Understanding the FDA’s new proposed regulations on human subject research and their impact on your clinical trial plans

Can you provide links to the NPRMs and new draft guidance that were discussed in the webinar?

• NPRM on Cooperative Research: https://www.federalregister.gov/documents/2022/09/28/2022-21089/institutional-review-boards-cooperative-research
• NPRM on Protection of Human Subjects and Institutional Review Boards: https://www.federalregister.gov/documents/2022/09/28/2022-21088/protection-of-human-subjects-and-institutional-review-boards
• Draft Guidance, Ethical Considerations for Clinical Investigations of Medical Products Involving Children: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ethical-considerations-clinical-investigations-medical-products-involving-children

Can you provide a link to the webinar recording?

You can access the WCG webinar recording at the top of this page.

Are the NPRMs open for public comment?

The NPRMs were open for public comment through December 15, 2022.  Comments that were submitted can be viewed here: 

• NPRM on Cooperative Research: https://www.regulations.gov/docket/FDA-2019-N-2175
• NPRM on Protection of Human Subjects and Institutional Review Boards: https://www.regulations.gov/docket/FDA-2019-N-2175
• Draft Guidance, Ethical Considerations for Clinical Investigations of Medical Products Involving Children:  https://www.regulations.gov/docket/FDA-2022-D-0738

Could the final regulations and/or final guidance have content that was not in the proposed regulations/draft guidance?

Yes, that is possible, although FDA would generally try to have all the changes they foresee in the NPRM or in a draft guidance so that they can get public comment. There may be changes made as the result of those comments as well.

What is the anticipated timeline for these requirements to become final?

It is very difficult to anticipate the timeline for these requirements to be final. It may be a year or so, or it might take several years. When they are released, there will be time provided for affected parties to review the final requirements and prepare for them.  For the NPRM on Cooperative Research, the proposed effective date will be 1 year after the final rule is published in the Federal Register. For the NPRM on Protection of Human Subjects and Institutional Review Boards, the proposed effective date will be 180 days after the final rule is published in the Federal Register. There is also the slight possibility that FDA will decide not to move forward with these requirements.

Would these requirements apply to studies already in progress?

When issued, they will not apply to studies already in progress. They will only apply to research initially approved by an IRB on or after the proposed effective date.

Do these new proposed elements also apply to consent in healthy volunteer studies?

Yes.

Is there more information available about what should be included in the key information section?

To date, there is no formal guidance on this topic. We hope that the Office of Human Research Protections (OHRP) and FDA will issue guidance to assist in the consistent interpretation of these regulations.

Will the sample consent form template on the WCG IRB website be updated to include this section?

The sample consent form template on the WCG IRB website already includes guidance for including a key information section. It was added when this became a requirement for studies regulated under the Common Rule and has been encouraged for FDA-regulated studies since then, as we knew that the harmonization of requirements was coming eventually.

Are there any drawbacks to sponsors making these changes to their informed consent templates now, even though they are not required?

No. The new proposed requirements do not contradict any existing requirements. Studies regulated under the Common Rule already require key information sections in their consent forms, and some local IRBs apply this to all research they review, so sponsors may already be encountering sites where this is a requirement.

Does this apply just to the use of specimens (blood or tissue samples) or to the data that may already have been obtained from analysis of those specimens?

It applies to both the specimen (and future analyses) and any data which has already been obtained.

How detailed does the statement about future use need to be?

That is unclear.  Hopefully FDA will release guidance on its expectations in this regard if it decides to adopt this language

What if the samples have been de-identified?

If the samples have been completely de-identified so that they are truly anonymous and cannot be linked back to any individual participant or their medical history, this does not apply.

Is the new proposed required language still required if you use a separate biobanking consent form?

The main study consent and the biobanking/ future use of specimens can be two separate documents- it will not be required that you cover future use of specimens in the main consent if you have a separate form for that.  But that if new language is required that would still have to be in that separate form.  That is, having a separate biobanking form would not be a way to get around this language requirement.

