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Implementing a New Human Subject and Clinical Trial Information Form

We have been talking a lot recently about NIH’s efforts to improve transparency and trust in NIH funded clinical trials. One important aspect of this effort is improving our ability to identify and describe the clinical trials we are supporting. In fact, a March 2016 GAO report GAO-16-304, entitled Additional Data Would Enhance the Stewardship of Clinical Trials across the Agency, highlighted the fact that “NIH is limited in its ability to make data-driven decisions regarding the use of its roughly $3 billion annual investment in clinical trials.” Many of the other aspects of this initiative, applying clinical trial specific review criteria, improving oversight, and registering and reporting in ClinicalTrials.gov depend upon our basic ability to identify and describe clinical trial applications and awards.

The new PHS Human Subject and Clinical Trial Information form will flag trials, helping us to achieve a number of goals. The form consolidates into a single location information on human subjects that is currently scattered across a number of forms. It allows us to capture structured and semi-structured descriptive information for each study included in a grant application or contract proposal, which will allow us to clearly identify which funded studies will require registration and timely reporting of results.

Each study record requires a minimum number of requested data elements. This starts with leading the applicant through the four questions that determine whether the study is considered by NIH to be a clinical trial. (See our August 11 post, 4 Questions for Researchers and Institutions Involved in Human Subjects Research for more on the NIH definition of a clinical trial.) The answers to those questions will determine whether or not the applicant will need to complete Section 4 of the form, the “Protocol Synopsis.” The form will help in peer review and will enable NIH to answer important questions, like how many clinical trial studies we are funding, the phase of those trials, and how many have as their primary purpose treatment evaluation or fundamental discovery.

Some information collected in this form is information that you likely would have included in the application elsewhere, either in the protection of human subjects attachment or in the research strategy. Now we are capturing that information in a structured format, which supports better monitoring of the studies by NIH staff after award. It also serves the purpose of leading the applicant or contractor through each of the elements we expect them to consider as they are planning for their grant application or contract proposal, which we expect will make for stronger applications. Collecting the protocol synopsis, study population characteristics, recruitments plans, and plans for statistical design and power in one place will also allow reviewers to more easily locate and evaluate these critical elements. For delayed onset studies, those studies for which the details are not known at the time of application, grantees will submit this information to NIH through the eRA Commons once it is known.

One question we are often asked is whether the information collected in the new form will be duplicative of the information provided in the research strategy. That is not our intent. The form allows you to spell out methodological details in the study record, allowing more space in the research strategy for higher-level descriptions and justifications of your experimental design(s) and methods.

A key element in the design of the form is that we were careful to be consistent with the data elements required for Clinicaltrials.gov reporting, which will help with data reuse and exchange between systems.

If you haven’t seen the new form, we have a 9 minute video external link icon that will guide you through and give you a good idea of how it works. The form will be included as part of the Forms-E application packages, which you will be required to use for all grant applications submitted for due dates on or after January 25, 2018. You will see the form associated with funding opportunity announcements as early as the very end of October/early November.  We expect to make the PHS Human Subjects and Clinical Trial Information form available for Requests for Proposals for contracts posted as of January 25, 2018 as well. We recently published the instructions for FORMS-E (HTML/PDF) if you want to take an early look.

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25 thoughts on “Implementing a New Human Subject and Clinical Trial Information Form

  1. I appreciate the overview to the new E-forms and the new clinical trial content that will be required.

    There are a couple of questions that I have.

    1. There appear to be various places within the new E-forms that allow for copy-n-paste of information into text dialogue boxes. The information requested, such as 4.1 Brief Summary (5,000 characters) or 4.2.a Narrative of Study Design (32,000 characters) ask for information that will likely require the use of citations/references. Will the copy-n-paste into the E-form retain the formatting of references, such as superscripting of numerical references?

    2. Now that the study timeline is a separate attachment (2.7), will it be sufficient within the standard 12 page R01 research strategy or 6 page R03/R21 research strategy to simply indicate “see Study Timeline Attachment”?

    3. Where a maximum length of characters is mentioned for content, does this include or exclude spaces?

    I am certain I will have more questions as I continue to go through the new E-forms in greater detail, but I appreciate any info on the questions above.

