The Food and Drug Administration (FDA) regulations require sponsors of clinical investigations involving an investigational drug or device to submit an Investigational New Drug (IND) or Investigational Device Exemption (IDE) application. Strict adherence to applicable regulations is vital to the success of clinical research. Unlike most major pharmaceutical sponsors, investigator sponsors often do not fully appreciate their regulatory obligations nor have resources to ensure compliance. As a result they can place themselves and their institutions at risk. Nevertheless, investigator-initiated clinical trials are vital to the further development of innovative drugs, biologics, and medical devices. The IND/IDE Subcommittee under the Regulatory Knowledge and Support Program at Harvard Catalyst, The Harvard Clinical and Translational Science Center worked in collaboration with Harvard and Harvard affiliated institutions to create and launch an IND/IDE Consult Service in a decentralized network of collaborating Academic Healthcare Centers (AHC). The IND/IDE Consult Service offers expertise, resources, and shared experiences to assist sponsor-investigators and IRBs in meeting regulatory requirements for conducting and reviewing investigator-initiated IND/IDE studies. The scope of the services provided by the Harvard Catalyst IND/IDE Consult Service are described, including the specifics of the service, lessons learned, and challenges faced, in a scalable model that builds inter-institutional capacity.
Under 21 Code of Federal Regulations (CFR) Part 312 and 21 CFR Part 812, sponsors of clinical investigations involving an investigational drug or device are required to submit, respectively, an Investigational New Drug (IND) or Investigational Device Exemption (IDE) application. An IND/IDE is a request for authorization by the Food and Drug Administration (FDA) for an investigational drug, biological product, or device seeking marketing approval to be administered to humans and for permission to be shipped across state lines. An IND/IDE is issued to a sponsor defined as a company, government agency, not-for-profit organization, or individual investigator (sponsor-investigator). Typically, an IDE allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data required to support a Premarket Approval (PMA) application or a Premarket Notification [510(k)] submission to FDA. Similarly, the data gathered during clinical trials of an IND become part of a New Drug Application (NDA) for review and potential approval of the product.
Both pharmaceutical and biotechnology companies and government agencies have significant resources dedicated to regulatory processes. When a researcher becomes a sponsor-investigator, however, she/he may not have specific experience or training, nor institutional resources, to assume the specific responsibilities as both investigator and sponsor of the study. A sponsor-investigator must have the knowledge to properly follow and adhere to the applicable CFR and FDA guidelines to ensure compliance in maintaining, conducting, and reporting research under INDs/IDEs. We sought to address this problem by developing a scalable, interinstitutional IND/IDE Consult Service, described herein.
About Harvard Catalyst | The Harvard Clinical Translational Science Center
In 2008, the National Institutes of Health (NIH) awarded Harvard University a Clinical Translational Science Award (CTSA), also known as Harvard Catalyst | The Harvard Clinical Translational Science Center. The overall goal of the CTSA program is to “accelerate discoveries toward better health” by addressing the challenge of translation of laboratory clinical innovation into practice. Harvard Catalyst is 1 of 61 medical institutions funded through the CTSA mechanism by the National Center for Advancing Translational Sciences (NCATS) and is dedicated to improving human health by enabling collaboration and providing tools, training, and technologies to clinical and translational investigators. Harvard Catalyst is a shared enterprise of Harvard University, its 10 schools and its 17 affiliated Academic Healthcare Centers (AHC)—each of which is a separate legal entity—as well as the Boston College School of Nursing, MIT, Harvard Pilgrim Health Care, and numerous community partners.11
A key component of Harvard Catalyst is the Regulatory Knowledge and Support Program (the Program) that works to minimize the regulatory burdens for investigators and to promote cooperation and interoperability by coordinating the diverse processes of interinstitutional research, including human subjects protections, patient privacy, quality improvement, and support for FDA-regulated research. In particular, the Program promotes interinstitutional cooperation and develops regulatory guidance and simplification where appropriate. In this context, the IND/IDE subcommittee of the Program regulatory oversight committee was formed to address the challenges of conducting clinical trials with IND/IDE sponsor-investigators.
The membership of the IND/IDE subcommittee includes both recognized IND/IDE regulatory experts from the Harvard academic, medical, and hospital communities and those new to the regulatory compliance arena. The breadth of membership makes the subcommittee uniquely qualified to ensure compliance of federal regulations and institutional policies and to promote best practices. The goal of the subcommittee is to assist institutions and sponsor-investigators to meet their regulatory and institutional requirements.
