Matters Related to Protection of Human Subjects and Research Considering Standard of Care Interventions Tuesday, October 20, 2015
Hubert H. Humphrey Building, Great Hall
9:00 a.m. – 10:30 a.m.
Wanda K. Jones, Dr.PH
Principal Deputy Assistant Secretary for Health
U.S. Department of Health and Human Services (HHS)
Introduction of Panel
Jerry Menikoff, MD, JD
Director, Office for Human Research Protections (OHRP)
Jerry Menikoff, MD, JD
Julie Kaneshiro, MA
Deputy Director, OHRP
Ivor Pritchard, Ph.D
Senior Advisor to the Director, OHRP
Julia Gorey, JD
Senior Policy Analyst, OHRP
Questions Submitted in Advance
Julia Gorey (Questions Submitted in Advance)
East Carolina University (Greenville, N.C.)
American Association for Dental Research
Dana-Farber Cancer Institute
Moses & Singer LLP
National Academy of Sciences
Chelsea Rutherford, JD, MS
Julia Gorey (Questions Submitted in Advance)
Julie Kaneshiro (Questions Submitted in Advance)
Mary Jane Welch DNP, APRN, BC, CIP
Rush University Medical Center
Julie Kaneshiro (Questions Submitted in Advance)
Deana Around Him, DrPH, SciM
National Congress of American Indians
Lisa Nichols, Ph.D.
Council on Governmental Relations
Ivor Pritchard (Questions Submitted in Advance)
12:00 p.m. – 1:00 p.m. Lunch
1:00 – End Audience Q and A
Questions Submitted in Advance
Ivor Pritchard (Questions Submitted in Advance)
Heather Pierce, JD, MPH
Association of American Medical Colleges
Rush University Medical Center
Jerry Menikoff (Questions Submitted in Advance)
Elisa Hurley, Ph.D.
Public Responsibility in Medicine and Research (PRIM&R)
Julia Gorey (Questions Submitted in Advance)
Ivor Pritchard (Questions Submitted in Advance)
Jennifer Renn, Ph.D.
Center for Applied Linguistics
Julia Gorey (Questions Submitted in Advance)
David Borasky, MPH, CIP
Wanda K. Jones, DrPH
MODERATOR: WANDA K. JONES
WANDA K. JONES [OPENING REMARKS]:
Ladies and gentlemen, if you would please take your seats, it is nine a.m. and we are ready to get started.
Welcome! In case you didn't know where you are, you are in the Hubert H. Humphrey Building, Headquarters of the U.S. Department of Health and Human Services, for the public meeting on the Common Rule with comments, questions that you all are empowered and enabled to ask today. So thank you for taking time to be here, for having registered, for coming and sitting and for planning to spend whatever part of the day you are able to spend with us.
Please note this meeting is being recorded live and broadcast via webcast. We will archive a recording of this meeting at a later date on OHRP's web site.
The proceedings will be added to the NPRM rulemaking record, so as I said, the purpose of this meeting is for OHRP, HHS agencies and other Common Rule departments and agencies to provide responses to questions from the public about the NPRM in order to clarify what the NPRM has proposed and to better inform public comment on the proposed rule. Those of you in attendance today will be able to ask questions throughout the day, and the public was also invited to submit questions in advance of the meeting, so we have those that we will tend to throughout the day as well.
So let me pause for a second and let you know who I am. I am Wanda Jones, Principal Deputy Assistant Secretary of Health here at the Department of Health and Human Services in the Office of the Assistant Secretary for Health where OHRP and 11 other offices reside.
If you have a Blackberry, IPhone, IPad, Blueberry, Strawberry, Raspberry, please put it on vibrate so we can keep our attention focused on what is said in the questions and what's said in the responses.
And you will see shortly that we will have a panel of HHS officials who will be speaking on behalf of HHS only.
My sole job here is to moderate and keep the trains running but we also have in the front row federal government officials who have been come today to be available if need be to respond when they're able to respond to questions that are directed at their agencies. But please note, some departments, some agencies have rules that actually do not permit their officials to make any sort of public response during an open comment period. So, those individuals will need to just apprise us of that we will just have to try to defer those questions as we get to them.
The majority of the meeting is indeed focused on responding to questions that have come in from the public and some of the responses to questions received in advance might be answered in a more general or in an aggregated fashion, particularly if more than one question was getting to the same point and the same issue.
The panelists will do their best to respond to all of the questions, but the audience is advised that panelist responses will be necessarily simplified and that the full NPRM should be referenced for a complete and fully accurate description of the proposed changes.
The Department has not made any decisions on the contents of the final rule, the comment period remains open. We have been asked about extending that deadline, but for now the deadline for submitting comments remains unchanged: December7th, 2015. Should there be an extension made to the comment period, we will make a public announcement to that effect.
So, let me turn now to our HHS representatives and to Common Rule agencies, and don't we have someone from OHRP volunteering to walk a hand-held mike, because we would like folks to be miked because we would like them to introduce themselves, who they are, where they are and who they're representing.
Irene, thank you.
There's Dr.Irene Stith-Coleman, if you haven't met her previously we will start here.
Good morning, I'm Victor and I represent NASA.
Good morning, I'm Anne Andrews and representing Department of Commerce.
Hello, I’m Toby from the U.S. Environmental Protection Agency.
Hi, I'm Tom Puglisi from the Department of Veteran's Affairs.
VA is extremely interested in hearing public comments on the rule, and we encourage you to submit your comments so that we can have an informed discussion with HHS going forward about the content of the final rule. Thanks very much.
My name is Carrie and I’m representing the National Institutes of Health, and we are also very interested in hearing from all of you about what is really one of the most exciting science policy developments in the past several decades. I think it's very exciting to see the long overdue evolution of human subjects protections, particularly moving towards more of a participatory model of research in which research participants are active engaged partners, which is something of course NIH is trying to do in our precision medicine initiative, and I want to take the opportunity to make a plug for some upcoming stakeholder engagement sessions on the Common Rule sponsored by the NIH Clinical and Translational Science Awards Program.
There are going to be three upcoming meetings, October28th in San Diego, November5th in Chicago, and November18th in Philadelphia and if you go to ctsacentral.org you can find out more about those meetings, and I look forward to hearing from all of you today and as we move forward.
Hello, I’m Nicole from the Department of Homeland Security, and my colleague Anneke Baran is here in the audience.
Hi, I’m Libby White, from the Department of Energy, and I want to add to the comments of the other agencies. I look forward to hearing your input and questions.
Alice Taylor with the Consumer Product Safety Commission. We're one of the much smaller federal agencies, but still one of the Common Rule agencies.
Good morning, I'm Joanne from the Office of Good Clinical Practice at the Food and Drug Administration. On behalf of FDA, I’d like to welcome you to the meeting. Just to echo what other agencies said, we really are interested in your comments.
Just to give you background, FDA has been involved in the rulemaking effort with the other agencies. We will continue to participate in that process, and we will also be engaged in our own rulemaking effort, so I just want to make sure that you all consider our regulations when you develop your comments on the Common Rule, because we will be doing a parallel rulemaking effort.
And people have asked that question along the way as to what FDA's intent it, because in the preamble, there are parts where it says it does not apply to the FDA, so we just wanted to make sure everyone know that we intend to harmonize, we recognize the importance of harmonizing across the federal agencies, we just want to make sure we're not duplicating or causing unnecessary burden. Thank you.
Hi, I’m Pat McNeilly, also with the Food and Drug Administration, and welcome to you all.
MODERATOR: WANDA K. JONES
WANDA K. JONES:
Thank you all very much.
We do look forward to an exciting conversation throughout the day as those of you in the audience bring your questions, as we think about, as we generate our responses, and then as we move forward throughout the entire process.
Someone just asked, we're not quite full, we had about 200 or so folks registered and we're not quite at that number, but as your first point of exercise this morning, raise your hand if you're intending to ask a question today so we can get a general sense? Be bold, come on, stick that hand up in the air, it may be the only exercise you get for a couple of hours. I count, one, two, three, four, or five right now, okay we're expecting that to grow a little bit but, that's great because we are intending to run this meeting until 5 o’clock o make sure that opportunity to anyone who has an interest in asking a question, but if we run out of questions including those that submitted in advance we will give everybody back free time. Sound like a deal?
Okay, so without further ado let me introduce my colleague and friend Dr.Jerry Menikoff, who is the Director of the Office for Human Research Protections here in the Office of the Assistant Secretary for Health and for the Department of Health and Human Services. Jerry has been the principal steward, backed by a phenomenal team within OHRP. You saw Dr.Irene Stith-Coleman earlier, Julie Kaneshiro is sitting over there, Dr.Ivor Pritchard, and Dr.Julia Gorey and Kristina Borror, and in the back Dr.Yvonne Lau, so there are many others likely but those are the ones that you test me on that I remembered their names and saw them here this morning.
But thank you for the work you have tirelessly to move and update the ANPRM process and now to the NPRM process as we move forward to our December closure date and then steps beyond that.
So Jerry without further ado, thank you to you and your team, and your timer will be running.
Irene gets to play the heavy. Okay?
Thank you so much, Wanda.
It's a pleasure to be here, I want to back you up in terms of thanking the OHRP staff, who have been working on this document and its precursor for many years now, and to the extent it does good things, again the credit is due to all the people at OHRP and all the other people throughout the federal government and the public who worked together in terms of moving us forward to where we are now. Thank you to everybody here for coming to the meeting.
My welcome to everybody out there watching us on the web or down the road on the archive.
I hope you enjoyed participating in this process and if nothing else, it's also educational, so what I’m going to do is I’m going to give a brief overview of what the NPRM is trying to do in terms of major provisions. I'll also note we've been discussing along this point other sources that are out there in terms of learning about it. There are three hours of webinars that you can find on the OHRP site, and what I will be talking about now, the overview, pretty much overlaps a great deal with one of these webinars there, so you may be hearing stuff you've seen before if you watch that webinar. So let me start.
What I will do is give you a little background very briefly and give you some of the goals of NPRM and then go on to a summary of the major changes.
So why are we proposing to revise the Common Rule?
I mean, the starting premise is that things have changed. A lot of the rules, major – most portions of the Rule have not changed a great deal in many, many decades. The Common Rule has been around for 25 years, but the precursor versions of it were not all that different and those actually date back decades before that, and the world of research has actually changed quite a bit. If you go back far enough, many studies, probably most studies, were single institution studies that perhaps one site. Now we live in a world in which many studies are just much more complicated, involve many institutions partnering together, could be many sites, many sites within the U.S., many sites across the world.
The way we do research has changed. Many types of changes there. Perhaps the biggest changes are those relating to what we could do in terms of the data we could generate and how we could process that data. So we have the internet with massive amounts of data that could be collected, indeed in minutes or seconds, across the web. We have whole genome sequencing. Again, massive amounts of data, probably unimaginable decades ago, that often the sort of stopping point in terms of our abilities is the computer and processing power in coming up with algorithms to process all this efficiently, so again, a lot has changed. The goal is should we change? Can we change our rules protecting research subject in a way that is befitting the type of research we are doing these days?
There are two major twin goals in terms of responding to those changes. One is that we want to better protect human subjects to the extent that is needed, that our current roles are not doing as good a job as they should. The second goal, which is certainly somewhat different, is we want to reduce the burden, delay, and ambiguity for investigators to facilitate valuable research where the current rules might be inappropriately burdening that type of research. So that's sort of the premise in terms where we're coming from.
Here's an overview of what the rulemaking process has been thus far. In July2011, there was an Advance Notice of Proposed Rulemaking, which didn't actually describe specific regulatory language changes but just sort of gave broader strokes. That underwent public comment. We're now in the second stage, a Notice of Proposed Rulemaking. As Wanda noted, a comment period is currently for 90 days and will expire on December7th, and the next stage after those comments come in, and they're evaluated and decisions are made about what a final rule should be, then a final rule will be announced which would actually change the regulations and that would have certain effective dates in it.
Here's a slide of various departments and agencies in the federal government that are subject to the Common Rule. You've heard and have introductions from many of the representatives of these agencies. There are 18 agencies. There will be 19, the Department of Labor is going to join.
So, let's go on.
What are the goals?
Which I’ve already basically told you, these two goals. On the one hand, better protecting subjects and on the other hand, reducing inappropriate burdens that are not doing much of anything to actually increase protections to subjects.
In terms of the way the NPRM sort of analyzes issues, it's actually going back to the core ethical requirements that were stated in the Belmont Report. Two of them were autonomy, often called respect for persons, and benefice, that is a third one, that underlie changes or justice requirements are less relevant for specific decisions that were made in terms of shaping the NPRM. By and large looking at how much you weigh autonomy, or how much you weigh beneficence, was most applicable in most of the decisions that were made in the document, and you'll see that as we go through these two proposals. Often these two ethical rules are in conflict and you have to decide how much to weigh one over the other in the scenarios.
So now we will go on to the major changes.
And this slide just gives you, so there's a list of them here and there are basically eight of them and I’m not going to read them because I will be going through all eight in a moment.
Here's the first four and here are the second four, and let's go on to covering what they are.
So the first change relates to improving informed consent, and if you're familiar with what the rules, are then most rules related to obtaining informed consent are in section 116, which will still be about informed consent even after the changes, but the introductory paragraph, which has a lot of basic rules about informed consent, will be revised to add a number of requirements.