How does this requirement overlap with HIPAA obligations?  If PHI is being used for research, IRBs must stay open due to the minimal risk to the subjects. Does that change with these?

HIPPA regulations and the FDA regulations are separate.  Therefore, any requirements of the HIPAA regulations would have to be met regardless of the FDA regulations not having the same requirements.  If the IRB needs to keep a study open for compliance with HIPAA requirements, it will need to do so regardless of the fact the study could be closed under the FDA regulations.

If participants are in a follow-up phase and not undergoing any study procedures but long-term collection of SAEs is continuing, can IRB oversight be closed out?

If the information still being collected would be information gathered in the course of normal clinical care, then IRB oversight can be closed.  If the information is in addition to normal clinical care, or if the investigator collecting the information is not someone who would normally have access to the information (e.g., the investigator is a specialist who is no longer seeing the participant to provide clinical care), then IRB oversight should continue.

Are a “single IRB” and “central IRB” the same thing?

Effectively, yes.  “Central IRB” has tended to be used to refer to an independent IRB that provides review for multiple research locations that do not have their own IRB (research facilities, private physician practices, etc.).  “Single IRB” seems to be the preferred term to indicate that one IRB would have oversight for multiple study sites regardless of whether those sites have their own IRBs.  But in practice they are the same thing.

What if the local IRB refuses to cede review to the single (central) IRB?

If the local IRB refuses to cede review, the site will not be able to participate in the research study.

Can our local IRB still require us to submit the protocol to them for review in addition to the single IRB review?

They can.  Local IRBs or institutions can put any additional processes, approvals or reviews on top of the process of single IRB review.  If there is a single IRB, though, the local IRB review will have no regulatory standing; there cannot be two IRBs overseeing the same study/site.  Even if the local IRB disapproves the protocol, if the single IRB has approved the protocol, the research is IRB-approved.  While the Human Research Protection Programs (HRPPs) or research administration of institutions may add some additional processes or checks (ensuring coordination with budget and contract offices, requiring approval from other institutional departments that will contribute resources, etc), it is hoped that processes will not be so duplicative that they contradict the purpose of reducing administrative burden the single IRB requirement is intended to achieve.

Will local IRBs disappear if the Single IRB requirement goes into place?

Maybe, at some small institutions that do a lot of FDA-regulated research.  But at most institutions, probably not.  Especially at larger institutions, there is still a lot of non-FDA-regulated research, unfunded investigator-initiated research, student research, and other research that requires oversight.  The local IRB may have training, quality assurance and other functions as part of the overall Human Research Protection Program (HRPP) at the institution that remain important.

Will a reliance agreement between the local IRB and the Single IRB be required?

We believe that FDA will still expect that there be a reliance agreement between the institution where the research is conducted and the single IRB.

Will the Single IRB mandate apply to IND and IDE- exempt studies?

As currently written, no.  These are an exception to the requirement.

Would the Single IRB requirement apply to ongoing studies that are already approved at multiple local IRBs?

No.  If this becomes a requirement, there would be a period of time before the requirement becomes effective for new studies, and ongoing studies would not be impacted. 

What ages does “children” or “pediatrics” apply to with respect to this guidance?

In this context, as defined in the federal regulations, “Children are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted.” In most cases this means 18 years of age although there may be exceptions in some states where the age of consent is different from 18, or in certain medical situations where state law allows minors to consent to specific types of treatment without parental permission (e.g., treatment of sexually transmitted infections). 

Please note that this is different from the age cohort distinction of neonates/ infants/ children/ adolescents that CDER uses for pediatric drug legislation, which is intended as a biologic/ scientific distinction.

Is the implication of these requirements that research in healthy children can never be more than minimal risk?