Rationale and early development of the consult service
The charge of the IND/IDE subcommittee was to create and provide a centralized IND/IDE resource in a large, diverse, and decentralized community. The IND/IDE subcommittee developed an IND/IDE Consult Service to provide sponsor-investigators and IRBs with a centralized resource for expertise and support related to the review and conduct of investigator-initiated IND/IDE studies. The IND/IDE Consult Service relied on volunteer consultants who were employees of the participating institutions and members of the subcommittee, and developed practices and services that aligned with the policies in place at each of the affiliated Harvard Catalyst institutions.
The goal of the IND/IDE Consult Service was to assist sponsor-investigators and IRBs in determining the applicability of an IND/IDE and to educate sponsor-investigators in their roles and responsibilities. The IND/IDE Consult Service aimed to ensure regulatory compliance. In addition to working with sponsor-investigators, the expert consultants trained individuals from the human research protections programs (HRPPs) of the affiliated institution such that they developed experience in this domain over time. Importantly, the model was thus scalable: utilizing individuals with experience in IND/IDEs to support and train personnel from institutions that did not have such resources.
The IND/IDE consult services focused on providing assistance to sponsor-investigators and HRPPs both during the preclinical stages of research development and in applying for, and then maintaining, their INDs and IDEs. The types of consultations available include (Table1):
Table 1. List of types of consultations available
IND and IDE Regulatory Requirements Education Services
• Overview of sponsor-investigator (IND/IDE holder) regulatory responsibility
• Overview of record keeping requirements for sponsor–investigators
• Overview of requirements for Clinicaltrials.gov registrations and reporting
• Review of reporting requirements including safety reports and annual report to FDA
• Providing tools/checklists to ensure regulatory compliance
Sponsor–Investigator IND and IDE Assistance
• IND and IDE applicability assessments
○ Identifying need for submitting an Investigational New Drug (IND) application
○ Identifying need for submitting an Investigational Device Exemption (IDE) application
• Provide an overview of IND/IDE application process
Certain consultations were determined to be beyond the scope of the IND/IDE Consult Service, including:
Assistance with submission and preparation of a specific IND or IDE application to FDA
Preparation, coordination, facilitation, and attendance at FDA meetings
Preparation of IRB applications
Preparation of annual reports and amendments to FDA
Preparation for and regulatory support during FDA inspections of investigator-sponsored clinical trials
Of note, the consult service is open to all participating Harvard Catalyst sponsor-investigators, IRBs, and institutions. Of the members of the committee, only four institutions have resources dedicated to support sponsor-investigators: Boston Children's Hospital, Brigham and Women's Hospital, Harvard School of Public Health, and Massachusetts General Hospital. However, there are 22 legally separate entities encompassing 18 AHCs and 16 Harvard schools for a total of 34 participating institutions and schools—all of which are eligible to request an IND/IDE consult. Thus, limiting the scope of services was considered necessary for two reasons. First, the IND/IDE Consult Service is a volunteer activity and the time commitment of the expert consultants was finite. Second, institutional liabilities were of concern and were thought best handled by the institution itself. To respect institutional autonomy and eliminate duplicative effort, a consult service request received by an institution with a dedicated resource would automatically be redirected to their institution's own designated contact.
The IND/IDE Consult Service is open to investigators at Harvard Catalyst participating schools and institutions and who either currently hold an IND/IDE or are planning an IND/IDE study, institutional officials responsible for the oversight of clinical and translational research, and IRBs or committees at Harvard Catalyst-affiliated institutions. To initiate a consultation, the requestor must complete and submit the Consultation Request Form available on a secure Harvard Catalyst Website. Access to the Website is limited to individuals who have appropriate Harvard password access (Figures1 and 2).
eRA Commons Username: An explanation is provided for individuals who are not familiar with eRA via a question mark hover link: “NIH eRA Commons is a Web-based system for applicants and institutions to participate in the electronic grant administration process; an eRA Commons is the unique username assigned to an investigator by his/her institution for NIH grant tracking purposes. The NIH requires us to supply this information. If you do not enter an eRA Commons Username at this time, you may be requested to obtain one. Click this link for simple instructions on how to obtain an eRA commons username. If you do not have an eRA Commons username and do not intend to get one at this time (students and nonfaculty staff exempt), please enter NONE into this field.” Per NIH policy, all investigators who submit NIH grants as PIs must establish an NIH Commons account; Harvard Catalyst has adopted this methodology to track utilization of NIH-supported activities.
After submission, the request is reviewed by the consult service to first determine the requestor's reasons for requesting a consultation; the requestor is contacted to discuss the details of the consultation. The final decision regarding determining the need for an IND/IDE rests with the reviewing and responsible IRB and the investigator.