The basic goal here is there has been a lot of analysis of how well the current system is working and there's acknowledgment that we will do a better job in terms of informed consent generally. There are complaints that consent forms are particularly in clinical trials, complicated clinical trials, they can be very long, very complicated, some people would suggest they are too long and too complicated. They're not well designed to actually accomplish the goal of informing the perspective subject and really letting them get a good understanding of what would happen to them if they're in the clinical trial, and often some people think it's often lawyers trying to protect the institution have written a document that's more helpful in terms of protecting institutions as oppose to the goal of genuinely doing a good job in terms of informing the subject.
So the goal here is to implement the number of changes that will shift that and make sure the consent forms actually are more oriented toward giving the prospective subject the information they need to make a good decision for them about whether they want to be in this clinical trial. So some of the changes will require the document to provide essential information that a reasonable person would want to know. So a reasonable person standard is a standard bar from the legal world in terms of clinical consent in a nonresearch setting, and there's a lot of experience with that, and the notion would be that the core information should be provided in a relatively short core consent form, and a lot of additional information could then be put in appendix to the form. So the bottom line is, it's not about restricting the amount of information a person could get, but it's shaping a process and the form in terms of what information is highlighted so that a person will know the most important information and they will get it up front and it won't be buried in a 20-page consent form. It's sort of the premise here. And this is giving you more details. Oh, sorry. So that's what I was talking about. Okay. And so the information must be present in sufficient detail and organized, presented in a way that facilitates the subject's understanding. So the goal here is pretty clear, and the goal is that the changes we're talking about here is going to achieve that goal.
Related to this is the second requirement relating to posting the consent forms in clinical trials.
And the specific change would be that after the trial is closed to recruitment, one copy of a final consent form must be posted on a public, on a government web site. And the goal here is basically transparency. It's not supposed to directly interfere with what happens during the conduct of that particular study, but the notion is since people will know that the consent forms are going to be made public, they're going to be better attuned to making sure they do a good job in terms of writing the consent forms.
The goal of this was also to make sure this is relatively minimal administrative burden, so in a results study you only post one version of the consent form, you do not need a version for every site in the trial and you also don't need to change the version that gets posted, you just post it one time. It's not trying to be perfect in every version of the consent form, it's taking more broadly. In the world of clinical trials we're trying to get more and more transparent over time in terms of various public registry places and places for posting information on trials.
Here's the key, many people would say the key document of assuring the ethics of trials that the federal government is either conducting or posting. Why are these secret? Let's open that up a bit and it will lead to better consent form. That's the premise here.
Let's go on to another very major change, and this is a new consent requirement relating to secondary research with deidentified biospecimens. I want to highlight when I use the term deidentified, it's in the sense it's currently used in the Common Rule and it is not using the way it is differently used in terms of HIPAA. And so what this will do is indicate that consent will almost always be needed when you're doing secondary research with the biospecimen, and by secondary research we mean you're using a biospecimen that's been collected for some other purpose other than the specific research study you're trying to do here. Well so, for example, it could be an excess clinical specimen. Some blood that was drawn for a clinical test, but there's some of it left over, and the researcher wants to use some of that.
Comparing this to the current rules, if you're currently doing secondary research with a deidentified biospecimen, so in other words take that blood sample I'm talking about, if it's currently given to a researcher and the researcher is not given information that allows them to readily figure out who the person whose blood it is, their name, information about them, you're not considered a human subject, no consent is needed, whereas the new rule would basic say in most instances and almost all instances you will be needing to get consent, and the way it's done is by expanding the definition of what the human subject is.
I want to know in terms of rationale for this, the premise, and it's important to note the rationale because there are other aspects of this rule, this is about autonomy, remember we were talking about autonomy and beneficence, and the notion is that there appears that people, and this is sort of an empirical point, people do feel strongly about wanting to control the research use of their biospecimens. So it's not so much about risks or that somebody's a researcher and will be able to figure out the identity of this person, it really is more about autonomy, and it's important to recognize that because that creates a dividing line between many of the provisions of the NPRM that relate to secondary uses of data, which you will see is treated differently than the biospecimen is. So be aware. It's again primarily not about risks or breeches of privacy or confidentiality but that people think, you know, that they should be able to control this and of course people debate, you know, how strong an interest this is.
I want to note because there will be probably some discussion of this, it's not in the slides, this is one provision that the NPRM specifically gives some alternatives and specifically asks people to think of alternatives, so instead of the main proposal which talks about requiring consent on all biospecimens, again with a few exceptions, the alternatives are narrower, they don't propose requiring consent on all biospecimens, and in particular, alternate proposal A talks about obtaining consent for doing whole genome sequencing, and in fact it will apply to biospecimens and for the whole genome sequencing data, and there is another alternative B which is somewhat broader than that.
Both of those though are much narrower expansions in terms of consent requirements compared to the main proposal, which applies to all biospecimens. Now there's going to be one subset of those biospecimens that will be excluded from requiring consent, and bottom line that means that a researcher could in fact continue after these rules are implemented to do this type of research without getting consent if the researcher obtains these in a deidentified way and this is designed to get information that is already known about a person. So let's assume some companies created a new in vitro test for a particular genetic mutation, and that company wants to see, does this test really do what it should be doing? Is it accurate or not? What? How many false-positives, false-negatives does it generate?
It could be given a bunch of biospecimens, blood samples, whatever it is, of people we already know, either do have that specific genetic mutation or do not have that specific genetic mutation.
If you did that study even under these new rules you would not need to obtain consent, and this gets back to the rationale, the autonomy issue, doesn't sound like the person would have a lot of reason to complain about that, you're not generating any new information about them, you're using information that's already known about them.
Now again there's this new consent requirement in terms of people recognize this could be a fairly burdensome consent requirement, so paired with that is a new proposal to allow broad consent.
That broad consent can be obtained for obtaining consent for use of the biospecimens and bottom line that would allow that person to be consenting to future uses of their biospecimen instead of as is generally the case, a person consenting to use of the biospecimen in a specific study.
So basically the government would create, it talks about a template in the document, a type of broad consent form, person could sign that form and it'll basically have the person giving consent both to storage of their biospecimen, which often will not mean moving it anywhere, it could be in a pathology lab or in a clinical center, but it could merely be tagged so that something will label it saying this person has given broad consent and they're okay with research being done with it in the future. So the broad consent form would give it to both storing it and also it will cover future unspecified uses.
So basically you don't need to go back to that person and get another consent when you actually have stored it, a researcher five years later says, oh this is a wonderful biospecimen, I want to do some research with it, you would not need any more consent there and the effect, way would be implemented is if this form is signed, there are new exemptions that would basically exempt that study, so by and large, you would not need IRB review of the specific study.
In terms of waiver, the waiver of consent requirements relating to research of biospecimens will be made more stringent. The first two bullets here give new criteria. There have to be compelling scientific reasons for an IRB to waive consent and the IRB would also have to determine that other biospecimens from which informed consent could be obtained. And the bottom line is that waiver of consent will be rare, if in the great majority of instances we will be obtaining consent from the persons. Note the third bullet: if someone is asked to provide consent and declined, then an IRB would not be able to waive consent at all, even if you met the two conditions. These are new strict waiver rules.
I want to say something about how these proposals at the secondary research of data, as indicated, the rules relating to data are different from the rules relating to biospecimens. There is no change to the definition of what constitutes identifiable private information, there was a proposal in the ANPRM to significantly expand, move to implement HIPAA standards. That is not proposed in this document, commenters indicated that was not a good idea.
Now the core rules of deidentifying data are also unchanged so if you do that type of research, it still does not constitute human subject and it's not even under the regulations. Furthermore, I want you to note that in terms of doing research with data, it doesn't matter whether the data was obtained from a biospecimen as oppose to obtained in some other way. As long as you're doing research with data, you look to the rules relating to data. So don't use the new consent requirements in terms of biospecimens to somehow say different types of data depending on where it comes from are treated in different ways. All data regardless of the source is treated the same way.
And you should be aware that the proposals in terms of data actually do increase the ability of researchers to conduct research with identified data without consent, assuming appropriate protections, protections relating to privacy and confidentiality, are in place. So note that in terms of the new broad consent form in terms of a person doing research and identifiable data, these researchers will actually have a number of options, and in the provided cases they may want to use one of those options instead of using the new broad consent.
You should contrast that with what would happen if these rules are imposed on the biospecimen side because in the biospecimen side, the rules will generally not allow researchers to do biospecimen research without the consent, so that researchers and biospecimen side by and large will have to use the new broad rule consent.
So here are some of the examples of ways secondary issue of data could take place. Research could use data stripped of identifiers, could keep one-way linked identifiers, they could obtain IRB waiver allowing the use of identifiers. There's a new exemption that allows use of identified data when the company who hold the data gives notice instead of consent and in many of these scenarios, new privacy and confidentiality protections would have to be adhered to. So note that any one of these for a researcher these might be preferable options to using the broad consent. Again very different scenario than how it treats biospecimens.
So that was discussing one of the most major changes. Let's go on to several of the other major changes, number three single site review of multisite research, what is required here as for multisite research conducted at U.S. sites, there would have to be a single IRB review unless one of the two exceptions noted here: that there's a legal requirement to have that type of local IRB review, or a federal department or agency determines single IRB review is not appropriate.
Paired with this is a change that will allow the federal government to hold independent IRBs directly responsible for compliance with the Common Rule. Two things to note about this: none of this prevents any site from conducting whatever additional review it wants, nor does it bind any site to participate in a particular study, and in many ways it can be viewed as making the system more flexible because it's eliminating in a sense the requirement that any site has to dig up its own IRB to participate in the study. There will be a single IRB and that that meets the regulatory requirement for all the sites.
Major change number four, eliminating continuing review in some instances, no continuing review would be required if the study undergoes expedited review, and in addition if the study is not subject to expedited review, no continued reviews is required to complete the intervention.
So it could be a clinical trial but you've done the interventions, you're only analyzing data including newly collected clinical data and there will be a requirement that there has to be confirmation that the research is ongoing, it has not been changed, and that could be done by for example just sending out an email to investigators and asking them to respond yes or no.
Note that the IRB or the IRB reviewer can override these defaults and require a continuing review but it would have to be documented.
Number five is extending the Common Rule to cover clinical trials. So the premise here is that if you're at an institution that receives federal funding for nonexcluded nonexempt human subjects research, then that institution would be required to follow the Common Rule on all clinical trials, and the federal government would have oversight authority over those clinical trials. Now this does not include clinical trials subject to regulation by the FDA, it's designed to fill a hole, a void, in which there's no federal oversight of these trials.
Note this is actually a narrower expansion of authority that was originally in the ANPRM, which was proposing to cover all research done at those institutions, but looking at the beneficence and autonomy it was decided let’s have a narrower expansion to look at studies that need additional oversight.
So number six, I already mentioned something about this, there will be new privacy standards that would apply to nonexempt research. There will be a number of ways so a uniform floor that privacy standards that researchers would have to adhere to. There are a number of possible standards that could be adhered to to meet this new set of standards, so one example is HIPAA. An institution could abide by the HIPAA rules, so any institution that is bound by HIPAA is already meeting these standards, but in addition as the second bullet notes, the Secretary of the Department of Health and Human Services would also promulgate standards that are very similar to many standards that researchers are already adhering to that would involve minimal cost and effort for an investigator to implement. So the goal is that these would be common sense, easily implemented standards. And the default position is that if the privacy standards in the new section 105 are met, there will be no need for additional IRB review unless those are deemed insufficient and some of the exemptions, so there's a new concept, exemptions would also have to adhere to these privacy standards.
So now I want to wrap up with two categories, exclusions and exemptions. The first one, exclusions, this is a new term, in terms of the Common Rule but it's not a new concept. These are activities that are excluded from coverage under the Common Rule and bottom line, no reviews are required. No administrator review that's required for these activities to go forward and note, it's not a new concept in the sense that for example, activities currently that do not meet the definition of research or do not involve human subjects, currently in general there's no requirement that they get reviewed, so in a sense it's just sort of clarifying the lines similar to the line that those two death- defying concepts already draw.
And there are a variety of categorizations that the new exclusions are clumped under various categories. I want to note these are primarily ways of describing differences between the different types of exclusions, but it doesn't have actually any sort of legal, you know legal binding, in terms of altering what is or is not excluded. They're just sort of descriptive categories so some people suggested maybe even having descriptive categories, so one is call low risk but you don’t need to define low risk, all you do is look at the description of what's under the category and meet that standard, so the low risk descriptor doesn't actually change what is subject to being excluded.
And this is just describing the different types of categories.
There are 11 total and it describes the different types of them. I will not go through that.
Here are some examples of the exclusions. So one relates to quality assurance activities, and implementation of an accepted practice. Now it doesn't involve actually a study designed to look at how well the accepted practice works, its risks, its benefits.
The second one relates to research subject to the HIPAA rules. So there we're talking about secondary use of research data. And basically HIPAA and the Common Rule in terms of those studies have similar goals: let's look and see whether or not appropriate privacy and confidentiality protections are in place. Given the similar goals, do we really need to have these studies of both sets of rules? And this exclusion says, no if you're subject to HIPAA, hopefully that's enough.
And the third one is secondary research using data where the research does not record identifying information such as from medical records. Note this is basically very similar to a current portion of the exemption four, if you're familiar with the exemption four, but again it's an exclusion, unlike exemptions which have to go through some administrative review, exclusions do not and let me wrap up with the exemptions.
So, there currently are exemption categories in the Common Rule, but the goal is to better calibrate the level of review to the level of risk, and the thinking is that some of the current exemption categories require more administrator review than is appropriate. So by and large many of the changes to the exemption categories would broaden the types of activities that are considered to be exempt and would not require an IRB approval.
