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4 Questions For Researchers and Institutions Involved In Human Subjects Research

Last September, and in January of this year, we wrote about a suite of initiatives aimed at improving the quality and transparency of the NIH-supported research that most directly engages human participants – clinical trials. These initiatives include dedicated funding opportunity announcements for clinical trials, Good Clinical Practice training, enhanced registration and results reporting on ClinicalTrials.gov, and required use of single IRBs for multi-site studies. We are now entering the final phases of implementation of these initiatives – so, if you are contemplating research involving human subjects, please read on.

We’ve received queries from members of the research community seeking clarity on whether their human subjects research will be affected by these new policies, and if so, how. So, we want to call your attention to four questions researchers involved in human s studies need to ask, and answer. These questions are:

  1. Does the study involve human participants?
  2. Are the participants prospectively assigned to an intervention?
  3. Is the study designed to evaluate the effect of the intervention on the participants?
  4. Is the effect that will be evaluated a health-related biomedical or behavioral outcome?

If the answer to all four questions is yes, then we consider your research a clinical trial.

The NIH definition of a clinical trial is “a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes”. The definition was published in 2014, after extensive public input, and affirmed, after even more public input, in our policy published in September 2016. The clinical trial definition encompasses a wide variety of study types, as shown in figure 1. These range from mechanistic studies to behavioral studies, to pilot/feasibility studies, all the way to large-scale efficacy and effectiveness trials.

Diagram showing that NIH clinical trials span a wide range of studies: mechanistic, exploratory/development, pilot/feasibility, other interventional, behavioral.

Figure 1

The breadth of the NIH definition is intentional, given the nature of the NIH portfolio and imperatives for maximal transparency. Transparency shows respect for the participants who put their trust in us, in the face of unknown outcomes, to help advance science. Our concerns about transparency stem in part from the issues surrounding the reporting of clinical trials data. For both NIH-funded and non-NIH funded trials, unreported data and untimely dissemination of results has been documented over and over again.  Others have expressed concern that the NIH has not collected needed trans-NIH data to enable it to function as proper stewards of clinical trials.

Some have argued that we should not expect trial registration and reporting for small or exploratory trials, for trials that focus on safety, or for trials that fail to meet enrollment targets. As we stated last September, NIH chose to emphasize the value of transparency for these kinds of trials as well, as “the benefits of transparency and the need to fulfill the ethical obligation to participants is as relevant to these types of trials as to any other type.”  We have an ethical obligation to report results, and this is especially true when volunteers contribute their time as study participants in prospective experiments, whether large or small. And, to be effective stewards of precious and constrained taxpayer monies, we need to collect a minimum of standardized data.

This transparency complements existing efforts to promote data sharing, public access to NIH-funded research results, and scientifically rigorous research design, all of which ultimately benefit the research community directly, as well. By developing and sharing robust data, we maximize the value of NIH’s investment in research by allowing scientists to build upon solid results. The definition, and our clinical trial policies, are an integral part of our efforts to enhance scientific stewardship, dissemination of information, transparency, and to excel as a federal science agency that manages for results.

Why is it important to know whether you are proposing to conduct a clinical trial? Correctly identifying whether your study is a clinical trial is crucial to complying with NIH policies, many of which are now in effect,  such as registering and reporting all NIH supported clinical trials in ClinicalTrials.gov and good clinical practice training. Very soon, your answer will be crucial to picking the appropriate NIH funding opportunity for your application, writing your research plan correctly (since some information will be captured in the new human subjects and clinical trials form), and ensuring that your application includes all the information required for peer review.

If you are having difficulty answering the four questions that determine whether a study meets the NIH definition of a clinical trial, we encourage you to consult the case studies and FAQs that are available on our webpage on clinical trial requirements for grants and contracts. We’ll be following up with additional blogs and NIH Extramural Nexus articles that provide more depth on the various initiatives. We strongly encourage you to look at these materials, and share them with your colleagues, to ensure that as an awardee conducting clinical trial research, you are aware of the need to register your trial and report its results.

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12 thoughts on “4 Questions For Researchers and Institutions Involved In Human Subjects Research

  1. The NHLBI implementation of increased oversight of R01-funded clinical trials through the R61/R33 mechanism restricted the timeline for a trial (planning/early enrollment in year 1, await R33 award to continue). This limits the types of trials that can be done. For example, a community trial working with a school district often needs to begin implementation of the intervention near immediately after participant enrollment, which can be conducted quickly and in large numbers – you can enroll several schools worth of children within 1 month with effective staffing. Intervention implementation may also need to occur within the first year of funding to allow for alignment with the academic year and enough time on the grant to follow students for several years. Enrollment/implementation does not happen on a rolling basis as in say, a drug trial.

    I hope as other institutes implement/improve the requirements for clinical trials, they are considerate of the variety of types of trials and are flexible regarding timing for planning/enrollment/implementation.

