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?
We covered the basics of investigator-initiated trials in Beginner’s Guide to Investigator-Initiated Trials. Now we will focus on the challenges hindering successful completion.
The range of settings in which a clinical investigator may undertake an investigator-initiated trial (IIT) is broad and may be the determining factor for success. A clinician in an academic medical center with resources available to assist in protocol and writing, statistical planning, funding sources, and study execution certainly has a great advantage over the individual clinician with fewer or none of these. It is essential then to survey the resources available before beginning and engage them at the outset, before the protocol is written. It is this IRB professional’s observation that IIT protocols often reflect great ideas but not much more. And a poorly written protocol is a signal of poor support rather than lack of good intent.
A frequently tapped source of support is the pharmaceutical/medical device industry; virtually every major pharmaceutical and device company has a dedicated investigator-sponsored research assistance program. They are happy to engage the medical community and its physician investigators, as it offers a rich source of “real world evidence” they seek outside the traditional investigational device exemption (IDE) and investigational new drug (IND) route. Recent regulatory changes have also made it possible for companies to expand product indications outside the traditional routes. Industry support also includes essentials such as assisting in protocol writing and statistical support. Though it offers a solution, a level of independence is sacrificed as these companies typically demand in return specific terms regarding publication rights and claims to new products or processes.
No matter how well intended or written a protocol is, all is in vain if it is insufficiently powered to validate the study endpoints and answer the research question. Likewise, all is lost if the study is not practically carried out in a reasonable time, even if the statistical plan is sound and able to reach robust conclusions. This may explain why some study results never get published; there is simply nothing to show. For an IIT to succeed, it is essential to engage knowledgeable and experienced researchers to provide a “second set of eyes” and review research proposals to assure their soundness and feasibility.
Clinical research is expensive, especially if it is undertaken in a way to produce valid scientific results. It requires physical resources such as facilities and clinical venues, testing capabilities like imaging and labs, and specialized personnel. Industry often fills this gap, but even generous industry support does not compare to Phase I-III industry–sponsored studies. This usually means doing much more with less. This explains why most investigators who venture into IITs add it to an already robust and well-supported and funded industry– or agency–funded research program.
Funding is an important issue, not only because of resource needs to conduct the study, but also because of legal and compliance risks associated with where the funds originate. It’s essential 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.
Industry support differs in many ways, usually in the form of funding, provision of product, or aid in study design and conduct. Other sources 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, laying out these terms in detail. Sponsor-investigators will also want to assure 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. Regardless of the funding source, a well-funded project is essential to successful completion.
The regulations governing human research originate from two main sources in the US:
- The Common Rule and its participating agencies governed by DHHS with rules published in 45 CFR 46, and
- The FDA governed by the rules found in 21 CFR 312 (drugs) and 21 CFR 812 (devices)
Compliance with the Common Rule is imposed when the HHS or its agencies provide funding. In addition, compliance with the FDA rules is imposed when using FDA regulated products in research. If neither of these apply, the institution conducting the research will impose its own rules via IRB standard operating procedures (SOPs), which may also elect to impose the Common Rule to any research conducted within its walls. Rules governing human subjects protections and IRBs originate from the Office of Human Research Protections and are published in 21 CFR 50 and 56, respectively.
These rules translate into a regulatory burden placed on the clinical investigators, and varies based on funding source and investigational article, if any. The regulations governing FDA–related products are often the most challenging for the investigator/sponsor to meet. If a clinician seeks to use an FDA–regulated drug or device outside its approved indication it may need an IND (drug) or IDE (device) to allow its use in an investigation. Since filing an IND or IDE require submission of all available manufacturing, safety and existing clinical data, it is wise to start down this pathway with the cooperation of the original IDE/IND holder so the data may be cross referenced by the agency from existing IND/IDEs. Monitoring and safety reporting requirements are critical and become exponentially burdensome if an investigator/sponsor seeks to mount a multisite study with colleagues in his field. DHHS funded research is currently bound by the single IRB mandate, but FDA regulated research may be conducted at multiple sites, each with their own IRB. As stated in Beginner’s Guide to Investigator-Initiated Trials, FDA regulated research requires the sponsor/investigator to comply with all relevant requirements.
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 versus benefit. Often, benefits include or are limited to benefitting others or society from the knowledge gained. If a study is not scientifically sound or unlikely to complete, this benefit is lost. As a result, IRB review cycles are often protracted due to the need for multiple requests for modifications to assure scientific soundness.
The IRB must also determine or validate the regulatory status of any regulated product included in the study. Medical devices require IRB review to determine significant risk or non-significant risk status. However, the device may be an exception from the 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 product marketing. Again, the answers to these questions are not always easy to discern.
Putting It Together
It’s clear, for all the reasons mentioned above, 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.