Note that some of the new categories are subject to the provisions such as new privacy protections. This is basically done because we've taken activities that would require IRB review before and not required IRB review. So it's not as if we're imposing a tighter standard than before.
Note, in contrast to exclusions. There are procedural requirements if there are exemptions, in particular, an exemption determination has been made according to specified rules and it has to be documented in some way so that we will know someone made this determination.
As to how it can happen, it can be made by the researcher using a government produced web-based decision tool, and the way this would work is that the researcher would answer questions and the tool would give an outcome, so the tool would say this study is exempt, this study is not exempt, or it may say this is too complicated, you need to go to an actual person and this person has to review what you're doing. But just to be clear, the tool itself would not give the researcher any discretion to make their own decision about whether the study is exempt or not.
Here's a description of the eight types of exemptions. They're in various categories which I won't go through right now. Let me go on to some examples.
So surveys, interviews, that sort of thing, even if sensitive information is collected, so long as appropriate privacy protections are in place. Again, if you're familiar with the current exemptions, this is very similar to exemption two, except exemption two wouldn't allow to you collect sensitive information. The new exemption would allow that because there will be new privacy protections in place that the researcher would have to adhere to.
So the second category here, benign interventions, is a totally new concept.
An example could be somebody sitting in front of a computer and watching something happen at the screen and then they actually have to click a mouse, at certain times, that sort of thing.
The third one is a very new concept, secondary use of identifiable private information if the holder information has given notice this may take place and the appropriate privacy protections are in place. So that's again a very new one and that wraps things up.
Of course we continue to be very interested in people submitting comments.
That's obviously the purpose of this meeting, is to allow people to better understand what's being proposed so they can better decide what aspects of this rule they want to comment on. You can just go to OHRPs home page and there will be instructions there about how to provide comments, and here's some contact information, and thank you for listening.
Back to Wanda.
[ applause ]
MODERATOR: WANDA K. JONES
WANDA K. JONES:
Thanks, Jerry, you had no small list of things to go through and did you that very nicely.
So we have a few more members in our audience, so now I'm going to give you some critical information for the day for your comfort and for your safety.
The main exit out of the building, should there be an emergency alarm, is straight out the door you came into. And the color of the day is your green wrist band. If you are not an HHS employee, you have a lovely green wrist band that you will need to keep on throughout the day that will allow you reentry. You will still have to come back through security, if you do go outside, but at the end of the day when you are done with the meeting and not returning, that band is yours to keep, so feel free. In the meantime keep it visible.
Now, there will be two breaks throughout the day, there will be one in about 45 minutes and then we'll have another one for lunch, and what you might like to note is that restrooms are just out that way and sort of a u-turn around to the left and if you would like to grab a coffee, you will need to be accompanied either place, but the cafeteria is up on the eighth floor, which in our elevators is labeled p, not for public health but for penthouse. Don't ask me. But press "ph" you'll have someone from HHS if you will connect with someone to escort you up to grab a coffee or get up there for lunch.
In addition on your agenda that was available to you, if you flip to the back, there's a screen shot of restaurants in the area that are just a couple of blocks away and some reasonably priced reasonably fast options for lunch. Do note though that our scheduled break, noon to one, will be sort of peak lunch time. So, you know, the cafeteria is good. Going out is also good and it's just the extra walk, the fresh air may take you a little bit longer to get your lunch, have some relaxation and then get back in time. But it's your choice obviously.
I would also like to note that we will have our OHRP panel join us here on the stage. So if you all would do that just now, just come on up, folks who are going to introduce, I mean answer questions that will be coming from attendees and if need be, we will spend less time addressing written comments that came in advance. But I did a pretest and we only got maybe five or six hands up. A few more people in the audience now so let's try this again, maybe inspired by Jerry's overview and remarks. Now who thinks they're going to ask a question? This is not a shy audience, but I'm still only seeing about a half dozen hands up. Okay, we will go with it. We are prepared, as I said, to stay here until five if the questions remain.
So what we would note is that the responses will be limited to what is articulated in the NPRM, that there will be no particular order in which we will ask for questions. There are three microphones in the room to my right, in the center, and to my left. and you can see those plainly, they have nice colored foam things on them. So momentarily we will get to the question period, and we would just simply ask you to cue up and we will take your questions in turn. We will restrict questions to two minutes if, in fact, again, there are only six of you. We got about, what was there, about 65 questions in advance, 56? Okay, I had them reverse the numbers there but regardless we will work through taking turns perhaps with the written questions with those in the audience. But again, if we finish early, we finish early.
We do ask you to limit your question to a single topic and then if you have other questions don't come up with six questions on different topics, try to keep focused on one so we can keep to time, we can keep the answers clipped and then you can come back up to ask your subsequent questions.
We've also – has anyone from HUD joined us? We have been joined by another federal colleague here in the front next to our colleague from the Consumer Product Safety Commission. Could you just jump up to a mike and introduce yourself please? Yes you, please? Oh well, my apologies.
So the Department of Labor you heard will be joining with us, but in addition, after our September8th issuance, the department of Housing and Urban Development actually has joined with us. They have issued a Federal Register notice saying that they support the issuance of the proposed Common Rule, and that they could not be part of the release on September8th because of their own Congressional advance notification and rulemaking processes, but we're very pleased now to have 19 agencies joining in and recognizing that we are moving forward together in the finalization process. But we're very, very pleased to everyone collaborating with us on this effort.
So let me turn first to the panel just to give you a general sense of how this will go, why don't we just let you see for example, Julia, I'm going to put you on the spot, Julia Gorey, and turn to you.
There were some general questions that were submitted in advance. So just to give you a sense of the run of show, I'll let Julia read the questions and then provide the answer, and then you can have that sense and then we will begin to call you to the microphones.
PRESENTER: JULIA GOREY
Okay, I'm delighted to be able to get the ball rolling, and the first couple questions that I'm going to go over were submitted by Public Responsibility Medicine and Research, or PRIM&R, submitted by Elisa Hurley. Here was the first question: How much flexibility is there at this point with respect to modifying the content of the proposed rule? For example, is the language of the single IRB mandate fixed, or could it be modified. And as Dr.Jones stated in her introductory remarks, we very much want to stress that at this point in time the department has not finalized anything in the rule. The rule is very much yours to shape, so we do very much encourage your comments, not only on the 88 questions that are embedded in the document itself, but on any and all aspects of the NPRM, so please do comment and comment freely.
The next question, again submitted from PRIM&R, asks the following. The NPRM removes a number of activities from IRB review and oversight. Does HHS have any plans for educating the researcher community so that they are equipped to make the decisions and determinations being proposed in NPRM? And the response is, yes, of course, absolutely. OHRP is very aware of the need in this domain for community education. We've already begun this process with our six webinar series. We've been involved in workshops. A little bit new for us, is that we're now collaborating with NIH in some regional workshops that focus specifically on the investigator or the researcher. And as time goes on and we have a better idea of what this final rule is going to look like, we'll certainly be accelerating our efforts, and I think particularly you'll be seeing a lot of online outreach activity. All right.
So an additional question, and then I'll stop for a bit, again, submitted by Elisa Hurley at PRIM&R. Why, in spite of the fact that a number of federal processes including NHRPAC, SACHRP and others have called for the development and promulgation of specific rules to protect individuals with impaired decisionmaking, aren't protections for this most vulnerable populations addressed in the NPRM. Well, I want to note there was a decision, intentional decision, made very early on in the NPRM process that issues determinations related to vulnerable populations, and the definition of those populations would be determined at a later time. They are going to be tabled and addressed at a later time. The rationale was that it would be premature to try and address those very complex important and significant determinations while you're still trying to carve out what the Common Rule was going to look like itself. So the decision was made to address it sequentially rather than in parallel.
So obviously, you see that the NPRM does not propose any new subparts, does not propose any new vulnerable population language, with the exception of some language which addresses some parts as they apply to exclusions and exemptions and that references that vulnerability should be a function of coercion and undue influence. But that that's really an extent of the language of the vulnerable populations currently seen in in the NPRM. So with that I will stop and hopefully there will be live questions, or not.
MODERATOR: WANDA K. JONES
WANDA K. JONES:
Thank you, Julia. So if have you your questions please pick a microphone, green, blue, or cream, there's a microphone here for you. This is not a shy audience, please cue up, and try to keep it to one question. You will have two minutes and then we will answer that question, respond and move on to the next questioner. Yes ma'am. If you’d like to identify yourself , that's perfectly voluntary.
PRESENTER: NORMA EPLEY
I'm Norma Epley from East CarolinaUniversity and I would like some information on the broad consent. It appears to me that the broad consent is restricting a 10-year time period for the investigator, and we're assuming it seems that these biospecimens are coming only from research, while in most academic hospitals a lot of those specimens come from clinical care.
I really commend that you're looking at this and trying to make this a more streamlined process, but the devil's in the details. How do we get consent from individuals who are not participating in research but are receiving clinical care, and then those leftover tissues or blood goes to pathology. Thank you.
PRESENTER: IVOR PRITCHARD
Thank you. So there are a couple of things I would like to note in response to this question. The first thing to note is that whether the person is participating in research or getting clinical care when broad consent is sought for the use of their specimens, the exemption that applies for research, secondary research of that sort using the broad consent, requires there be an IRB review of the procedures that are used to obtain broad consent. And so, presumably the IRB will be looking to make sure that in those circumstances where broad consent is being sought from someone who is getting clinical care that the circumstances of that consent will be such that the person can make an informed and reasonable decision about whether they want to participate or not.
The second thing I want to say is to note that the 10-year limit only applies to the research, the broad consent, in the circumstance where the person is getting clinical care and the specimen is obtained in the process of clinical care, not in the circumstance where the person is asked for broad consent where the original collection of the specimen is for research. The rationale for this difference is that we think it's going to be more straightforward and obvious to the person where the specimen is being collected specifically for research purposes that they can also be asked, “In addition to your providing the specimen for the original research study, we'd also like to ask you for broad consent to use your biospecimen in secondary or later research studies.”
That's something which is a relatively straightforward situation, where the person coming in appreciates that they're being asked to participate in research and that that will be easier for them to understand, that indeed the use of the specimen or the collection of any specimen that might occur could happen anytime from now until the end of that person's life. The 10-year limit for research for involving, for the collection of a specimen in the context of a clinical circumstance, is precisely because if you're getting clinical care, the notion of how much and when biospecimens might be collected is limited to a 10-year period because we think that the person will, in that circumstance, there ought to be some limit set on how far in the future additional biospecimens might be collected from that person.
And presumably yes, this does mean that in this context of biospecimens that collected in what was originally a research context, the tag that was put on that specimen if the person consented will presumably indicate that this specimen is part of a collection that could occur for an indefinite period of time, right? But in the circumstance of clinical care that the collections only occur within that 10-year limit.
But I guess there's one last thing that I should point out. There's actually another question that was submitted ahead of time. The 10-year limit addresses how far in the future specimens can be collected under that broad consent. It does not have to do with the period of time that investigators can make use of that specimen for research. That is something that is addressed in a different That's addressing indeed a different provision of the broad consent template, and the time limit for that is entirely flexible insofar as any amount of time could be identified as the amount of time as they could have access to that biospecimen in the future.
MODERATOR: WANDA K. JONES
WANDA K. JONES:
Thank you, Ivor. And just a note, there is a timer here that will give the questioners two minutes, and it will turn red, and two minutes is a lot of time. and to reintroduce the panel, Dr. Jerry Menikoff, Julia Gorey, Dr.Ivor Pritchard, and Julie Kaneshiro. I will go back to the mike.
Hello, I’m Carolyn Mullen from the American Association for Dental Research. I submitted the question beforehand, so can you scratch it off your list and you may have answered it more generally, but I want to be very specific because it's coming from one of my members as a researcher: So will the Common Rule provide consent for extracted teeth for research? And to be clear, these teeth are extracted for research reasons, premolar teeth extracted for orthodontic reasons or third molars that are later used for research.
The teeth are not extracted for the purpose of research, of course, there's a considerable body of research on dental materials and preventative products performed on such teeth, and they would be an important model to maintain for restorative dental model research.
PRESENTER: JULIE KANESHIRO
Yes, thank you. So I think a couple different parts to your question and they all relate to the proposed expansion of the definition of human subjects to encompass biospecimens. One fundamental question you're asking is whether extracted teeth from living individuals would be considered to be a biospecimen under the proposed expansion, and in general the answer to your question is yes.
But there is a however, because there's another part of definition of human subject that the NPRM is not proposing to modify that talks about the need for that information that's obtained from the biospecimen to be about the individual, so to be “about whom,” so to speak, the definition of human subject. And so, I think the answer to your question is really going to be dependent on the nature of the kind of research that you're specifically addressing.
I think there's some types of dental research on extracted teeth that might not meet that so-called “about whom” test. One example might be where you're actually testing some kind of new product to see a new material, to see how well it adheres to a tooth. Right? And really you're not trying to find out information about the tooth, about the individual, it's really just about the product that you're developing, and in that case, we have said even under the current rules that that kind of research might not in fact involve human subjects because it's not designed to develop information about the individual.
So I guess another thing I'll point out is that we do ask in the NPRM whether we should propose or include a definition of biospecimen in the final rule, and so we welcome your thoughts specifically about that issue and whether there are reasons perhaps not to include teeth, extracted teeth or some subset of extracted teeth. For example, if doesn't include nucleic acids, should we exclude teeth from concepts of what is a biospecimen?
MODERATOR: WANDA K. JONES
WANDA K. JONES:
Here, to the green mike.