    • Good questions!
      1- We are doing testing now to verify how the form will handle different character types. We will be sure to add the question and answer as an FAQ.
      2- The research strategy should tell your overall story. You can point to the human subject form for the details of the timeline.
      3 – Yes, spaces are counted in character count limits.

      • Thank you for the quick reply.

        To follow up on my question and the answer regarding the timeline, could the same be said for many of the other materials asked for within the new E-forms?

        For instance, Section 2.2 Eligibility Criteria, Section 2.5 Recruitment and Retention Plan, Section 4.2.a Narrative Study Description, 4.2.c Intervention description, Section 4.3. Outcome Measure Description, and Section 4.4. Statistical Design and Power uploads?

        These appear to be items/information that would routinely be within the Approach section of the standard research strategy. Thus, with the new E-forms, can an applicant simply indicate for reviewers to see the new attachments?

        This would allow for more space to be dedicated to Significance and Innovation.

        Any advice with this is appreciated.

        • Yes. I encourage you to read the form instructions. The FORMS-E instruction for the Research Strategy indicates:

          “Note for Applications Proposing the Involvement of Human Subjects and/or Clinical Trials:

          – Use the Research Strategy section to discuss the overall strategy, methodology, and analyses of your proposed research, but do not duplicate information collected in the PHS Human Subjects and Clinical Trials Information form.

          – The PHS Human Subjects and Clinical Trials Information form will capture detailed study information, including eligibility criteria; inclusion of women, minorities, and children; protection and monitoring plans; and statistical design and power.

          – You are encouraged to refer to information in the PHS Human Subjects and Clinical Trials Information form as appropriate in your discussion of the Research Strategy”

          • Thanks Mike for the quick reply.

            I have been reading and keeping up to date on these new developments and still am confused about the non “duplicate information collected in the PHS Human Subjects and Clinical Trials Information form”.

            It seems to me that all the info asked for in the E-forms would have typically appeared within the research strategy.

            Thus, if one can point to the E-form for the Timeline, then why not for the duplicate info asked regrading analysis, power, inclusion/exclusion, etc…?

            Again, any clarification you can provide is appreciated.

            Thanks.

          • I’m still waiting any additional information Mike might be able to provide regarding my previous question.

            Thanks for your time.

  2. Hello Mike- I’m speaking here from the experience of currently dealing with 3 separate clinical trials under the current definition. I would make several observations.

    1. There’s a misconception that the online system is easy to deal with and the reporting requirements are not burdensome. This is not the case. The system is balky, very time-consuming & reporting on the primary and secondary aims is both counter-intuitive and frustrating. Online support is not especially helpful.
    2. IMHO, extending the definition of a “clinical trial” to routine cognitive and neuroimaging experiments as is proposed , makes an existing problem far worse in terms of time spent dealing with unnecessary reporting requirements.
    3. The rationale provided for expanding the scope of what constitutes a clinical trials seems dubious at best.

    Thus I would urge the responsible officials at NIH to really think hard before moving forward to implement these new proposed regulations. I don’t think that anyone will be helped by adding these new rules.

  3. Another form means more time and energy spent by the proposer. Why should the research scientists / clinicians have to spend THEIR time on it? Surely the NIH can hire someone to go through the grant proposals that involve clinical trials and complete the form?

  4. It looks like that NIH is trying to make clinical trials more and more complicated without mentioning the FDA requirements. This has been reflected at the grant review study sections. The study sections allow the reviewers to state that “we want you to do xxxx although the FDA does not require them”. As I am aware, there have been communications, meetings and training as collaboration between the NIH and FDA to emphasize the FDA requirements for clinical trial projects on different products and studies. Given the funding limits for clinical stage research, for effective translation, NIH should enforce on clinical trials to follow the FDA requirements and the extra non-essential components should be optional.

  5. The entier idea is very poorly thought out. It is rooted firmly in ignorance of different types of research that is carried out by NIH grantees. I am convinced that individuals who come up with the guidelines of ‘What is a clinical trial’ have backgrounds in very limited areas, and hence have no idea how this will impact research in various fields. This will significantly harm basic research. Completely non-clinical, basic research cognitive studies have been included by an overly broad definition of ‘clinical trial’ that reeks of ignorance. Here are a couple of examples:

    – You take some healthy individuals, put them in an MRI scanner, show them some stimuli like words or pictures, and measure their brain activity. Then they go home. You are trying to learn something about different brain areas. There is no actual ‘intervention’, there is no effect on the participants. This is called a ‘clinical trial’. This would appear to be a joke, but it is not.