  2. I can’t help but quote Nancy Kanwisher here: “The massive amount of dysfunction and paperwork that will result from this decision boggles the mind.”

    I’m an early career researcher doing basic human subjects research funded by the NIH. Our science is directly relevant to understanding the basic cognitive and neural mechanisms that support a healthy brain. Yet our “interventions” (a simple example: testing memory for words shown in the same font vs a different font) might now be treated with the same level of scrutiny as a true clinical trial. If so, it is difficult to even imagine the impact of this policy on our research, but a fair estimate is that every new experiment would take twice or many times as long to complete. I further suspect this will disproportionately impact early career researchers, who often have smaller labs without the resources to compensate for the added paperwork. Will grant budgets be increased accordingly? And for what? There is no clear benefit for our participants or for the general public.

  3. The decision makers at the NIH who instituted this policy have to be aware that they are in effect killing basic science research with this implementation. I am specifically referring to case #18: “The study involves the recruitment of healthy volunteers who will perform working memory tasks while an fMRI is performed. It is designed to determine the brain functions involved in working memory.” This is deemed a “clinical trial.” This encompasses the entirety of basic cognitive neuroscience research. At best, this will incur serious increases in paperwork and bureaucratic demands for research that is NOT truly any sort of “clinical trial.” At its worst, it is going to nearly eliminate funding for basic science research as actual clinical trials will push out basic research in competition for monetary resources. I thought that the NIH supported basic science research, but with this move, it clearly does not. I am so incredibly disappointed by this decision. The effect that it is going to have on basic science research in the U.S. will be profound. I am incredibly saddened that after all of the hard work, effort, and dedication so many scientists have put forward to understanding how the human brain works, that we would be betrayed in this way.

  4. I couldn’t agree more. While the goal of more oversight of trials is laudable, the implementation of all of these policies makes it nearly impossible to do and fund trials particularly for new investigators and disincentivizes collaborative trials since all sorts of hurdles have been put in place for doing even a 2-center trial (NHLBI) without going through years of planning at NHLBI without guarantee of funding for advancing to next stage. As a clinical trialist myself, I suspect the implementation of these is going to significantly discourage investigators from proposing smaller physiologic studies that provide crucial scientific and clinical data and rob the investigative community of realsitics pathways for funding clinical trials and for young investigators to get experience in clinical trials.

  5. This broadening of the “clinical trial” definition is frankly insane. What could possibly be gained by pretending that having healthy volunteers perform a cognitive task (essentially equivalent to playing a lame computer game) for half an hour and measuring their reaction times (or even neural signals) constitutes a “clinical trial”, equivalent to trying out a new pharmaceutical on a patient population??? I have not seen a single credible argument in support of this absurd over-stretching of the “clnical trials” definition. How is having someone push buttons in response to pictures on a screen an “intervention” that affects “biomedical health outcomes”? It is as if this was cooked up by people who have absolutely no clue what we do in basic cognitive and cognitive neuroscience research. The proposed additional administrative burden and massively reduced flexibility in running research would be a huge killer of innovative basic research and a gigantic waste of taxpayer monies to pay for the additional admin costs. Our best and brightest graduate students would move from being able to follow their creative sparks to essentially becoming “research technicians” who just have to implement to the letter some experiment we proposed in a grant application several years ago. Please, someone tell me: What is the point of this???

  6. In the scientific and clinical communities and in the general public, “intervention” is generally considered to be synonymous with “treatment.” I am a clinical psychologist and neuroscientist, but even if I were a member of the general public, I would be shocked to hear that the “intervention” my doctor planned was simply an assessment of my current functioning, even if that assessment involved asking me to do certain tasks (stick out my tongue and say “aah” for example). Many of our experimental research studies, especially in psychology and neuroscience, are the behavioral and neurobiological equivalent of asking people to stick out their tongue and say “ahh.” They are not designed to have any lasting effect on health or wellbeing. In fact, the opposite is more often true; we design the studies to have as little lasting impact as possible. If the suggestion to change the definition of an intervention has arisen because of concerns about any potential risks involved in these studies, these concerns should be addressed through the appropriate channels (i.e., in human subjects review and through institutional review boards). Please do not dilute the definition of a clinical trial by including studies without a true intervention. It will mislead the public, obstruct scientific progress, and create mountains of red tape for everyone involved, with no apparent benefit to anyone.

  7. Neuroscientist: know that this new interpretation of what constitutes of a clinical trial deems ALL experimental (rather than observational) studies on humans funded by NIH as clinical trials (whether they use fMRI or just behavior). This is because any task/instruction to the subject will be considered an intervention, and all outcomes that NIH funds are, by definition, “health related.”