Hi, I’m Michelle from the Dana-Farber Cancer Institute. So building on this discussion of consent and biospecimens, if you have a scenario where biopsies are done at hospitals that are typically not engaged in the conduct of research, and the biopsies are sent to teaching hospitals for further diagnosis and second opinions about possible treatments, those specimens from nonresearch institutions assume they were collected without any broad consent and they're sitting in pathology laboratories right now. And let's assume that the individuals for whom the specimens from whom were taken are not people who come into the teaching hospitals where the specimens are now housed. What guidance would you give us if the NPRM goes into effect in terms of how an investigator would be able to do research on those specimens?
Michele, let me ask you, just to make sure I'm understanding your question, are you talking about the grandfathering provision, meaning specimens that are already being collected now before the rule takes effect? Or are you talking about prospectively, after the rule actually is effective, how would you go about ensuring that you could use these for research purposes?
After the rule goes into effect you can assume these are people with breast cancer, let's say, and they had biopsies at hospitals that are not research institutions, so they would not likely have a system for broad consent and the specimens are then sent let's say to a teaching hospital somewhere at a distance.
I thought that was the case but I wasn't sure.
So I think the NPRM is proposing a change in that regard. You know right now, we know that often – well, first of all, two things.
One, assuming this specimen is not identifiable, currently under the rules that’s research that falls outside of the scope of our regulations. And for research that is currently using identifiable specimens, there are pathways currently under the rules where the information or use of the specimens could have a waiver of informed consent by an IRB.
So I think your question really is getting at the heart of one of the proposed changes in the NPRM, which is first to consider all biospecimens used in research as human subject research and then secondly, the NPRM is proposing to have much more stringent waiver criteria, as Jerry noted in his presentation, specific to the use of biospecimens, such that the waiver of informed consent by an IRB for biospecimen research could be quite rare in the future.
So I think what is envisioned is that this broad consent would become much more routinely obtained, or sought at least, at institutions where currently there is not that kind of process in place, the expectation or hope is that those specimens would be able to used for research under the Common Rule. So I do think that this would involve the change in culture or change in practice and administrative processes that would enable those specimens that currently fall outside of the rule to now become compliant with the regulation if it were to go into effect as proposed in the NPRM.
MODERATOR: WANDA K. JONES
WANDA K. JONES:
Over here to the cream or yellow mike.
Allyson Beach in NewYork. My question's about whole genome sequencing data and information. Currently in the NPRM, HHS states that they do not currently consider whole genome sequencing data to meet the data of PHI for purposes of the Common Rule, however under one of your proposed alternatives you say that technology applied to a biospecimen, that generates information unique to an individual such that it is foreseeable that when used in combination with publicly available information the individual could be identified. Under this definition, various information, genomic information that is gathered under sequencing would fall in this category as identifiable information under the Common Rule.
The question really is this: How are these changes going to interact with OCR's definition of whole genome sequencing under PHI, and is there any intent for OCR and OHRP to come together and once for all define whether any genomic information is included in that 18 catch-all category under HIPAA?
PRESENTER: JULIE KANESHIRO
I'll take a crack at answering the question.
We were certainly aware of this issue, and we have been in communication with the Office of Civil Rights, and we noticed that in the proposed rulemaking there could be the need for other changes to other federal regulation, including to the HIPAA privacy and security rules. And this is something that if moving forward to adopt that proposal, you know, which is alternative B in the Notice of Proposed Rulemaking, we would certainly be engaged with OCR in those conversations to see whether it was appropriate to have harmonization on this point.
WANDA K. GREEN:
Alternating microphones, the gentleman who just came on up come back to the microphone and then I'll return to the green one momentarily. It's your turn sir.
Oh it is.
WANDA K. GREEN
Okay, I'm alternating.
PRESENTER: ROBERT HOUSER
I'm Robert Houser, National Academy of Sciences, and I'm concerned about one of the reasons for this revision, as best I understand it, is to get rid of the over-regulation that has occurred in some instances over the years, and I've heard you refer to education as one of the means to get the message out about the differences between what now exists and may exist if the ideas in the NPRM go forward.
The question is: is there anything else that can be done through the NPRM mechanism other than efforts to educate institutions that have a variety of vested interests in doing what they do now in order to really see these new ideas get implemented? For example, one of the recommendations in the report that the Academy did was to institute an appeal process so that researchers would have some leverage on their own institutions, but I didn't see any reference to that in the NPRM, so I would be interested in your thoughts about that. Thanks.
PRESENTER: JERRY MENIKOFF
So you're certainly correct, the NPRM does not currently propose an appeal process. We have been having discussions during the NPRM process in terms of the appeal process, and we certainly welcome comments in terms of should there be an appeal process, what should an appeal process look like, and it certainly is a very relevant thing for people to be commenting on, in terms of a variety of provisions of the document, such as the new exclusion categories, are specifically designed to take things away from being subject to administrative reviews. On the exemption side, the new decision tool again was designed to respond to criticisms that some researchers go through a lengthy administrative review process in terms of making a decision that something is exempt, and these are the things you're talking about, low-risk studies that shouldn't require much of an administrative burden. So the goal was how could we, you know, get quicker determinations. Let's remove an added reviewer, let's build expertise right into the decision tool so they fill it out, get the green light, and start the study.
You raise an interesting point in terms of what will happen if these changes are implemented in terms of institutions still wanting to review studies, for example. What if institutions don't want to allow the use of the decision tool, for example? These are issues that came up during the discussion of the ANPRM, presumably they will come up during discussion of the NPRM.
I guess I would say part of this requires sort of a partnership between the research community, the public in general, and the government in this terms of what are the best way to design rules that will achieve the goals we want to achieve. So if we're all agreed we want to reduce administrative burden, how do we accomplish that, and I think you’ve hit on there is some degree of difficulty here.
Certain players with institutions just are very risk-averse and want to review every type of study, even very minimal risk studies. There are limits to the government's ability I think to sort of, I don't think you can see the government kind of ordering institutions and saying you absolutely are not allowed to do any kind of administrative review on even studies that might or might not be exempt.
It does require...this is a difficult issue...it does require everybody working together, and again, comment from the regulating community in terms of, are there other options that we did not suggest in the NPRM that might better address some of these things. Because certainly there has been in a variety of instances concern from people who are involved in human subject regulation who will say, you know regardless of this change in the rules, we want to continue to review this type of study. There have been questions and proposals already coming out in terms of changes in the concepts of excluded. Maybe institutions want to review that, too. That is a difficult problem in terms of if the review, the desire to have a review is coming from institutions.
It's a hard thing for the government to sort of say we are going to prevent you from doing that, similar to the central IRB review requirement – if institutions want to continue to have additional ethical review on their end, they are going to do that, probably, and the question is you have to somehow convince them down the road to not do that. So I guess I would say this is a work in progress and we certainly look forward to comments from you and others in terms of are there other ways to achieve the goals that we may be agreeing on.
WANDA K. JONES
I will come over here.
Hi, my name is Chelsea Rutherford and I have a question about the expansion of scope. Can you more clearly clarify sort of the types of studies the new clinical trial definition intends to capture and how this definition sort of, or minimally, extends the jurisdiction to other intervention-based research activities conducted by an institution?
Similarly, I understand there's a request for public comment out on this but if the rule is finalized as written, can you specify the extent to which a one-time recipient of one dollar from a supporting department or agency for nonexempt, nonexcluded research would be required to have the other clinical trial subject to the Common Rule? And the extent to which that expansion of scope would extend to subawardees who may indirectly receive federal funds in connection with a nonexempt, nonexcluded study?
PRESENTER: IVOR PRITCHARD
There is currently in the NPRM a proposed definition of a clinical trial, and I draw your attention to at least one adjective in the definition which is health-related outcomes. The idea, which I think Jerry alluded to in his remarks, was to limit this expansion to the kinds of activities where human subject protection is most important, and the notion was that rather than saying survey research or whatever other kind of research studies in an institution getting federal funds should be covered, you know, the NPRM is less ambitious in saying only clinical trials.
Now if it is the case that you all think that the definition needs to be further shaped in order to single out the kinds of trials which we have in mind, like the clinical trials of a surgical technique, say, or two different surgical techniques, please provide us with those suggestions because that's what we're trying to do and if the definition that's currently there doesn't do the job, then we need to figure out a way to make it do that that’s separating out that job.
I guess another point I wanted to make about the proposed expansion to cover clinical trials, you know, one of the other caveats here that we're imposing was that it not be subject to regulation as Jerry mentioned or already subject to FDA’s rules, and in addition we're also limiting this proposed expansion to only site that received federal funding for nonexemption or nonexcluded funding that are in the United States . That would not apply internationally.
The question about the subawardees at least on the face of the proposal: you know we were talking about an institution that received federal funding for nonexempt, nonexcluded research, so I think that it would apply even to subawardees, that there's no limitation that we’ve directly spoken to in the proposal that would limit it to just direct awardees.
You were also talking about the issue of how much money the institution has to receive and I take your point, if you just receive $1 that year... I don't recall if the NPRM has questions about it, but regardless people should comment on these issues, and just putting in a plug, some of you are familiar that the Secretary's Advisory Committee on Human Research Protection will be having a meeting tomorrow and the day afterwards and will no doubt discuss a number of these issues, and this is webcast so people may want to look at that. But there's certainly likely to be a discussion of the issue of, should there be, a minimum amount that an institution receives for funding before they should kick in. Should that minimum amount have to occur during a certain period of time close to when the new study is being proposed.
These are all legitimate issues relating to, I think people understand the basic policy goal is that should we be having clinical trials where people are randomized to some medical intervention and there's no federal oversight of it, but we want to be reasonable in terms of balancing autonomy, beneficence, the government versus the authority of institutions, you raise legitimate concerns that we would certainly welcome help and join lines in terms of what types of rules should there be to best implement this goal
And just one additional notion is that when you raise the issue of subawardees, these kinds of clinical trials are likely to also be subject to the proposed provision regarding single IRB review. So it's likely that that kind of clinical trial will only have one IRB doing the review of the clinical trial.
WANDA K. JONES:
Thank you. And as you can see from the complexity of the question and the answer, we're hoping to stimulate your further comments, so the docket is open. There's still time to comment and we're seeking your input and ideas on how to clarify some of these critical issues. That's what public comment is about.
Yes ma'am, back to the center microphone.
Norma Epley, East CarolinaUniversity. I'd like to get some clarification on the tool that will be provided to investigators to make the determination that they would be excluded from IRB review, because it references documents such as the Privacy Act, E-Government, the Paper Reduction Act, will those pieces of information be built into the tool, or is the expectation that we're going to be able to educate investigators to understand what all of those Acts mean?
PRESENTER: JERRY MENIKOFF
Okay, the assumption is that the tool will in fact have for example yes-no questions that an ordinary person will be able to answer based on knowing what research they are proposing to do, so in general there's no specialized knowledge for someone to use the tool.
In relation to the specific privacy provisions that you're talking about, in general those are privacy provisions that apply to federal employees, so they won't be relevant to a researcher who's not a federal employee. And there are ways the government makes sure that people on the federal side who are federal employees can in fact find out, when you're doing a research study whether in fact or when they are in fact subject to those three provisions, which are in fact very complicated provisions. In terms of those provisions by and large, our understanding is a nonfederal employee, you will not have to worry about those, for example some of those exclusions exclude certain surveys when the subject is going to be subject to those three provisions.
But you're not a federal employee, you're not under those that will not be relevant to you. What will be relevant to you will be under exclusion or exemption, if you comply with the new 105 standards, then this study might be exempt or excluded and the 105 standards, some of them can be HIPAA, but the alternative would be the Secretary's proposal which isn't out there yet, but that's designed to be something relatively simple that even an investigator who is not an expert in privacy can understand.
So at the heart of it, yes, the goal is that the tool would in fact not require somebody to know anything about the Common Rule or know anything about privacy rules but can ask a bunch of questions such as, “Are you going to put any the information with identifiers of who your subjects are on the computer?” “If so is that computer going to have a password?” Then “if you're going to transmit it electronically, are you going to use some type of encryption,” and it may tell you the encryption and it may say, is it one of these five software products, I don't know, but that sort of thing, and it certainly wouldn’t require you to be applying to federal rules and federal employees who are bound by certain privacy and other standards.
PRESENTER: NORMA EPLEY
And a follow up question to that: Will the public have access to this tool before the comment period is over?
PRESENTER: JERRY MENIKOFF
We have agreed to provide there will be some sort of notice and comment about the tool and at this point, I don't know exactly what they'll involve so this is the difference of the thing. It's some sort of program that will operate on the web but I believe we did promise in the NPRM to give some sort of opportunity for the public to see the tool and understand what it does, how it operates, and that will be shaped over time but feel free to comment about the aspect of the tool and what you think the public perhaps needs to see ahead of time to be able to say this is or is not a good thing.
Okay, thank you.
That's an excellent question.
WANDA K. JONES:
I'm going to take the two questioners cued up and then we will take the break. So please, your questions.
This question is regarding the new broad consent forms. It may actually be better addressed to NIH. A question has been raised that with the NPRM now allowing broad consent forms to allow adult participants to opt on from allowing their deidentified, nonidentified data to a publicly available database. However, the NIH genomic data sharing policy requires this information be input when genomic sequencing is occurring. Is this a conflict in the rule? Is this something that is potentially going to be a problem? Is this something that's been addressed? Or in the process of being addressed with NIH?
PRESENTER: CARRIE WOLINETZ
So we feel that the NPRM is largely consistent with the GDS policy. We do recognize that once the rule is finalized we may have to issue some additional guidance to investigators to reconcile any discrepancies, but generally speaking we see this as being largely consistent.