    – You take some stroke patients, have them do a behavioral task like lexical decision or picture naming. You are trying to learn what sort of impairments these patients have. There is no therapy, or treatment, there is no attempt to change or improve their behavior or symptoms. They are also clearly told that this is not therapy or treatment, and will not help them directly. They volunteer of basic research. There is nothing ‘clinical’ about this at all. This is again not an ‘intervention’, but this is called a ‘clinical trial’. It is silly, wrong, and harmful.

    – You take healthy participants, apply rTMS on a brain areas for 10 min. This will mildly affect the brain area for about 10 min. During those 10 min. you have them do a behavioral task like reading words or naming pictures. You measure the reaction time or accuracy. The effects disappear in 10 min, and subjects go home. This is a very common and safe procedure that has no clinical aspects to it. Again, it is silly to call this a ‘clinical trial’.

    This ill-thought-out, overly broad definition of ‘clinical trials’ will do tremendous harm to basic cognitive research that has nothing to do with anything clinical.

    • You may not fully understand how NIH is applying the definition of a clinical trial. Observational studies are not trials. You may want to look at our case studies and FAQs. In particular, look at case study #18. Applying case study #18 to your examples, we can see that neither the first or second example would be considered clinical trials. We would need to know more about the third example to make a determination.

      • But, if the example quoted below included making the words more difficult (or easier) to process, by using homophones, or making faces easier or more difficult by using different views / faces in shadows, would that not be a clinical trial now?

        “You take some healthy individuals, put them in an MRI scanner, show them some stimuli like words or pictures, and measure their brain activity. Then they go home. You are trying to learn something about different brain areas. There is no actual ‘intervention’, there is no effect on the participants. This is called a ‘clinical trial’. This would appear to be a joke, but it is not.”

        • We would still consider that an observational study with some kind of measurement (like measuring blood pressure). See case study 18B.

          • Thank you for that reply. From your comment, it sounds like showing faces from different angles (shading, etc) to modulate people’s ability to recognize them, while measuring brain activity in an fMRI scanner, would not be a clinical trial.

            If instead, say, you taught people (fictional) names for the faces and looked at their behavioral performance and face system activation before vs. after, would that be a clinical trial? (i.e., hypothesis would be that the face processing system becomes more active after you know a name associated with a face).

            Thanks in advance.

          • We recommend you, and others with related questions, to ask your NIH program official for guidance on whether your specific research project would be considered a clinical trial.

          • “We recommend you, and others with related questions, to ask your NIH program official for guidance on whether your specific research project would be considered a clinical trial.”

            This is meant to be a place to receive answers. I understand that this will differ between studies, but this is supposed to be a place that others can come to and find out answers – with an opaque response like this, you are just increasing the e-mails to program officers as dozens, if not hundreds, of grant applicants all ask a very similar question. If the actual reason is that you are not sure of the answer, I think that is telling.

          • The second study you briefly described would likely be considered a clinical trial under the new definition, including considering the intervention involved. An “intervention” is defined by the policy as a manipulation of the subject or subject’s environment for modifying one or more health-related biomedical or behavioral processes and/or endpoints. Further, we still feel it is important to include the program officials in making these determinations to ensure everyone involved in the grant application is on the same page.

  6. I agree with Godfrey, Philip, HYF, and let’s face it, the whole research community – the system is extremely burdensome for clinical trials, as it stands. While the goals of increasing clinical trial transparency is a worthy one, the solution of extending the definition of clinical trials to include a huge portion of non-clinical-trial studies makes no sense whatsoever.

    Real clinical trials will get buried among the experiments that no member of the public or researcher would ever consider a clinical trial. I have several intro textbooks on my shelf for psychology and neuroscience – if the administrators were answering the multiple choice questions in these books on whether a given example is a basic research experiment vs. clinical trial, they would get those questions wrong according to the textbook’s answers and from judgment of every researchers in the field. I admit, that part of me wonders if this is somehow driven by a broader push of the current administration to ignore expert opinion. There is something wrong when first year students, textbooks and the public understand and agree on what a clinical trial is, while the NIH does not.