In many cases that is correct, but there are possible situations where there can be a prospect of direct benefit to healthy children.  For instance, the inoculation against an infectious disease through an experimental vaccine could be justified as providing the potential for direct benefit to children who are currently healthy.

If more than minimal risk procedures cannot be allowed in a placebo arm, how does that correlate with the FDA’s requirements for a “well-controlled trial”, which often means a placebo control?

This is an ethical dilemma, where the competing demands of providing appropriate protections for children conflicts with the need to conduct well-controlled clinical trials.  The resolution of this dilemma will be very case specific, and alternative appropriate trial designs will need to be considered.

If the protocol specifies that participants in the placebo arm roll over to open label administration of study drug at some point in the trial, would component analysis allow for greater-than-minimal-risk procedures to be performed during placebo phase?

This is very much an “it depends” situation where there is no specific guidance.  If the blinded period were only a few days to a couple of weeks, and the procedures were a minor increase over minimal risk, an IRB might be comfortable that all the participants getting placebo would reach the study drug phase, and thus they might be comfortable approving the study.  If the blinded period is several weeks or months long, and/or included multiple or riskier procedures, it would be more difficult to find that study approvable, in part because the participant may not be in the study long enough to get to the study drug phase, and then they’ve had the risks with no direct benefit.  If the open label roll-over is promised but not actually submitted as part of the review (e.g., “an open-label cross-over extension is planned” or “will be submitted”), it cannot be considered a potential direct benefit.

How does the minimal risk/more than minimal risk versus direct benefit assessment relate to whether the signatures of one or two parents are required?

Under 21 CFR 50.55(e), “Where clinical investigations are covered by § 50.53 or § 50.54 and permission is to be obtained from parents, both parents must give their permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child.”  In other words, if the IRB approves research with no prospect of direct benefit and more than a minor increase over minimal risk, then the signatures of both parents are required, with certain exceptions.

For the assent process, does the FDA require the assent to be obtained on a separate document or can the minor sign on the main informed consent document/ parental permission form along with the parents?

The FDA does not specify how this should be handled or documented and leaves this up to the IRB to determine.  The sponsor/ researcher can certainly suggest an assent/ parental permission process that would be feasible and would be appropriate based on the physical and/or developmental age of the pediatric participants.  For older adolescents, it may make sense to collect a signature on the same document as the parent.  For younger children who could not read at the grade level of a parental permission form, having them sign a form they can’t read or understand would not be appropriate, and if documentation of assent is required, a simple form at their reading level is more appropriate.

How does this new guidance affect single-patient expanded access/ compassionate use in children?

It should not affect single-patient expanded access at all.  In expanded access (which is not considered research), the patient is always getting the investigational agent, so there is the prospect of direct benefit. 

Will the medical review divisions of FDA be considering component analysis as part of the review of protocols when they are submitted to INDs? The conundrum created is that the requirement for potential for direct benefit incentivizes the design of single arm studies with no placebo, which is a less scientifically strong study design.

Yes, we agree that that is a conundrum.  We hope that the medical review divisions will consider the component analysis requirements when discussing potential study designs with sponsors and when reviewing protocols submitted to INDs, or that they will consult with the pediatric ethicists within FDA on these issues.  We have seen some difficult situations where a study design has been agreed upon between the sponsor and the FDA reviewing division, but the IRB cannot approve it as designed.

If a procedure or intervention fails the 21CFR50.51-53 review, is special review required for the entire list of procedures or only those which have failed?

The review would most likely focus on the acceptability of the procedures that were more than minimal risk, but the entire protocol will be considered.

If a study has to go to 21CFR50.54 special review, what is the timeline?

There have not been enough examples of this situation to provide a very good estimate of the time; in the example discussed in the webinar, it was about 8 weeks from the referral of the protocol to FDA for 21CFR 50.54 review to a full, in-person Advisory Committee meeting (in 2017).  The shift to virtual or partly-virtual meetings over the last few years may help to compress this timeline.