In the course of caring for patients, a physician has a lightbulb moment: maybe it’s an epiphany about a medical device that could be adapted for a new clinical indication, or an inspiration to explore the possibilities of a commercially available drug used for a new purpose in patient care. In any case, the great idea comes down to a research question that can only be answered by a classic controlled clinical trial. How hard could that be?
One Concept, Many Forms
The concept is simple: a physician/investigator determines to take on a clinical study as both the sponsor and investigator. Projects like these can be described as investigator-initiated research (IIR), investigator-initiated studies (IIS), or investigator-initiated trials (IIT). For the sake of this blog, we’ll use IIR going forward.
The terms “sponsor” and “investigator” are defined by the applicable regulations. Essentially, the “sponsor” is the person or institution/organization that initiates a clinical investigation. “Investigator” is the individual who conducts a clinical investigation. Each of these has very specific obligations in the regulatory construct, and a clinician who undertakes an investigator-initiated study assumes the roles and responsibilities of both as the sponsor-investigator.
Whose Rules Are Imposed?
The funding agency as well as the products being employed in the clinical study will determine what regulations must be followed. If an FDA-regulated product is involved, 21 CFR 312 (drugs) or 21 CFR 812 (devices) dictates the conduct of the study. If another federal agency funds the research, HHS rules may apply (45 CFR 46). If a study is federally funded by an agency other than HHS, but involves an FDA-regulated product, both sets of rules may apply. Because of the regulatory burden imposed when using FDA-regulated products, many sponsor-investigators hesitate to undertake a clinical study that involves regulated drugs or devices. The FDA does provide ample guidance for those willing to try.
The FDA regulations governing responsibilities of investigators and sponsors in investigational new drug (IND) studies are fairly straightforward and provide a helpful overview of what a sponsor/investigator should expect in conducting an IIR:
Investigator responsibilities include the following:
- Ensure that the investigation is conducted according to the investigational plan
- Maintain case histories
- Provide reports
- Submit progress, safety reports, final reports, financial disclosures
- Protect the rights and safety of subjects under the investigator’s care
- Obtain informed consent from each subject
- Control the drugs under investigation
- Assure review by a responsible IRB and comply with its requirements
- Permit FDA inspections
Sponsor responsibilities include the following:
- Select qualified investigators
- Include executed 1572 and financial disclosures from each PI
- Assure the protection of human subjects
- Provide the investigator with information to conduct the investigation properly
- Monitor progress of investigation
- Control and document disposition of investigational product
Funding is an important issue, not only because of resource needs to conduct the study, but also because of the legal and compliance risks associated with where the funds originate. It’s important to tread carefully when seeking funding from industry sponsors. The HHS Office of Inspector General (OIG) has entered into several high-profile multi-million-dollar settlements with pharmaceutical and device manufacturers resulting from anti-kickback penalties related to sham clinical trials. Most settlements resulted in fines as well as corporate integrity agreements to assure compliance. In the current research landscape, nearly all industry players have strict corporate policies to both support and minimize risk in IIR.
Industry support can differ in many ways. It can come in the form of funding, provision of product, or aid in the study design and conduct. Other sources of funds include cooperative groups, nonprofit research organizations or networks, or the sponsor-investigator’s own healthcare institution. If industry provides support, the issues of intellectual property, data ownership and publication rights become sensitive, especially for academic institutions. Industry funders will insist on a robust contract that lays out these terms in detail. Sponsor-investigators will also want to assure that liability concerns (indemnification, subject injury, etc.) are also addressed. Industry sponsors also have varied approval processes that might include legal/regulatory, biostatistics, and safety review. A 2015 ACRP survey of investigator-initiated sponsored research indicated that most (93%) industry respondents have a formal review process for IIR and indicate a review/approval time of between 46 and 90 days. Review requirements and turnaround times vary widely among other funding sources.
Regardless of the funding source, a well-funded project is essential to successful completion. The ACRP report indicates the average time to completion was 2-3 years, and about 75% of the trials ultimately finish.
Challenges for IRBs
From an IRB perspective, the most common challenges are incomplete, scientifically inadequate or underpowered studies. A primary concern of the IRB is risk vs. benefit. Often benefits include or are limited to benefit to others or society from the knowledge gained. If a study is not scientifically sound or likely not to complete, this benefit is lost. As a result, IRBs find that the review cycle is protracted due to the need for multiple requests from the IRB for modifications to assure scientific soundness.
The IRB must also determine or validate the regulatory status of any regulated product that may be included in the study. Medical devices require IRB review to determine significant risk or non-significant risk status. However, the device may in fact be excepted from the investigational device exemption (IDE) regulatory requirements if it is being used as labeled in the study—but this is not always a straightforward determination. Likewise with FDA-regulated drugs: These may be exempt from IND requirements if they are used as labeled, or if the study is not intended to support a marketing application for change of label or for use in marketing of the product. Again, the answers to these questions are not always easy to discern.
Challenges for the Researcher
The challenges to the researcher are multiple but not insurmountable. They include:
- Regulatory burden
- Medical writing
- Statistical support
These subjects are covered in conferences and publications that offer specific and more exhaustive guidance. An example is from the Investigator Initiated-Sponsored Research Association (later acquired by ACRP) from 2010, entitled “Setting Up an Investigator-Sponsored Research Program.”
Here are a few additional resources clinicians interested in beginning their first IIR might consider:
- Investigator-initiated studies: Challenges and solutions, Perspectives on Clinical Research, 2018 Oct-Dec, 9(4); 179-183
- Clinical Study: Legitimate or Disguised Kickback? B&F Law Blog 4/2/2018
- Guidance for Clinical Investigators, Sponsors and IRBs; Investigational New Drug Applications: Determining Whether Human Research Studies Can Be Conducted Without an IND, September 2013
- Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators; Guidance for Industry (draft guidance), May 2015
- Setting Up an Investigator Initiated-Sponsored Research Program, IISRA Position Statement, April, 2010
- How Everybody Wins When Playing by the Rules: The Benefits of Investigator-Initiated, Industry-Sponsored Clinical Trials, AJNR 2/10/2011
- NIH Clinical Trial Protocol Template
Putting It Together
It’s clear, for all the reasons mentioned above, that succeeding in investigator-initiated research takes determination and dedication. However, because the research originates from the clinician’s own inquiring mind, the level of satisfaction can be very high.