    But, independent of disagreements of definitions, researchers will get bogged down in these cumbersome forms, and members of the public and researchers will find it more difficult to find information about clinical trials that matter. A good way to hide something is to bury it – the opposite of transparency.

  7. I am testing the new Forms-E Clinical Trial dialogue boxes where an applicant has to copy-n-paste information regarding the Eligibility Criteria (Section 2.2, 15,000 character limit) and other dialogue boxes.

    I am finding that the online dialogue boxes will NOT allow commonly used characters. This include quotes (“”) or dashes (–).

    When I include such characters I get the following error message:

    “The input text contains characters not supported by NIH. To avoid this issue, do not cut/paste from word processing documents into the form fields.”

    This is only two instance I have identified within a few minutes of attempting to use the forms.

    With information spanning up to 32,000 characters, the ability to identify these issues and any others is unlikely.

    Based on the error message, NIH appears to think that investigators should draft their research components within the online forms. This seems unreasonable.

    Also, the dialogue boxes do NOT allow for tables or figures to be included. These are commonplace and essential components in all grant applications where investigators describe numerous, and often complex, aspects of their study. Is the NIH now not allowing this important information in applications to help reviewers understand study features?

    Any clarity on these issues is appreciated.

    • Thank you for your comment. We have add a new resource to our application guide, Rules for Text Fields that provides information that I think you will find helpful.

      Here is an excerpt from the page that addresses the two specific issues you called out:

      “The standard character set for our application forms is Unicode, with UTF-8 encoding (including Greek and other special characters).

      Characters known to cause issues and recommended substitutions
      o “Smart quotes” or “curly quotes” that curve into your text – use straight single and double quotes (the ones you type from your keyboard) instead.

      o “Em-dash” (the long dash) – use the short dash instead.”

      We encourage you to look at the rest of the page for additional tips that may be of use.

      • Thanks for the clarification. I have been testing the forms as well and run into the same problems. I was wondering if you could provide some clarity on why the fields are text boxes instead of attachments. It seems that by simply allowing investigators to upload an attachment for the Brief Summary and Narrative Study Description would circumvent these issues. Further it would allow investigators to include tables and figures in their narrative description.

        • We very much appreciate your feedback. We know some fine tuning will need to be done to the form the next time we update our application forms. Whether the longer text fields would be better as attachments is certainly something we can consider. One of the considerations will need to be the implications for our ability to exchange information with ClinicalTrials.gov.

      • I appreciate your reply, but am still confused by the entire process.

        First – the help page indicates “…use straight single and double quotes (the ones you type from your keyboard) instead.”

        If I am copy/pasting from a Word document, then naturally I am using my keyboard to type. Thus, the reference to straight or curly quotes and using your keyboard is nonsensical.

        Second, apostrophes, such as in participant’s, are also identified as an error.

        Third, if original formatting is lost in the text boxes, this is highly problematic for several reasons. One, the use of selective bolding or underlining is essential to refer to important content for the reader. If bolding or other formatting is NOT important, then it would NOT be used on the NIH’s help webpages to make reference to subject headings, etc…

        Overall, this makes drafting, submitting, and reviewing all the harder to do.

        Allowing attachments seems much easier and would fix all these problems.

  8. A solution appears to already exist within NIH’s existing online interface.

    Specifically, the summary/abstract (30 lines) that’s submitted as a PDF attachment within the to-be-phased out forms package is somehow transferred into text boxes that populate NIH Reporter. Also, the same 30 line summary also populates summary statements received from reviews.

    Thus, if attachments can be translated into text that pre-populates other information, such as in summary statements and NIH Reporter, it would seem that the same could be done in the FORMS-E to replace the copy-past issues for the extensive information asked for (e.g., 32,000 character description).

  9. It’s not clear if behavioral interventions need to be classified in phases under the new system. The new SF424 application guide for the Human Subjects and Clinical Trials Information form links to this definition for determining study phase – https://prsinfo.clinicaltrials.gov/definitions.html#StudyPhase – which indicates that behavioral trials are not phased. However, the same page of the guide also links to this definition, which suggests that they are – https://grants.nih.gov/grants/glossary.htm#NIHDefinedPhaseIIIClinicalTrial Could you clarify this? Thanks.

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