    The outcomes for patients, researchers and science at large will be terrible.
    – Clinicaltrials.gov will be inundated with experiments that are not testing a method for improving health, that is, they are not really clinical trials, making it harder for the public to find real clinical trials. We will have people calling basic neuroscience researchers wanting to participate in their “trials” only to find out that our studies will not improve their memory, decision making, etc. This will lead to frustration with NIH and with science as a whole (on the part of the public), and a huge waste of taxpayer money.
    – Researchers will have to register basic science studies in advance with very limited ability to adjust them later based on findings of other basic science research. We will effectively be locked into wasting taxpayer dollars on research that is not good research, just because we put it in a grant proposal, possibly several years ago.
    – The paperwork and reporting burden will be significant, including adding new offices/staff to manage clinical trials in universities that may not have such an office as they previously did not have a medical school or run any (real) clinical trials…
    – Reviewers and study sections may employ different standards for “clinical trials” that will now be applied to basic medical science work. This means that, in neuroscience, instead of trying to understand the brain, we will be held to the standard of trying to improve it without even knowing how it works.

    That is, this new regulation will potentially decimate basic neuroscience research in humans, putting us years behind where we could be in understanding the brain and really treating neural disease clinically. Worse, it will make the public think that thousands of clinical trials are leading to no clinical outcomes, suggesting to them that medical science as a whole is faltering, and should not be funded. I do hope NIH will reconsider the implications and consequences of this decision.

  8. Case #18 is stretching the definitions NIH provides for (1) “intervention” and (2) “health-related biomedical or behavioral outcome.”

    1) “Intervention” is defined as a manipulation of the subject or subject’s environment for the purpose of modifying one or more health-related biomedical or behavioral processes and/or endpoints. Examples include: drugs/small molecules/compounds; biologics; devices; procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine, face-to-face interviews); strategies to change health-related behavior (e.g., diet, cognitive therapy, exercise, development of new habits); treatment strategies; prevention strategies; and, diagnostic strategies.

    It is clear that all these manipulation produce a long-lasting alteration of the body or behavior. I don’t think Case #18 fits this idea. Even if memories are changed, there is no long-term change in behavior after the experiment.

    2) A “health-related biomedical or behavioral outcome” is defined as the pre-specified goal(s) or condition(s) that reflect the effect of one or more interventions on human subjects’ biomedical or behavioral status or quality of life. Examples include: positive or negative changes to physiological or biological parameters (e.g., improvement of lung capacity, gene expression); positive or negative changes to psychological or neurodevelopmental parameters (e.g., mood management intervention for smokers; reading comprehension and /or information retention); positive or negative changes to disease processes; positive or negative changes to health-related behaviors; and, positive or negative changes to quality of life.

    Again, Case #18 does not fit with this definition. Participating in a memory experiment does not produce any effect on participant’s biomedical/behavioral status or quality of life. It does do not produce any long-lasting effect on their body or behavior.

    More generally, basic research that does not produce a long-lasting change on the body or behavior should not be classified as a clinical trial. The goal of these studies IS NOT to produce a permanent change. They are MEASURING the body or the mind, not CHANGING them.

  9. Applying these policies to psychopathology and other basic research studies as in case 18 will put an undue burden on such studies with no benefit that I can see. I think that the definition of an intervention has to be restricted to one that is designed to reduce or prevent symptoms rather than leaving it so broad as to include any manipulation that is designed to have some measurable impact on the participants.

  10. This onerous new requirement will indeed discourage investigators from proposing and carrying out the exact sort of creative, small-scale, physiological studies that have provided the crucial scientific background for actual clinical trials. I fail to see how this will help with the goal of making “findings … available to the public as soon as possible after the trial has concluded”. Instead, it will sterilize the very earth from which findings grow.

  11. I am a mid-career researcher with NIH funding to study basic mechanisms of memory in human subjects. I fully agree with the other commentators that this policy will cripple the research effort. The administrative burden will be immense and it is not reasonable to assume that additional funds will be available to cover this burden. I already spend too much of my time addressing the various arbitrary administrative burdens that are required to meet NIH regulations, none of which I feel have contributed meaningfully to the quality of my research. This new NIH policy will further disrupt the work of scientists by forcing us to spend our time and mental efforts working as pencil pushers. Every new administrative burden hampers innovation and harms the scientific enterprise by reducing our ability to devote our efforts to the research we were trained to perform, rather than paperwork. This new policy is also ignorant of the dominant trends towards open science and data sharing already at play in the field that it targets. Scientists are willingly and sensibly working together as a field towards open science, transparency, and accountability in a way that makes sense and will actually lead to a better research enterprise. This NIH policy does not have the collective experience of all investigators in the field to guide it, and therefore it will be a roadblock to innovation and will not improve the scientific enterprise or the public’s ability to use science discoveries. It will reduce them.

  12. The implication of case #18 is that almost all basic science behavioral research and experimental psychopathology research would be viewed misleadingly as a clinical trial – such research does not constitute a clinical trail in the traditional sense because there is no actual intervention and participants are not receiving a treatment. Adopting this policy will cripple research and constitute an injustice to research participants who will be consenting to participate in a clinical trial that doesn’t exist.

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