WANDA K. JONES:
The response was from NIH, for the record. Thank you.
Julie, you mentioned that not expansion to clinical trials would be to everything would be applicable to the FDA, they're undergoing their own rulemaking progress. Are you expecting any crossover from what you're doing and what FDA might do, or do you think what FDA might do in their own proposal making will be separate from what you guys are proposing – ?
PRESENTER: JULIE KANESHIRO
Well, certainly. as Joanne Less from FDA already noted, we will certainly work together as FDA develops their proposed changes to their regulations, and we work to finalize our Common Rule, so it is very difficult to answer your question, sort of, in a general way, in terms of exactly areas where we will determine that we will harmonize in an identical fashion, and I imagine there will be some areas where FDA may have statutes, for example, that may prohibit them from harmonizing to the exact same language that we have, but certainly we share the goal of creating harmonization wherever it's possible and appropriate to do so.
Specifically with regard to the clinical trial expansion we're proposing here that we're really trying to fill a hole, as Jerry mentioned in his opening remarks, that we're not trying to create duplicative regulation.
And so the extent that that's really the intent behind the proposal, I think, that will really shape us moving forward, unless and please do provide us with comments about this, if there are thoughts there ought to be duplicative regulation, that there is something the Common Rule for example, provides in terms of human subject protection that FDA does not, then we are interested in that but the premise is that if the FDA's regulation already applies and has human subject protection for that, for those clinical trials, that it's not necessary for the Common Rule to apply too.
So in terms of timing, I guess this may be a question for FDA, but if there will be coordination between the two agencies, FDA and participating agencies, I guess, for the Notice of Proposed Rulemaking, when that will happen, will they wait for the final rules to be proposed or would FDA engage in rulemaking concurrent with the comment period and the changes that they're making to the notice of the proposed rules?
WANDA K. JONES:
Joanne, would you like to take that?
PRESENTER: JOANNE LESS
FDA's intention is to look at the comments that come into the NPRM and use that to shape our proposed rule, so hopefully we could do them in tandem, but we're obviously a little bit behind where the NPRM is so we'll move forward with that, but we'll have to go out with the proposed rule, look at the comments, and then do a final rule. So we would be behind the Common Rule, but we would use as much as we can of the NPRM as we draft our Common Rule, and as I mentioned earlier, we've been involved with the drafting all along so we're familiar with the issues, but we are interested in how the public and researchers view those comments and proposals and how they would affect FDA’s regulated approach.
WANDA K. JONES:
Excellent. I'm going to call the break, and please reconvene at 10:45 as originally scheduled, so that gives you just 10 minutes. Restrooms are past the elevators around to the left. The cafeteria up on the eighth floor labeled "ph" on the elevators. You will need an escort so find a friend that has an HHS badge to accompany you. Thank you.
MODERATOR: WANDA K. JONES
WANDA K. JONES:
If you joined us after I made the initial announcements, we have three microphones set up, nice blue, nice green, and lovely cream or off-white, yellow, I can't see it well enough but one central and on either side of the room. So please cue up if you have a question to ask our distinguished OHRP panelists. They will be responding within the contours of the NPRM and again, why don't we kickoff this session with some of the advanced questions sent in, and I will turn again to Julia Gorey, who will take some more of the questions that were submitted in advance.
Okay, so I will lead off with a question that was not submitted by PRIM&R, this is by Monique Lanz from Bridge Clinical Research, and she's asking as you know, many minorities are significantly underrepresented in research. How is the minority patient respected and taken into account in these guideline proposals. And I think the response to this is we are very much hoping to gain a robust minority perspective through the public comment process. Again, we want to point to that process, and we urge you to submit comments, particularly in this domain with the ethical balance that's struck between autonomy and beneficence, and we look forward to getting those questions.
And the next question was submitted by Marco Brodo, College of Nursing and Health Innovation at University of Texas at Arlington, and he says: I did not see much on the issue of conflict of interest, which is an area where enhanced protections are needed. How will this be addressed? You're absolutely right. You didn't see much on conflict of interest other than what is there, status quo, and the language regarding IRB membership. That's an area that's addressed through policy from NIH and FDA, but it's not addressed in the NPRM.
WANDA K. JONES:
Is that it? Oh. I had three questions listed?
Oh, okay. Well, then excellent. So again, folks in the audience your time at the microphone, feel free to cue up.
Let me turn while you're assembling yourself to the OHRP staff, or perhaps – no, Irene’s not back yet, are you aware of anyone who indicated they were coming that had to catch a morning flight and wouldn't be here until late morning or afternoon or anything like that?
Okay, well then we may well be on a glide slope toward finishing and saving you a chunk of time to go home this afternoon and send your written comments in on the proposed rule.
So let me turn to more questions sent in advance then, Julie Kaneshiro, it's your turn.
So I will answer four questions related to biospecimens. It was going to be five, but we already addressed one this morning, and three of them are related to the definition of human subject and the proposed expansion to cover biospecimens irrespective of identifiability, and one is related to the exclusion for the use of nonidentifiable biospecimens.
So let me address the three first regarding the definition of a human subject.
So there are a couple of questions that we received specifically asking about how the alternative A would apply to certain types of research, and alternative A is the proposal that in contrast to considering all biospecimens to be human subjects research, which is the primary proposal in the NPRM, we would instead narrow that expansion of the definition of a human subject to only research involving whole genome sequencing data. So this is proposal A that's asked about in these couple of questions.
So the first question I’ll take on is one submitted by Celia Hagan, and she is representing the Association of Public Health Laboratories, and they're two sort of related questions that she posed. One was if the states were to mandate whole genome sequencing of newborn blood spots to detect pathogens, would this be considered human subjects research? And to this question the answer really is that it depends on the purpose of the whole genome sequencing activity. If the whole genome sequencing is being mandated by the states in order to treat the newborn, so it's a clinical purpose for the whole genome sequencing, then this is something that under the current rule is not considered to be a research activity and this would fall outside of the regulations, and that would continue to be the case even under alternative A that I mentioned. In contrast, though, if the whole genome sequencing was being done for a research purpose, such as to develop some kind of new test to identify a pathogen, then this kind of research would be covered by the regulations. Okay?
So her next question related to proposal A was: would whole genome sequencing of human specimens to detect pathogens be considered human subjects research? And so this kind of research would involve the filtering of human sequences in order to analyze the nonhuman sequences, the nonhuman sequences of pathogens for example. So assuming that we're talking about this sequencing being for research purposes, then as I mentioned earlier in one of the responses to a prior question, the issue really turns on whether this is human subjects research or not.
So in the circumstance where the human sequence is being analyzed simply to parse it from the pathogen sequence, which is really the interest of the researchers, right? And if the research is only going to be performed then using the sequence of the pathogens of interest, then this is the kind of activity we would consider to be not involving not a human subject because the research on the pathogen sequence is not about the individual. So this again gets to the part of the definition of a human subject that relates to the need for the information to be about the individual. And in this case, if it's really just about the pathogen then we would consider that not to be human subjects research. Okay?
So the second question, also related to the alternative proposal A, was submitted the same person Celia, from the Association of Public Health Laboratories, and her question was: If one of the two alternative proposals was put in place, for example, only whole genome sequencing is considered a biospecimen, would informed consent be considered for all biospecimens or just limited to whole genome sequencing data?
So as we pointed out earlier in the day, the two alternatives that are discussed are in fact narrower proposed expansions of the definition of human subject than the ones actually proposed in the NPRM.
So under the first alternative proposal, the one about whole genome sequencing, only research use of the biospecimen involving whole genome sequencing data would then be covered, right?
It wouldn't be covering all biospecimens irrespective of identifiability. And similarly, with regard to proposal B, which is also a narrower expansion of the definition but broader than proposal A, we would be only covering information or biospecimens used to create the so called biounique information. So information that is unique to an individual that if combined with publicly available information, it would in fact create a possibility that at least some individuals whose specimens could be identified. So this proposal B again, is not proposing to cover all biospecimens use, indeed research, but only the subset of biospecimens used in research to generate this biounique information.
The third question I will address, again submitted by Celia Hagan, from the Association of Public Health Laboratories, relates to biospecimens too, and her question here is saying that the identification of the human subject from whole genome sequencing or even partial sequences in most if not all cases, would require intentionality on the part of the researcher. Has OHRP considered making it unlawful to reidentify a deidentified specimen?
So some of you may remember that our Advanced Notice of Proposed Rulemaking actually did discuss the possibility of prohibiting reidentification of nonidentifiable information, and this is something we did receive public comments on in response to the advance notice, and some of the commenters were noting that for some types of research, it would in fact be legitimate for researchers to reidentify subjects if they were initially just obtaining nonidentifiable or deidentified specimens, and one example put forward in the comments was that there's some research that specifically is designed to evaluate or develop a methodology to reidentify people, right.
So certainly in that circumstance, the public commenters were saying to us,that ought to be at least an exemption if there would be created a rule that would prohibit reidentification of nonidentifiable information. So I guess specifically, a bit more specific to the question, I guess I wanted to mention that there are rules that our regulations could put in place that would prohibit reidentification, and it's a question of whether there are certain types of research or certain types of activities that we ought to prohibit or permit reidentification.
A couple places where our rules could speak to this issue for example would be in the exclusions, you know as a condition of satisfying an exclusion, you know should there be sort of built into that exclusion some kind of prohibition on investigators being able to reidentify individuals.
That would be one place.
Another would be a place in terms of one of the exemptions and more than one of the exemptions, a condition of the exemption would be that investigators would be prohibited from attempting to reidentify individuals, and then another place in the proposal that I think might be appropriate for this question to be considered is in the proposed safeguards for privacy, where there could in fact be built into those sort of baseline protect ions, some kind of standard about prohibiting reidentification where appropriate: so just some thoughts about if you want to submit comments on this issue, places where you might think about providing a specific comment in the proposals.
And finally, the fourth question that I'll take on now relates to the exclusion for the use of nonidentifiable biospecimens, and you'll remember from Jerry's presentation that this is the exclusion that is specifically talking about the use of a specimen collected for some other purpose, right? So the secondary use of a biospecimen that's not identifiable where the purpose of the research is to generate information that is not already known about an individual.
So this question was from Carol Wilde, and there are really two related questions that she has posed to us. One is, would molecular research on biological procedures or mechanisms meet this exclusion? And to this question the NPRM is really not specific as to whether or not this kind of research would fall into this proposed exclusion. You know where the information that's expected to be generated isn't necessarily going to be about an individual per se but instead is going to be more about the biological processes, right? Where the research is designed to provide information about biological procedures or mechanisms and not necessarily trying to develop information specific or unique to the person but more generalizable knowledge, right? To inform the field about this biological mechanisms of interest.
So we certainly encourage comment on this issue whether this should be clarified, in terms of whether such research should be either within or outside of the scope of this exclusion, or whether perhaps there should be additional exclusion for the use of nonidentified biospecimens that would be used for this type of research.
Her second question related to this exclusion is, how does the exclusion account for the possibility that research to develop or validate a diagnostic assay could produce new information about specimen donors such as suspected germ line data in a tumor sample? So I’ll just call your attention to the part of the exclusion proposed that talks about the purpose of the research or the design of the research only being to generate information about an individual that is already known. Right? So in the case where the research is in fact being designed to develop or produce new information about specimen donors, such as some kind of suspected germ line data in a tumor sample, then this kind of research would seem to fall outside of the proposed exclusion.
But again, we're looking for public comments about whether we've drawn that line appropriately, whether we should draw the line somewhere else and allow for more research like this to fall into an exclusion, either this one or another, or if such research should not be included within this exclusion, whether there are ways in which we could make that more clear. So I’ll stop there and turn it back to you, Wanda.
WANDA K. JONES:
Thanks, Julie, and for those of you just returning with hot beverages, now that you are fortified, the microphones on the floor remain open. So we encourage you – we have a lucky volunteer ready to step up. If you weren't here for the original orientation, it's two minutes. Are we still running the timer? We haven't needed to enforce, everyone's been so amazingly respectful and I do take turns across the mikes, but we will start here in the middle. Identify yourself and affiliation if you choose and we will provide an answer to your question.
Thank you, Tracy, Clemson University, thank you for the opportunity to have the discussion.
The proposed changes allow investigators to self-determine exemption using the decision tool.
In response to Norma’s earlier question about the decision tool, you mentioned that the tool may ask something like, “Are you using encryption to transmit data?” If the investigator answers that question “yes” and exempts and then they fail to do that, they fail to use encryption, they fail to do something else they asserted they will do in that decision tool, what are the repercussions?
Who's held responsible for that?
PRESENTER: JERRY MENIKOFF
Okay, so a good question.
Just getting back to the starting premise, this may be just terminology, again the tool will give the investigator a determination about, so whether you call that self-determination, it's designed to take the investigator's input in terms of what they're going to do, I guess I would analogize the scenario you're coming up with as similar to what would occur now if most institutions do in fact review protocols to determine whether or not they're exempt and as part of that review, it is dependent on the facts that the investigator puts in the protocol. I think our premise in terms of decision tool is that's a way of laying out exactly what the facts are in terms of what this research study involves.