Upon completion and submission of an IND/IDE request for consultation (Figure2), the Webform sends an automated reply message of receipt both to the requestor and to the affiliated hospital IRB that is notified of the investigator's request for consultation. The request is entered into a database maintained by Harvard Catalyst that tracks the consult and provides project management tools. The database is JIRA, a proprietary issue tracking project management tool developed by Atlassian. The received request is automatically routed to a designated Harvard Catalyst Regulatory team member. This designated contact confirms the request with the requestor via e-mail and reviews the information to appropriately delegate to one of three workflow pathways/models, diagrammed in Figure3 and described below:
Workflow example 1
Requests received from Harvard Catalyst institutions that have their own IND/IDE support group are redirected either to the institution's designated IND/IDE contact or, if oncology and by prior agreement, to the Dana-Farber Cancer Institute. Upon completion of referral, the Harvard Catalyst designated contact closes the open request.
Workflow example 2
Consults requesting assistance in determining the necessity of an IND/IDE application are reviewed by Harvard Catalyst IND/IDE subcommittee members. The Harvard Catalyst designated contact distributes the study and request information to the IND/IDE subcommittee listserv. The committee members review the material meeting either by e-mail or by teleconference and prepare a written response to the investigator and/or to his/her corresponding IRB office, if the study has been submitted to the IRB. Upon completion of consultation, the Harvard Catalyst designated contact closes the open request.
Workflow example 3
For all other requests, the Harvard Catalyst designated contact assigns the received request to a volunteer consultant based on availability and expertise. The consultant, requestor, and a Harvard Catalyst regulatory trainee from the home institution of the requestor then schedule a consultation session either in person or by teleconference. The consultant reviews the IND/IDE process with the requestor, answers all questions, and shares useful tips, tools, and expertise. If needed, follow-up meetings may be scheduled. Upon completion of consultation, the Harvard Catalyst designated contact closes the open request.
All requestors are sent a satisfaction survey to complete.
Feedback and analysis
Since its launch in October 2011 and as of May 2013, the total number of consultation requests received was 16. The requests ranged from IRB administration members requesting education on (1) IND/IDE reporting requirements for safety, (2) annual reports to sponsor-investigators needing assistance with IND/IDE determination, (3) application support, and (4) understanding the clinical research process of transitioning from animal to human studies. Most of the consultations average an hour in length with a few needing subsequent follow-up attention.
After completion of each consultation, the requestor is e-mailed a link to a satisfaction survey hosted on REDCap. The objective of the survey is to capture both the satisfaction rate of the consult service and to identify, if any, areas of improvement. Five surveys have been completed (31% response rate). Four out of the five respondents had a satisfied or very satisfied experience with the services they received while one was very dissatisfied.
Respondents were asked to describe any IND/IDE needs where additional assistance could have been helpful. The five respondents selected the following:
Preparation of FDA annual report.
Preparation for IRB applications.
Preparation, coordination, and attendance at FDA meetings.
Assistance with submission of an IND/IDE application.
Question regarding FDA submission strategy.
The survey had an open field question addressing if the requestor had any suggestion that could improve the service. The respondents provided the following comments:
The actual service was helpful. It took longer than expected to set up the meeting.
It would be good to have a service that would actually prepare IND application together with the PI rather than just provide advice.
Create a searchable database for FAQs.
Collectively, most users found the IND/IDE Consult Service to be helpful, but additional assistance beyond the scope of the service was requested. It is important to note that our sample size of five responses to the satisfaction survey was small and may not be representative of the other 11 users of the service. We are currently focusing on achieving a higher response rate to the satisfaction survey in order to evaluate potential improvements to the consult service.
A challenge in developing an IND/IDE Consult Service was creating a centralized tool in a decentralized community of the Harvard-affiliated institutions. The objective of the consult service was not to add additional burden to participating institutions that have their own policies and standards of operations, but to create a service that would ease the burden of sponsor-investigators and IRB offices. An additional goal was to train regulatory administrators from institutions that lacked the support and knowledge.
Several investigators from institutions that did not have their own IND/IDE support initially suggested that the Harvard Catalyst offers an IND/IDE Consult Service. This suggestion was met with some concerns: legal, administrative, and political. As with other initiatives, the Regulatory Knowledge and Support Program worked through the challenges by parsing through each issue to resolution. First, institutions were concerned with legal liability, should an outside consult err in direction or advice. The consult service was therefore entirely voluntary, with explicit direction that the IRB of record retained all authority—for the determination of IND/IDE necessity, for the submission documentation to the FDA, and for all interactions with the FDA. Limitation of scope was important. Second, institutions providing the consultants were concerned both about the required effort of the individuals and the level of volunteerism necessary. We therefore committed to a pilot program of 1 year and reanalysis, committing to a charge-back mechanism if the level of effort was substantial. Significantly, one institution volunteered to initiate the service; others soon joined as the shared learning, even among resource-rich institutions, was substantial. The political concern that investigator-initiated studies would be seen and reviewed by individuals from outside institutions was simply addressed by communication and time. It was indeed helpful that the investigator community was motivated to enable, and in favor of, the service.
