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.
1Holbein ME. Understanding FDA regulatory requirements for investigational new drug applications for sponsor–investigators. J Investig Med. 2009;57:688–694.
*As part of a QA project, a large AHC assessed compliance with regulations concerning investigator determination of exemption of a clinical study from IND regulations. In this unpublished project, 23 proposed studies purported to meet the requirements for IND exemption were examined, and only 3 were found to fully meet the regulatory exemption criteria. The issue common to the studies that did not meet the exemption requirements was the inability to provide support for the third criterion on the issue of safety as laid out in 21 CFR 312(b)(iii), which states, “The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.” A common misunderstanding was that the investigator's clinical care experience with off-label use of a product was adequate to answer the exemption requirement noted above. Because IRBs within AHCs are composed in large part of those very same researchers, this concern is not limited to the individual investigators involved in such research.© 2011 Association of American Medical Colleges