Let's imagine under the current rules a scenario in which the investigator says they will do x, x was in fact something they had to do to be exempt under the current rules, and they ended up not doing x. If the study was conducted and it was not subject to IRB review, but at some point required IRB review, because perhaps one characterization could be the investigator changed the study, but they changed the study in a way in that changed a study that was exempt to not being exempt at that point, yes, there would be a legitimate issue that a study was being conducted at that point that no longer was exempt, and I assume the same thing would happen under whether it's OHRP or some other branch of the federal government or policy. If somebody pointed this out to us that we could look into it and say yes, there's a determination of this thing happened and this study should have obtained IRB review in terms of our policies and procedure. In general we're about making sure the right thing happens goes forward, so generally an institution then proposes remedial action to make sure in the future that this type of thing does not happen. In terms of that, we generally try to make sure the facts are laid out to make it clear where the blame is, so if it's some investigator who on their own is not a problem with the institution’s policies or procedures, that this investigator didn't do the appropriate thing, namely informing an administrator that the study was changed in a way had that change would conclude, someone would conclude it's no longer exempt.
I'm saying we would highlight who’s at fault and the main issue in terms in remedial action would be to make sure the institution makes it clear, “investigator you did a bad thing and you shouldn't have done this,” and to an extent there was training needed to tell other investigators when you change a study even if it was originally exempt, you need to get review again.
I think, again, analogously, I don't think the way that is dealt with is all that different under the new procedures except that one part of review would be going through the decision tool instead of currently having administrator make the determination, but if the study gets changed in a way that it went from being exempt to not exempt, and we probably say this somewhere, my assumption is that we would have to get it reviewed or get it filed for a change or whatever. There will always be circumstances when you start out with a study that's exempted and you change it in a way that it's no longer exempt and there that to be a procedure to allow to that to happen and have appropriate review.
Does that get to what you're asking about?
Good point. Thank you.
WANDA K. JONES:
Thank you, over here.
Chelsea Rutherford. I have a question about the quality improvement and healthcare operations exclusions. Could you all clarify the types of quality improvement activities or healthcare operations that would fall outside of the scope of these new exclusions and thus potentially be considered human subjects research. By way of example, how would the NPRM treat activities designed to determine whether a medical treatment is or is not more effective than the other which the NPRM notes would not meet the quality exclusion definition?
PRESENTER: JERRY MENIKOFF
Okay, yeah, so basically I think you're correctly stating, the purpose of the exclusion was the starting premise is we have something that we know works, and the problem, for example, is that not enough doctors are doing this. We know again just one of them laid out because this is one of the things, the checklist study where we're inserting a researcher, Dr. (indecipherable) was involved with the study to insert central lines into people and it was known that there were certain types of things doctors should do that everybody agreed are good things, appropriate things to do to minimize the likelihood of infections coming along, and let's assume the doctor who was doing this thing in the future discovered that only 60 percent of doctors actually doing this, so you implement some method to identify the patients who are getting central lines to try to see if there's a way to increase the 60 percent to closer to a hundred percent.
That is the type of activity that the exclusion is about and the premise is that, well, you're trying to actually get more of the right thing to happen, and that is a good thing, and hopefully the risks of these types of studies are low, and some of these studies could be real research or an institution just implementing something that's designed to again, the premise is that you're doing something to encourage implementation of a good practice or the reverse, discourage implementation of a bad practice. But in terms of the alternative study you're talking about, if the research question is whether or not the accepted practice, you're looking at how good the accepted practice is, no. This exclusion is not designed to exclude that.
So for example, comparative effectiveness studies. Those, and it depends on the studies, some may involve minimal risk. And in any effect this exclusion is about the implementation, studying ways to implement and encourage people, healthcare providers, to do the right thing in terms of using things we think are good.
The premise of the alternative study is very, very different. It's looking at what are the risks of the practice, what are the benefits of the practice, is this type of treatment better than another type of treatment. Those are almost standard, more standard types of clinical trials that this exclusion is not designed to exclude.
If that clarifies at least what we're trying to get at in terms of the dividing line, it could be some of the research studying to answer the first question may end up providing information that tells you something about how good the accepted practice is, but you can't start out designing a study that really is for evaluating the accepted practice. To be excluded, it has to be a study that is designed and generally intended to be about looking at implementation of that accepted practice instead of the practice instead of the purpose really about is it as good as we think it is, is it better or worse for the same type of practice for the same time of medical condition.
WANDA K. JONES:
Thanks, to the microphone.
Hi, I'm with Washington University. I want to hear more about the revision of the proposed informed consent process, specifically talking about reducing the burden of informed consent on participants and better educating them on truly the risk, but with the essential elements of consent right now that are documented in each document, how would those essential elements be revised and what do you see being pulled out of the consent document and maybe put in an appendix?
PRESENTER: JERRY MENIKOFF
Okay. I'm not sure I'm going to be able to give you a lot of detail on this because the NPRM at present has sort of somewhat general new rules about this and a lot of this will come out both from seeing what the public comments are, and so we certainly encourage you to provide public comments on this.
Various groups over time have looked at issues relating to consent forms, and many of them have said, as I indicated earlier, we can hopefully do a better job, all the things I sort of laid out in the overview – consent forms are long, often you bury the key things in the midst of other language that isn't all that important.
So the premise is that in particular the listed items in terms of required elements of consent have to be in this core consent document, and guidance will be provided, and of course, based on the comments, the NPRM itself may give more specifics but that - let me give you an example of a clinical trial, the heart of the clinical trial, somebody has a bad medical problem, they have a cancer that's hard to treat. What they're primarily concerned about is, “What's my chance at being cured with the treatments that are out there now?” If I'm enrolled in the clinical trial, what are the various arms, what will happen to those arms, what is the thinking about the differences in terms of what would happen to me if I receive those arms and what it would mean for me? So presumably for that person, they're going to worry about, “Is this going to increase my chance of the cancer being cured? Or is it going to increase the time period in which the cancer would be in remission? Is it perhaps only going to make my symptoms better?”
Some of this relates to the core consent form being shorter, being more to the point in terms of immediately in the first several pages, again, this core consent form verses the appendixes saying here's the cancer you have, here's what's likely going to happen if have you standard care.
If you enrolled in this research study, here's what's going to happen to you and it may be a 50% chance of this, 50% chance of this.
What does this mean in an appropriate level of detail? And just to give an example, if you're doing a clinical trial in which pretty much it's very, very sure or very, very unlikely that you will actually increase the chance that the person gets cured, you shouldn’t have a benefit section that’s vague says you may or may not benefit which is not all that uncommon in certain types of consent forms and give that specific. It's very unlikely it will increase your chance of cure. What may occur, but we're not sure this will occur, but if you randomize with the arm to the new drug you may have a longer period of remission, you may feel better, et cetera, et cetera.
In terms of risks, this is picking up the things FDA has said in terms of recent guidance and in terms of what to say for informed consent, “Are there ways of summarizing the risk instead of having 12 pages of these charts about very likely, some are likely, unlikely that are so complicated that nobody can make sense out of this, and particularly if they're drugs people have been using for years but not using on this cancer, they'll say here's how sick you will be if you're in arm A, and in arm B you will be sicker, more nauseous in one arm, 20% of in one arm verses 50% in one arm. These are the things, the things people should be worrying about and thinking about being in this trial.
And some of the other things that are a little less consequential, for example, the details of which days in the week you're going to go to this place or that place or how many of this blood test or that thing are probably not that crucial in terms of pages and pages of listed procedures. Again all this information should be given to the person, but it should be in the appendix. Does this give you some sense of where we're going toward?
We acknowledge it will be difficult.
[indiscernible]. If you can hear me? Just to add to what Jerry said, the NPRM does include three specific additional elements for informed consent if they are appropriate that have to do with whether or not you may be recontacted at some point in the future. If a commercial product is going to be developed based on the use of your specimen or information, whether you will get to share in the returns of that product or not, and thirdly if there are, might be individual clinical results that might be returned to you.
And just another point to make it explicit, building on Jerry's comments, you know this is an area in terms of what ought to be included in the so-called core consent document verses the appendix that we recognize would need guidance from us. And so we certainly are encouraging comments along the lines of helping us develop a guidance document that would be more useful to the community. What are the areas of clarification that would be most helpful in terms of the guidance that we would develop to make it more clear what the regulatory expectations would be in this regard?
WANDA K. JONES:
Okay, we are going over here.
Hi, I’m Michelle from the Dana-Farber Cancer Institute. Can research that would fall under one of the proposed exclusions be done with children, pregnant women, and prisoners, currently vulnerable populations with special protections? I think the simple answer is yes.
Okay. Go ahead.
The one exception would be the exclusion that has to do with educational tests, surveys, interview techniques, observation of public behavior.
WANDA K. JONES:
So here's my working plan. We have two questioners at the microphones, we will take those, I will turn back to questions submitted in advance, after we get these questions, so we're trying to give equal opportunity to be heard, but you're here and I think you deserve time at the mike and we will get to the written questions. So please.
PRESENTER: NORMA EPLEY
You're going to get tired of me! Norma Epley, East CarolinaUniversity.
My question has to do with, first, have you talked to NCI about the length of their consent forms?
And have you considered something like a tiered consent? Where the core elements are there at the first, but we don't give them additional information until that procedure is actually coming up or that visit is coming up? Maybe the visit before? Something like that?
PRESENTER: JERRY MENIKOFF
So at various times, we have had discussions with people at NCI and NIH, there are conversations occurring all the time about consent forms, and we all acknowledge this is a complicated difficult area, and I think all of us probably share similar goals and it's just not easy to do. I mean people have debated this over decades and it's like, what can you do to improve things. So this is where we're trying to go in terms of that.
Then in terms of tiered consent, I don't think anything in the NRPM specifically proposes that, but we certainly again welcome comments about it, this is a complicated area.
Our goal is for people who share the goal of getting prospective subjects better informed, absolutely, we encourage people, as Julie and Julia and Ivor, too, were noting, if you have ideas about ways to sort of modify what we're proposing in terms of the general changes in the informed consent rules including tiered consent, just changing over different periods of time. People have talked about as we're moving more to, for example, doing more interactive things with computers and web-based things which give you different opportunities, for example, allow them to click on things to get extra information and sometimes not to click on things. These are all interesting areas that we certainly welcome comments about what you think would or would not work and particularly innovative ideas of what you're saying in terms of tiered consent. Those will be useful so do provide them and I encourage others to provide them.
WANDA K. JONES:
Over here in the front.
MARY JANE WELCH:
I'm Jane Welch from Rush University in Chicago, and I think this conversation about informed consent is very interesting, and of all of this in my humble opinion this is the most important piece of work you're doing. So listening to your conversation, I wonder: Is it within the purview of HHS to say, “Under no circumstances will an informed consent form ever be able to be used in a legal manner?” In other words we've had lawyers coming in saying, “There's not an informed consent form I can't break in five minutes,” I'm quoting. That's really not the purpose of the informed consent, the actual purpose of the informed consent is to inform the subject, but then we have institutional attorneys who are listening to people going, “We have to get this in there, we have to get that in there, we have to get this in there.”
If you were able to say, an informed consent's one purpose is to inform the subject and it can't be used for any other purpose, is that even feasible?
PRESENTER: JERRY MENIKOFF
Very interesting question. I suspect it's going to be hard to – it's a nice idea, I suspect that would be a hard thing to do because the legal issues you're concerned about are probably state law issues. You're talking about, you know, lawsuits under tort law in terms of malpractice and whether adequate consent was obtained. In general those are not lawsuits that actually involve violations of federal rules but rather violations of state law. And I think for HHS to be overriding somehow state laws, probably, certainly isn't within the scope of the grant of authority that OHRP and the other Common Rule agencies have, and I would guess you would need, like, federal legislation or something, and whether it can do it. So this is way beyond the scope of probably what HRP, you know a recommendation oh to congress, or to the states to not use it, maybe that is something you can do at your end in terms of working with your state legislators, and saying here's what you do or do not want to allow these consent forms to be used for. My general sense is this would be a very complicated thing, but it's a very interesting idea and thanks for mentioning it.
WANDA K. JONES:
Super. So folks who cared enough to send their questions in advance, we are going to try to work our way methodically through them. I would note that it's just about 11:27 and aside from my echo, Julie Kaneshiro, you had more biospecimens.
Red mike, okay, continuing with the biospecimen theme, there were five additional questions on biospecimens that I was going to address with you now. Three of them relate to identifiability under the regulations. One relates to the proposed more stringent waiver criteria with the research use of biospecimens, and the final one relates to the definition of research as it pertains to research of biospecimens.
All right, so first to get to the ones that address identifiability. The first one I will speak to was submitted by Celia Hagan, again from the Association of Public Health Laboratories, and the question was: if consent has to be obtained for the research of biospecimens that lack identifiers, doesn't this process increase the chance that the identity of these specimens will be discovered?
So, this certainly is possible. We don't know whether it's going, this consent requirement would make it more likely that specimens could in fact become identifiable. We did receive comments along the lines of this commenter or this question as well, noting that needing to track the consent associated with biospecimens could in fact increase the risk of reidentification.
I believe that the answer in part at least depends on how that link would be maintained and it doesn't necessarily have to be a link back to identifiable biospecimens; the consent, whether it could be done in some other kind of format. You know maybe it's just a different kind of code, right? Or even like a color coding that we've talked about in the past. So I think this is an open question. We recognize that this is a concern, though, and certainly are open to hearing your comments about this issue.
The other question about identifiability, again from Celia Hagan from the Association of Public Health Laboratories: “Is there consensus that the DNA of that specimen renders that specimen identifiable, and are there specimens that do not contain vanishing small amounts of DNA that could be amplified and sequenced?” And you know, to this question, there are certainly different views about how to appropriately identify a standard of identifiability, so I don't think there is consensus per se about how identifiability should be defined, but I want to say that for purposes of the NPRM this is not a line that we draw with regard to whether specimens should be involved to human subjects or not. Instead, we're proposing that all specimens irrespective of identifiability, or irrespective of whether they contain DNA, ought to be considered in the scope of the definition of a human subject.
