and requiring review of all IND/IDEs before submission.
Arbit and Paller9 described a central IND/IDE support office focused mainly on support for IND/IDE application submission and IND exemption determination, approaching a full-service model. The approach to implementing mandatory use of central services and oversight requires careful consideration in order to avoid introducing an unintended “bottleneck” in the research approval process.
As noted in the results of the IND/IDE Taskforce survey, only 5 of the 20 institutions provided any formal IND/IDE support before receiving a CTSA grant. Most CTSA grantee institutions have recognized the IND/IDE regulatory burden as a barrier to translational research. Further, as a result of the NIH CTSA initiative, most are now working to develop the capability of providing IND/IDE support services. In addition, the CTSA IND/IDE Taskforce has collected and made freely available to all AHCs, resources for investigator education, tools, and templates (such as IND templates and checklists for IND exemption determinations).10 Regardless of the approach taken, it is important to assess how well a given model manages the institutional considerations presented in Supplemental Digital List 1.
The NIH Roadmap for Medical Research and the CTSA initiative have contributed to increased recognition of the complexities introduced by innovative clinical research conducted at AHCs. Although the encouragement of academic researchers to assume the role of sponsor–investigator does support development of FDA-regulated studies that “foster high-risk/high-reward research” and “enable the development of transformative tools and methodologies,”4 providing appropriate regulatory support within AHC institutional structures can be challenging. As we have emphasized, various models exist for providing training, support, and oversight to AHC sponsor–investigators. An increasing number of institutions have developed central regulatory offices charged with some aspect of sponsor–investigator support and/or oversight. It is our opinion and the opinion of the CTSA Consortium IND/IDE Taskforce that human participant protection in research conducted by sponsor–investigators is best served by an institution–investigator partnership designed to adequately support and provide oversight of the IND/IDE regulatory responsibilities with either a central consultative or full-service office. To ensure robust protection of human participants and to mitigate regulatory risks, AHCs are encouraged to assess our recommendations and develop programs appropriate to their institutional structures and their portfolios of investigator-initiated drug and device research. In this way, they can ensure support for investigators in managing the complex set of regulatory requirements of a sponsor–investigator.
This project has been funded in whole or in part with federal funds from the National Center for Research Resources, National Institutes of Health, through the Clinical and Translational Science Awards program, a trademark of the Department of Health and Human Services, part of the Roadmap Initiative, “Re-Engineering the Clinical Research Enterprise.”
The study was determined to be exempt from IRB review and approval.