Informed consent is often regarded as one of the immutable requirements for ethical research. Yet, in 1996, the United States Food and Drug Administration (FDA) created a regulatory pathway that would allow scientists to conduct experiments on human subjects without their informed consent. The motivation behind this “Exception from Informed Consent” (EFIC) pathway was to facilitate research on populations that could not consent—in particular, those incapacitated by life-threatening conditions requiring treatment that would be too time-sensitive for proper informed consent from surrogate decision-makers.
There are now more than 40 trials that have used the EFIC pathway, and these trials have included more than 54,000 research subjects. All trials must submit data to a publicly available FDA docket documenting the satisfaction of certain EFIC requirements. The map below depicts the population of trials that submitted such data to the FDA between inception of the EFIC pathway in November 1996 through October 2017.
The map is organized by trial start date along the x-axis and the condition (e.g., ischemic stroke) on the y-axis. Each node in the map corresponds to a single trial; its size corresponds to the number of human subjects; nodes with an “x” through them were terminated early (you can mouse-over the node to see the “reason” for this); color corresponds to the findings for the primary outcome (green = favored experimental intervention; red = favored control; gray = no difference; yellow = some data available, but complete results not available; white = results unknown).
Use the tools on the top right to zoom, pan, and save an image from this figure. Mouse-over a node to see more information. Click the node to visit its corresponding publication or registration page.
What does this show?
Perhaps the first thing to note about this landscape is how EFIC trial activity picks up after 2005—both in terms of the numbers of trials and their size. This corresponds with the founding of the Resuscitation Outcomes Consortium (ROC) in 2004, a group of 10 regional clinical centers that pooled their research efforts to try and better advance the state of care for cardiac arrest and trauma. Indeed, many of the cardiac arrest trials on this map were led by the ROC. But this lag between the creation of the EFIC regulations (in 1996) and the spike in activity (around 2005) shows how a regulatory pathway can be a necessary but not sufficient condition to promote some kinds of important research.
It is also striking how many of the trials showed no difference between the experimental treatment and the control. This is not necessarily problematic, because a null finding can still be informative. But this distribution of outcomes does raise some ethical questions, particularly given that one of the requirements for EFIC is that there is scientific evidence suggesting that there will be “the prospect of direct benefit to the subjects”. If this requirement were satisfied, then why were so few of the tested interventions associated with superior outcomes when compared to the controls? Are investigators and regulators systematically over-estimating the potential of these experimental interventions? Could it be harder to show a difference in trials investigating treatment for these conditions? Or is more preliminary work needed to better screen or identify new interventions that will be genuine improvements over the current standard of care? While the map doesn’t answer these questions, it does help to bring these important questions to the forefront by revealing the entire EFIC landscape at once.
Finally, it is worth noting that the data on EFIC trials is not easy to find. The FDA does not publish a centralized list of trials that have been granted an EFIC. All trials are expected to submit material to a publicly available docket, but the full docket is available only in-person or through a freedom of information act request (a partial version of the docket is available at Regulations.gov). Moreover, there is often a significant lag between when a trial begins and when the FDA receives material submitted by the trialists. The FDA docket itself is not organized by trial and contains over 15,000 pages of material. The material includes a mix of information related to public disclosure and community consultation, but it does not consistently contain information about the results of the trials or the demographics of participants.
These barriers to obtaining information about EFIC trials are problematic for a few different reasons:
First, part of the reason for collecting informed consent from research subjects is that it shows respect for the subjects and safeguards public trust in the research enterprise. But even if consent is not possible, this does not eliminate the need to demonstrate respect or safeguard trust. Transparent public disclosure can help fulfill these ethical requirements in the absence of consent, and therefore, robust community engagement (before the EFIC trial) and complete transparency (after the EFIC trial) should be standard practices. One relatively straightforward mechanism for transparency would be providing a centralized, public-facing website that tracks all EFIC activities.
Second, it is important for independent researchers to be able to critically evaluate regulatory programs, like EFIC, to ensure that they are accomplishing their goals. The harder it is for independent researchers to get information about trials using the EFIC pathway, the harder it will be for anyone (outside of the FDA) to know whether the program is working as intended.
Therefore, in addition to illuminating the population of EFIC trials, we believe that the map on this page can also be understood as a proof-of-concept for how to enhance transparency around EFIC trials (or research and regulatory programs in general). By providing an interactive resource, grounded in hard-to-access data, this map helps to make the impact of this pathway visible, and thereby raise or sharpen important questions about the program as a whole. In so doing, we believe that this map can help to foster respect and maintain trust in these important research activities that forego the typical consent process.
This is the dataset used to generate the figure above. It includes only trials that submitted public disclosure material to the FDA docket by October 23, 2017 (the date of our in-person request at the FDA). We intend to update this (and the map) regularly. We would welcome contributions and feedback from the EFIC community. If you have information on EFIC trials that is not included here, please let us know. We would welcome collaboration in keeping this data as thorough and up-to-date as possible.
Note: You can click the column headers to sort the table by column values.