NIH Forms E clinical trials requirements - how's it going?

Have you had your first experience with submission of the new NIH human subjects attachments? Have you written the sections for a clinical trial application?  How did it go?

Since February, I have had the nightmare-inducing task of working on several applications that count as clinical trials under the new guidelines but would not have under the previous ones.  The amount of extra work involved in completion of the text fields and attachments is staggering. Considering that roughly 90% of submitted proposals will not be funded, that is a lot of extra time and financial burden to researchers and administrators.  I hope there are enough complaints from faculty and reviewers to catalyze changes that will minimize this burden.  Perhaps much of this information could be requested at the Just-in-Time stage instead of at the time of proposal submission.  It would save wasted effort and require only those investigators who truly have a chance at being funded to submit their clinical trial details.

New NIH human subjects requirements will encourage you to befriend statisticians

As if data science experts couldn't get any more valuable, NIH has given us one more reason to bestow chocolate, baked goods, lunches, and other gifts upon our statistician colleagues in order to remain at the top of their long lists of priorities. The new Statistical Design and Power attachment is required for NIH applications that propose a clinical trial.  In this section, you must include statistical power calculations and analysis plans for each Outcome Measure listed in the fields in section 4.3 of the human subjects form.

The Statistical Design and Power attachment must include the following for each outcome measure:

• number of subjects you expect to enroll
• expected effect size
• power
• statistical methods to be used

As you can imagine, it is virtually impossible to write this section well without the full involvement of a qualified statistician. Yes, much of this information will duplication what is included in the Approach section of your Research Strategy, but the attachment requires a more in-depth level of detailed explanation than is often included in the text due to space constraints. 

NIH forms E Human Subjects and Clinical Trials Information Form- Try this video before you bang your head against the wall

This video will show you all of the required fields on the new Human Subjects and Clinical Trials Information Form that is required of all Forms E applications as of January 25, 2018.  That's right- not only are there an obscene number of new attachments, but there are also required form fields that must be completed.  Some of this is repetitive of information provided elsewhere in the application, but some is not.  For example, be prepared to provide the date of enrollment of your first subject.
Eventually we will all get used to this, but right now it is a steep learning curve and the February R21 deadline is proving to be quite painful for many of us.  Hopefully by the time the next cycle rolls around, NIH will provide us with examples to help decipher what is needed in each section of the application.

Single IRB policy for multi-site trials

By Metropolitan Transportation Authority of the State of New York (Blizzard of 2015: Empty Grand Central Terminal) [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons

The new policy requiring a single IRB for multi-site clinical trials goes into effect on January 25th, 2018.  All of your IRB approvals will now need to be routed through one IRB that will serve as a central hub.  For details, including links to the many previous NIH notices regarding this change, visit this page.

Is my grant a clinical trial?

It can be very confusing to determine whether your project meets the NIH definition of a clinical trial.  Given the new Forms-E that will be effective starting with January submission deadlines, it is now more important than ever to correctly characterize your project. 
NIH has provided investigators with a useful tool in order to make this determination.  This series of questions will help you to ascertain whether your proposed project meets the NIH definition of a clinical trial, which will help to guide you as you complete all of the newly required Human Subjects attachments.

New NIH criteria for review of clinical trial applications

Beginning with the January 25, 2018 deadline, NIH will instruct reviewers to use additional criteria in the evaluation of grant applications that propose clinical trials.  The full policy change notice is located here.

The additional review criteria are as follows:

Significance
Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy?  For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Investigator(s) 
With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Innovation 
Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach 
Does the application adequately address the following, if applicable?

Study Design 
Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis 
Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Environment 
If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Additional Review Criteria

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?  Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Another video to help you through the new human subjects process

This 9-minute video guides viewers through the various components of the new human subjects form.  Some of this content may also be relevant to research administration personnel.  There is a lot to learn in order to comply with the new policy.

New NIH video to help with human subjects policy changes

NIH recently released a new video tutorial to help applicants understand and comply with the new human subjects research procedures.  These new guidelines will take effect in late January, so if you are planning a proposal submission for the February R01 or other spring and summer deadlines, you must comply with the new policy.  You can view the video here.

IRB approval does not protect you from unethical research projects

I was shocked to read this article about a study of premature infants at the University of Alabama-Birmingham.  The study examined outcomes such as blindness in premature infants who were provided with varying levels of oxygen.  This 5-year project found that infants who received higher levels of oxygen were more likely to become blind, while those receiving lower levels were more likely to die.  The reason that DHS is now crying foul is that the researchers provided parents with a consent form that failed to adequately inform them of the foreseeable risks of participating in the study.  My question here is why the researchers, and not the university's IRB, are taking the blame for this.  Isn't the point of an IRB committee to ensure that risks to subjects are properly explained?  Why call out the PI by name and tarnish the name of a researcher who appeared to do everything that was required? Every university and health facility where I have worked requires that consent forms are reviewed and approved yearly by an IRB board. In this particular study, 23 additional separate IRB boards and a Data Safety Monitoring Committee reviewed and used the same consent forms.  If these researchers had the necessary approvals and believed their study had been judged to be ethically appropriate, why not lay the blame on an IRB that appears to have dropped the ball?  Instead of being addressed to one researcher in particular, I think the more appropriate course of action would have been to address it to the head of the IRB and members of the review board. 

Training on Human Subjects Protections

Though most universities offer CITI or another type of human subjects training and certification, if you are located at a hospital or other institution, you may not have easy access to human subjects protection training. NIH offers a great training that is free and easy to access, located here. You do have to register, but it is free. What better place to obtain training than straight from NIH?

The Sissy Boy Experiment

The next time you complain about having to write a tedious human subjects section or fill out a lengthy and confusing IRB application, read this article. It will make you appreciate the protections offered to research participants today.