And just to echo what you heard from Jerry and others already, the premise for this proposed change didn't have to do with the risk of reidentification, the risk of potential harm to subject from being able to be reidentified, but instead is intended to indicate our respect for individuals’ interest in controlling the use of their specimens in research irrespective of identifiability. So you know we certainly recognize this point is arguable, debatable, whether we've drawn the appropriate line, whether we're emphasizing the appropriate ethical principle in this proposal. There are ways we could have drawn this line, and specifically as I mentioned before, there are two alternative proposals that we discussed in the NPRM about how that line might be drawn differently and cover a smaller subset of biospecimen, so please do provide us comments on this point.
And the third question related to identifiability by Celia Hagan, from the Association of Public Health Laboratories, she said or asked: notwithstanding obligations to maintain confidentiality, does it matter if a specimen is identifiable if most uses will require informed consent anyway?
So an interesting question. It is true that the NPRM treats all secondary research involving biospecimens in the same way at least for the most part, but there were two areas identified in the NPRM that seemed to draw distinction between the use of nonidentified versus identifiable specimens, and one of those has to do with the exclusion I mentioned, previously the exclusion of the research on nonidentified biospecimens specifically to generate information that's already known about the individual, so this is an exclusion that would not apply to the use of identified biospecimens.
And the other is we propose new waiver criteria in addition to the waiver criteria that are already in the Common Rule, and one of those new waiver criteria proposes that the IRB would have to find that in the circumstance where the research involves accessing or use of identifiable biospecimens or identifiable information, that the research could not practicably be carried out without accessing or using those identifiers. So it's establishing sort of a default that a researcher has to justify the need for the identifiers, and this is something that we try to make harmonious with the Privacy Rule, so these may look familiar with the Privacy Rule with the waiver of authorization because we try to incorporate a new element that mirrors the Privacy Rule element for waiver.
So those are the questions related to identifiability.
One question we got related to the provisions for waiving informed consent that are proposed specifically for the use of biospecimens, and we've talked about these a bit already, where there are new waiver criteria that are intended to make a waiver of consent very uncommon or rare for the use of biospecimens and Jerry spoke to these in his presentation.
There are two additional criteria here that we're proposing.
One is that they're actually compelling scientific reasons for the research use of biospecimens, and second that the research could not be conducted with other biospecimens for which informed consent could be obtained. So the question that we received about these waiver criteria was from MarciaIverson from the Blood Research Institute and Blood Center of Wisconsin, and specific to these waiver criteria, she asked whether a waiver of consent could be granted for so-called valuable research using residual biospecimens from outside sources where there is no opportunity to obtain consent.
And so to this question, I think that the waiver criteria are really establishing a different bar that it not just be that the research is valuable, I think valuable research alone would not seem to meet these two waiver criteria, that there was in fact a compelling need, compelling scientific reason, for conducting this research and that the research could not in fact be carried out using specimens for which consent had been or could be obtained, so this is the NPRM is proposing to modify the standard that IRBs are currently using and making the waiver of informed consent for research involving biospecimens much less common.
The second related question that she asked about the waiver criteria is how IRBs should determine that research could not be conducted with other biospecimens for which consent was or could be obtained, and here the NPRM really does not specify how IRBs should make this determination, and so we are certainly encouraging your comments on this specific issue to help elucidate this question. If it would be helpful for the proposed regulatory text itself to provide more specific details about what that standard ought to be or whether there ought to be guidance on this point or any other creative ideas you have, we would certainly welcome your input.
And then finally, the fifth question I'll address here relates to the definition of research and the question was submitted by Celia Haganfrom the Association of Public Health Laboratories, and the question is: “Would genomic sequencing require consent if it were part of a mandated newborn screening program?” And this is a question that isn’t specifically related to any of the changes proposed in the NPRM. It's about our core definition of research and the answer is that no, this kind of activity where the states or presumably the states are mandating newborn screening fully for clinical and not for research purposes the Common Rule would not apply to this activity currently under the regulation or under the proposed rule.
That wraps it up for me, Wanda.
WANDA K. JONES:
Let me check with the audience. We have a volunteer jumping up to the microphone.
If you have questions in the audience this is your chance, we have two other microphones available.
PRESENTER: DEANA AROUND HIM
DEANA AROUND HIM:
I’m Deana, I'm with the National Congress of American Indians. I had a question that relates to questions about minority perspectives with the NPRM previously. American Indians and Alaska Natives are often classified within that minority group, but federally recognized tribes actually have sovereign status, they’re tribal nations. So for some tribes research review processes are guided by regulatory entities like IRBs, and those bodies have FWAs, and those bodies are able to take into account both individual protections as well as community protections. And I was wondering how the NPRM accounts for tribal consultation policies and interaction with tribes? Not all tribal entities have a research review process in place, so how can we protect the sovereignty of those tribal nations and citizens in this process?
PRESENTER: JULIE KANESHIRO
You know the straightforward answer is that the NPRM isn't actually proposing any change in this regard, so please do tell us if you think there are changes to the rule that you believe would make the input from tribal governments either necessary or more explicitly required as part of our regulations.
We welcome that.
Then there is a provision currently under our regulations that we're not proposing to alter, so this is status quo under the rule, that indicates that compliance with the Common Rule requires compliance with pertinent federal laws or regulations which provide additional protections for human subjects. So depending on the federal rules you're talking about, this is one area where those rules might in fact also be required, even under the Common Rule.
And in addition there's another provision in the current Common Rule, again, that we're not proposing to modify, that states this policy does not affect any state or local laws or regulations which may otherwise be applicable and which provide additional protections for human subjects. But to the extent you think there's additional provisions that would be beneficial for protecting subjects, particularly the populations you're interested in, please do provide us with input.
Yeah. Just one other place where the proposal might take that, those kinds of considerations into account. The proposal having to do with single IRB review of multisite trials does have a loophole if you will for the agency to decide that you know for a particular trial, single IRB review might not be appropriate. There might be a need for additional review of some sort. This might be an example of the kind of circumstance in which the agency would make use of that provision.
Lisa Nichols from the Council on Governmental Relations. I know there's been some concern, we've hear concerns from universities, about the fact that the NPRM looks a lot like an ANPRM, just in that it has a lot of questions and proposals and areas where tools and safeguards haven't been developed, and we were wondering if OHRP would consider a round of comments on something that looks closer to a final rule, such as interim final rule for example?
PRESENTER: JERRY MENIKOFF
I think as Wanda and others noted earlier, everything is on the table now so do feel free, yourself or others, in terms of proposing what things should happen now, including possible changes in the procedure by which we move forward to a change in the regulations.
WANDA K. JONES:
Other questions from the audience? We will turn again to questions submitted in advance.
This is a practical question and it is about the broad consent, if in fact we're expecting clinicians to obtain broad consent for the use of specimens that they are collecting and then sending to pathology: who's responsible for maintaining those consent documents? Do you envision these documents going with the sample to pathology, or is the physician going to be responsible?
Are they going to forward it to the IRB office? How do you envision that working?
PRESENTER: IVOR PRITCHARD
I suspect that there's going to be more than one way to skin this cat. That depending on what the institution is, what the volume is of the specimens that it collecting, that some institutions may choose to simply tag the specimen directly. Some institutions may use a more elaborate procedure, if they're talking about a larger number of specimens. I don't think it's the case that the clinician necessarily is always going to be the person who is going to make the request for the broad consent. It might be someone else on the institutional staff. I don't think this is something for which there is a single model envisaged.
So if OHRP comes in for a visit and we don't have in our institution copies of those consents, then are we out of compliance?
You mean in the IRB office you don't have copy of those consents?
No, you would not be out of compliance. The issue, the only circumstance where noncompliance would occur would be at the point at which someone could demonstrate that a specimen was being used without having someone's checking to see whether broad consent had been achieved, or had been received for the use of that specimen.
Okay, thank you.
WANDA K. JONES:
And for the record, Ivorthe cat did not consent to being skinned, so we will make that clear for the record in the vernacular. So now we have a chunk of broad consent questions, so I'm going to turn to Ivor for answers to those questions that were submitted in advance, and if again if you're thinking of something, something is taking hold in your brain, get it ready because I will turn back to the audience once Ivor takes these broad consent questions.
I confess I don't know anything about the animal consent regulations. So I will address questions that are somehow related to broad consent regulations.
There were two questions submitted related to the 10-year limit provision. Sarah Goldkind, who is a bioethics consultant, asked the question about why the 10-year limit specifically, and I already answered that in terms of the tradeoff between how much time is reasonable for someone to be able to have a full appreciation of the period of time over which specimens or information could be collected, versus allowing for a significant amount of time for that consent to cover.
The other question was submitted by the industrious Celia Hagan, her question is related to the 10-year expiration date on residual clinical specimens after consent has expired. Would laboratories need to destroy the biospecimens or can laboratories keep these specimens but not link the old specimens to any new data unless consent is obtained again?
The answer is there is no requirement whatsoever to destroy residual clinical specimens. The 10-year limit refers to how far in the future specimens and information can be collected under the broad consent, not how long they can be kept. A separate provision at 116(c)(1)(iii) calls for a description of how long investigators may conduct research using the collected specimens and data, and that length of time could be any number of years afterward or indefinitely.
There were two questions that we received that somehow have to do with the process of informed consent with regard to the broad consent provision. The first one comes from Carlos Rodriguez at Wake Forest University School of Medicine. His concern was that the prospective subject in a clinical context might be concerned about whether their care is going to be compromised depending on whether they agree or don't agree to the broad consent for secondary research use of their biospecimen.
And of course we believe that the voluntariness of the consent in the broad consent circumstance is an important thing to make sure it takes place, and one of the things that the limited IRB review provision for this exemption, which looks at the procedures for the obtaining of broad consent for research use of biospecimens, would obviously be to make sure that patients who are prospective subjects fully appreciate that their care is unrelated to their decision about whether to participate or not through the broad consent.
We had one question from Celia Haganabout the involvement of multiple institutions in research and how many broad consents are necessary in that circumstance. Public health laboratories do not deal directly with patients. Is the consent only applicable to the institution that collected the consent, the healthcare provider, or would public health laboratories need to get additional consent? If the broad consent is applicable, how would laboratories document that the submitting institution received research consent?
So the answer is that the original broad consent would be the only consent that would be needed for research involving multiple institutions. The healthcare provider’s institution would be responsible for obtaining broad consent and assure the public health laboratory that this had been accomplished. Sections 116(c)(i) and (vi) address how the broad consent identifies the range of other institutions, how they may perform research with the specimens, and how the specimens documented would depend on the institutions involved.
So I have five down and five to go. You want me to keep going or do you want to pause?
WANDA K. JONES:
Audience, are there questions coming to the microphone? People seem a little antsy.
So the webcast is working well, and I have a question. It goes to the phrase “about whom” to the biospecimen exclusion, and if I could take us back to the extracted teeth, and the question that came up was: Are extracted teeth biospecimens? I think yes, and the panel has said that they might not fall under the definition of human subject depending on what you were doing the with the extracted teeth, am I correct? Okay.
So is the question that has come up is, and there was further discussion I believe about this in the context of the word pathogen. I think, Julie, you said if you were looking at the pathogen you weren't look at the person from whom the specimen was obtained. So the question is, if you have a biospecimen that's been deidentified, how could it ever be about that person? In other words it's never going to be “about whom” because it's been deidentified.
PRESENTER: IVOR PRITCHARD
The presumption is that possibly you could reidentify them.
And beyond the issue of identifiability it's about the information on the individual that the exclusion is getting to, not necessarily the availability of the individual to be identified. Right?
Because you know the biospecimen provision isn't sort of premised on that notion and similarly the exclusion isn't. It's really the autonomy interest that is driving the basis for that proposed exclusion and as Jerry noted, you know if the research is designed not to generate new information about that person, right? That you already know they have x disorder, right?
And you're trying to develop a new diagnostic test to see whether it accurately identifies whether that person has or doesn't have that disorder, you're not generating anything new about that person, right?
So irrespective of identifiability, I think that that question or that issue is still relevant.
So if you have 20 biospecimens deidentified from individuals who had a diagnosis of Alzheimer’s and you are looking for a mutation, does that fall under the exclusion?
You're looking for a mutation on to see whether it's exists if are predicting or indicating whether they would actually get Alzheimer’s.
All these people if they have the same mutation, then maybe that's the mutation scientists will look for in the future? Is that research that would be excluded?
You know I think this is similar to the question I answered before about whether if you're looking at sort of basic questions about basic biology you know and it's not really about the individual per se, should it fall within the exclusion or not. I'm not sure whether it's exactly the same or not but in this case, and others may have other things to say here, it sounds like you're talking about trying to find out whether these particular individuals who are known to have Alzheimer’s actually also have a mutation?
And in that case it seems to me like new information about those individuals, right? And if that's true then it would seem to fall outside of the exclusion.
Do others have something to add here?
Yes. I fully agree with that.
You're learning something new about the person, and even if that person is in front of you they may have concerns that you shouldn't be able to learn that piece of information about them, so more broadly for example, the Presidential Commission on the Study of Bioethical Issues has written about whole genome sequencing on the theory that part of it may relate to privacy interests and risks relating to sort of identifiability, but also it could be that many of us perhaps think that there shouldn't be somebody out there who has the ability to decode or sequence our entire genome and they're able to do that and we don't been that and we have no say so about that.