A key to success was cooperation among the affiliated institutions working collaboratively to build consensus on the scope of the service. It was important that the workload was reasonable given the volunteerism required. And it was equally important that the consult service was strictly advisory: each responsible IRB retained the authority to counsel its investigators and determine IND/IDE applicability.
Limited but consistent feedback indicated that the consult service was too limited in scope. Sponsor-investigators appeared to desire more assistance in the IND/IDE FDA application and submission process, including facilitation and coordination with their IRB offices and the FDA. A more comprehensive service would ensure regulatory compliance and greater investigator time for direct research. However, supporting these efforts does not absolve the IND/IDE sponsor-investigator of the regulatory responsibility.
Feedback from the users of the IND/IDE Consult Service suggested future development of the consult service including:
Advise on strategies to identify and address issues related to regulatory compliance.
Support with scheduling, coordinating, preparing, and attending meetings with the FDA.
Assistance with IND/IDE preparation and submission, including IND electronic submissions.
Prepare and submit applications for IND exemptions.
Support with submitting annual reports and other regulatory submissions.
Interface with regulatory authorities.
Identify appropriate resources for addressing regulatory issues.
Assist with the development of intradepartmental strategies and polices related to IND/IDE processes.
Provide consultative services with regard to the design and delivery of continuing education programs related to meeting GCP/GLP/GMP requirements.
Provide consultative services to IRBs regarding review, approval, and overseeing of investigator-sponsored IND/IDE studies, as well as the determination of significant versus nonsignificant risk devices.
Some of the requests for further services are amenable to the development of additional educational resources and a potential “tool-kit” available to all. Harvard Catalyst is currently working to address some of these apparent obstacles. For instance, the “how-to” of scheduling, preparing, and attending a meeting with the FDA is (somewhat) formulaic and not dependent on the specific content of IND/IDE and may be helpful guidance to those who have never attended an FDA meeting. A description of IND exception process, and models and examples of approved exception documents, are being developed. A dynamic, Web-based listing of additional regulatory resources should be made available.
Some of these additional consulting services, however, are complex and specific to the IND/IDE application and process itself. If these services are to be offered to investigators and IRBs, Harvard Catalyst will need incremental resources to recruit trained staff who will serve as liaisons between the FDA and the investigator, will attend FDA meetings for and with investigators, and will assume operational responsibility for the process. Financial limitations—and legal liability concerns—make it unlikely that Harvard Catalyst will provide such a service at this time. Consideration of a charge-back mechanism (and a contractual agreement clearly addressing responsibilities and accountabilities) would need to be engineered, and currently whether sufficient need exists to render such a service revenue-neutral is unclear. The sponsor-investigator's institution can, of course, assume such a role.
We are refining the metrics to determine success of the services to include tracking the number of requests for assistance, average time spent per consultation, and feedback survey responses. Importantly, metrics that demonstrate increased IND/IDE applications and decreased time to first-in-human studies will validate the utility of such an investment. While the IND/IDE subcommittee of the Program regulatory oversight committee was formed to address the challenges of conducting clinical trials with IND/IDE sponsor-investigators, the need for greater regulatory support and assistance is compelling. Time to clinical trial completion and quality are measures of the success of clinical and translational research enterprise: supportive measures—such as “IRB navigators” or, as in this context, “IND/IDE consultants”—that decrease time and enhance quality and integrity should be considered.
This work was conducted with support from Harvard Catalyst| The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 8UL1TR000170–05 and financial contributions from Harvard University and its affiliated academic health care centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. Authors would like to thank the Harvard Catalyst IND/IDE Subcommittee members that have contributed in creating the IND/IDE Consult Service and serving as volunteer consultants: Stanley Estime, Harvard School of Public Health; Keren-Nicole Insalaco, Harvard Medical School; Eunice Newbert, Boston Children's Hospital; Emily Ouellette, Partners HealthCare System; Leigh Read, Joslin Diabetes Center; Sarah White, Partners HealthCare System; Matthew Wladkowski, Boston Children's Hospital.
1Harvard University, its 10 schools and 17 affiliated academic healthcare centers are: Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Broad Institute of MIT and Harvard, Cambridge Health Alliance, Children's Boston Hospital, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Business School, Harvard Divinity School, Harvard Faculty of Arts and Sciences, Harvard Graduate School of Design, Harvard Graduate School of Education, Harvard Graduate School of Government, Harvard Law School, Harvard Medical School, Harvard School of Dental Medicine, Harvard School of Engineering and Applied Sciences, Harvard School of Public Health, Hebrew Senior Life, Immune Disease Institute, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Radcliffe Institute for Advanced Study, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and Veterans Affairs Boston Healthcare System.