So we have an autonomy process. And when the BRCA1 or BRCA2 mutations were discovered, there were concerns in the Ashkenazi Jewish community, and there was concern that maybe we don't want researchers to have the ability to sort of detect this genetic mutation because it could mean that this community could be targeted or identified as being particularly sick or something in a way that would cause them to be thought of in a negative way.
So again this has nothing to do with particular individuals but it's getting back to the premise, even being able to learn that certain people with Alzheimer’s disease have a particular genetic mutation. It could be down the road that that particular mutation means you're going to go downhill very, very rapidly or something, so this gets back to the proposal being very broad basically in terms of saying: as long as you're learning something new about an individual that has this sort of genetic code or whatever it is, that might be something that for good or bad reasons that person wants to be able to control and say yes or no to. So at least the proposal accepts that in terms of a broad sense of autonomy, and that's why we're going out for comment, people may disagree with that dividing line. They may say this whole autonomy thing is not counterbalanced by the down side in terms of our decreasing ability to do this research because we need to get consent. So those are some of the issues and we certainly welcome lots of comments on this dividing line.
WANDA K. JONES:
Thank you, and I'll note it's 11:56, so I have five more questions. Ivor, we also have 10, 20, 32 questions. When finished we intended to answer all the questions submitted in advance throughout the day today.
We will reconvene after lunch.
We're not going to make you skip your lunch and soldier on through answering these questions but your prerogative, you want to wait? We'll break now and reconvene at 1:00o'clock. Since we have just those few minutes, I've wasted one of them already.
Okay, so folks again on the back of your agenda, a little map of the area if you want to leave the building. Looks like a beautiful day back here, but do be back here at 1:00o'clock. If you would like to try our cafeteria, if you have not already, there's a wide range of options and price-wise you're going to come out about the same. Timewise it might be better going up stairs, you will need an escort so if you made a friend for your hot beverage, find that friend again or other HHS colleagues, you know let folks know that can you help them get where they need to go. We will see you again at 1:00o'clock and we will likely be finishing early, but thank you all very much for your interest and participation this morning and we hope to see you at one. Thank you.
BREAK FOR LUNCH
MODERATOR: WANDA K. JONES
WANDA K. JONES:
So, here we are back again for the public question and answer session on the proposed rule on human subject protection known as the Common Rule. We're joined here at Health and Human Services headquarters by a number of our federal colleagues, and it has come to my attention that we had three departments who did not take the opportunity to introduce themselves earlier. So I'm going to call upon them now, and there's a microphone right next to these three gentleman, so USAID and the Department of Labor and Department of Education, if you would each introduce yourself please. If there are federal colleagues on departments and agencies, Common Rule agencies who joined us, please also jump up to the mike.
I'm Lee Claypool, from the U.S. AID, The U.S. Agency for International Development. So I certainly am glad to hear the input and discussions this morning and continuing and welcome any comments that are directly shared with USAID and myself, Lee Clayton, thank you.
JEFFERY W. RODAMAR:
I’m Jeffery Rodamar, I’m with the Department of Education, no longer deidentified. I look forward to any comments related to socio-behavioral research and educational testing especially. Thank you
I'm Chris Chapman representing the Department of Labor, Bureau of Labor Statistics.
WANDA K. JONES:
Great. Thank you. Are there any federal colleagues that didn't get a chance to introduce themselves? Is anybody new to the meeting? Jane from FDA, okay.
Christina Heide. Office for HHS Civil Rights and we do HIPAA. Thank you.
WANDA K. JONES:
So all your HIPAA questions, there's your woman. Excellent. Has anybody just newly joined us for the afternoon session?
No, okay, so we understand too that some of you may have had a chance to chat or formulate questions, so we're going to continue on that same format that we followed this morning.
I'm going to turn first to Ivor Pritchard and have him finish his five. There were five questions in the broad consent bucket that he had left to answer that were submitted in advance, and then I'll turn to the audience for microphone opportunities, and then we'll come back to the panel and we'll keep going like that until we get through the remaining 37 questions. Okay?
And as a matter of fact I made a mistake and overlooked one question, so I actually have six more questions about broad consent to respond to.
Speaking of time, Sara Goldkind also asked a question about one of the NPRM estimates that it would take an investigator five minutes per person to conduct the consent process specific to broad consent, which included the time for the investigator to log information into the appropriate database. It would take an additional five minutes for subjects to engage in the process of having broad consent for future research uses of their biospecimens or information. What is the basis for this 10-minute estimate?
We did consult with various colleagues within the government to try and get a handle on some kind of estimate. The evidence as you might expect is somewhat scant, but we did have some information to inform this estimate, but it is certainly an estimate, and you have good data about how long this process would in fact take, that's certainly something that you ought to, we would like for to you submit, so that we can have the best possible estimate of what the regulatory impact is of this provision.
There was another question about the informed consent process, also from Sara Goldkind. What provisions of the NPRM will ensure the process of obtaining broad consent in the clinical setting over a large population of patients will remain ethical acceptable and meaningful and will not degenerate into a perfunctory signature on a form?
This is a reasonable question to ask. The limited IRB review of the procedures used to obtain broad consent would be expected to address this concern, of course, because it's looking at procedures for obtaining broad consent and would we want to make sure it was a robust process. Please comment on how this would best be accomplished.
There were three questions that had to do with the understanding of people who were asked to provide broad consent. With apologies to MinolofaPrieto, and how I pronounced her name.
She asked whether prospective subjects would understand whether there's going to be DNA included in research involving biospecimens and genetics information for future unspecified studies, and according to section 116(c)(i), the template for the broad consent is supposed to include a description of the types of research that may be conducted and what kind of information is expected to be generated. So presumably that would be something if the biospecimens were going to be used for such research that would be required by the template.
Then Monique Lanz asked the question in which she's concerned about whether prospective subjects who have provided broad consent can withdraw their consent and whether this will be made clear. The broad consent template includes at (c)(1)(v) the provision that subjects can withdraw at any time to the extent that this is feasible. It is possible that a biospecimen could have been deidentified and then given to someone else to do research on, and of course that's something that one could no longer do anything about if the subject had withdrew their consent.
But to the extent it is practicable, people can withdraw from the research study, and the template specifically includes an indication of who to contact in order to withdraw their consent.
And the third question about understanding is whether somebody understands the concept of broad consent itself and whether they might not be comfortable with research uses of their specimens. And of course, the broad consent template is supposed to indicate what types, plural of research might be conducted with the specimen, and the limited IRB review is supposed to be designed to make sure that people will be going to a process in this which they appreciate what the scope is of what it is that they're consenting to. That was a question by Monique Lanz, in fact the last two were from Monique from Bridge Clinical.
And then the last question on broad consent was by Emily Eld, who wants to know whether a specific consent can be combined with a broad consent, and the answer to that question is yes, so long as the prospective subject can make the two decisions separately.
And I think I'm done with the broad consent questions and answers.
WANDA K. JONES:
Thank you. It's audience time again and we already have our first question.
Thank you, I'm Heather Pierce from The Association of American Medical Colleges, I have a broad consent follow-up question. Ivor, I wonder if you could talk a bit about the expectations for tracking the types of information that go into the broad consent about what types of research will be conducted in the future and what is the expectation of determining a future date whether the specimens being used, whether the type of research suggested at the time, whether it's a decade down the road, is in line with what was listed in the broad consent as a type of research at the beginning. Is that clear? I hope?
PRESENTER: IVOR PRITCHARD
I think so.
Again, I don't think that -- the NPRM does not specifically describe exactly how that would be accomplished and I doubt that there is only one way in which it can could be done, but presumably it would be necessary for whatever tracking system one had, if there is any variation in the types of research that are described as being possible secondary research studies at an institution, either depending on what the biospecimens are or whether changes are made over time in the description of types of research, presumably there would be need to be some way of tracking which version of the broad consent form or of the broad consent that person had agreed to, and there would need to be some way of reviewing to determine whether the particular secondary research project did or did not fit into the range of types of research that were described.
I would just add a comment to Ivor’s response to say as we described in the NPRM, it's described that it would cover a broad range of future research activities, so it's just a question, I think, of how much specificity would be required for this particular sort of research to be considered covered. But it is, the thought is that the broad consent really would be covering quite a large somewhat open-ended type of future research.
WANDA K. JONES:
More questions from the audience? We'll have subsequent sessions.
Actually she asked the majority of what I was going to ask about the broad consent, but taking it a step further, wouldn't it make more sense to just ask an individual if in fact they could have their specimens used for future research and not specify the types of research, because we don't know what kind of test or assays or types of research are going to come up five years from now, or 10 years from now – ?
PRESENTER: IVOR PRITCHARD
Certainly you're right that one of the things that's important to recognize about the nature of broad consent as being different from a consent of a different research study is that people need to appreciate that to some degree there may well be research studies that are invented that we don't now have a full appreciation of being able to do those.
At the same time, providing some amount of elaboration of the range of different kinds of research studies that could be done with a biospecimen, I think, gives a person, particularly someone who's not in the business of medicine, for example, of appreciating the various of ways in which biospecimens can be used for research rather than just saying, please agree to let us do any research under the sun.
I don't think that does as good a job of accomplishing some kind of meaningful consent if you don't at least provide some sense of the range of studies that the biospecimen are aware of used for now, and indicate the possibility that there are some research studies that have not yet been imagined that we would also like you to agree to allow your specimen to be used for once they come up.
Would it be then be more appropriate to direct the individual to say yes or no to perhaps a disease route rather than a procedure route? That your specimens will be used for the study of cancer rather than your specimens will be used for procedures a, b, and c?
Well, it's types of research so that could include both the topic, cancer, whatever, blah, blah, blah, and the description of the range of procedures that might be used in doing research involving that biospecimen.
I guess my concern is that we're going to make this so complicated for those individuals that are trying to track what the specimens can be used for, and how we're going to set up systems to ensure that the person's wishes are followed.
Well, as Julie indicated, the general direction of the broad consent template is meant to mean that the consent will be requested for a pretty wide range of activities such that hopefully, you might well only need to use one version of a consent form in the clinical side and one in the research side that covers the whole range of potential research activity.
If you go back to the ANPRM, the ANPRM suggested a more elaborate procedure where you could describe different types of research, check off different kinds of research that you did not want your specimen used for, and that would have been a much more elaborate approach. You know it would have been more presumably more informed, but it would also be a much more elaborate administrative challenge, and so this is, one could view this as a middle way sort of position between no consent at all and a highly specified, articulated series of consents on the other side.
I look forward to seeing your template.
So do I.
WANDA K. JONES:
Shall we will take this question at this microphone and then we'll swing back to questions in advance.
Hi, I'm Stephanie in The Office of Research Compliance. My question is related to the single IRB policy, and it's described that the proposal only effects the decision regarding how an IRB would be designated as the reviewing IRB for institutional compliance. It further goes on to describe how the policy would not relieve any site of its other obligations under the regulations to protect human subjects. So my question is really in regard to the institutional responsibility. What's the expectation, when I think about oversight of human subject protections in regard to conflict of interest as an IRB has oversight over that and management plan or allegations of scientific misconduct? Or quality assurance reviews when that single IRB is not part of the institution?
PRESENTER: JERRY MENIKOFF
So a good question. There's still a variety of issues that will be on the table along with local institutions dealing with these other issues.
In terms of the language you were talking about, it’s specifically designed to get at, the core aspect of the single IRB requirement is about the core of things that IRBs are always doing in the reviewing study – approving it, approving informed consent and consent forms, that sort of thing, and recognizing there are other tasks that IRBs, some IRBs do these at certain institutions, often other entities do those at those institutions. My understanding is that the NPRM is not centralizing those tasks, and whether or not they might get centralized, I think, will depend on the particular study and the particular players and the particular funding agency, and again the specifics laying out what is being proposed, clearly indicated to things like adverse event reporting and things like that which are not related to necessarily an IRBs approval, whatever it is, still has to be dealt with at local institutions.
I think you're raising a number of issues about ancillary activities that human subject protection programs often deal with, or some other entity or institution will deal with, and these are relevant and interesting topics to comment on, and some people have said centralizing the IRB review is a relatively narrow thing and it will not do anything about these other things. I will encourage you and others to comment on KAMESHIRO these things.
Because for us we're an AHRP- accredited institution, our human subjects protection program, IRB is only one component of that, so...
Yeah. Sure. It's good point and you could go in both directions, and people will comment on it, and some people will say just centralizing the IRB review will not accomplish much in terms of making the system more protective or more efficient, and you might say, well, you shouldn't bother doing that or you might go in the other direction I guess, and say, try to centralize other aspects of it too, but they sound like they're all good things to comment on and I appreciate that.
Thank you. We’ll do that.
NORMA K. JONES:
Great, and Jerry, you have the mike. So we have about a half dozen questions are related to informed consent that you were going to address.
Thank you, so these are not broad consent questions, these are general informed consent type questions. And in fact the initial three questions specifically relate to the posting requirement with regard to posting a version of the consent form.
The first question, and I apologize in advance for the pronunciation on this, Shun-Kun Heo from the University of Arkansas College of Nursing. This is a question asking or suggesting maybe the posting requirement will not accomplish the purpose or the goal of improving consent forms, so let me read you part of it. It is questionable whether it will improve the quality of consent forms. Based on the proposal, the final version of the consent form and the specific clinical trial will be submitted within 60 days after the trial is closed for recruitment, so how can this submission improve quality of consent forms? And the question went on to note that consent forms in clinical trials will be very similar because it will more strictly rule the required components, thus it is unclear why the consent form should be collected and presented in the public. And it goes on as to why the public has to see the consent form, to improve the quality of consent form, is it the point to improve the quality of the specific consent form?
So in terms of response to that, the requester is absolutely correct, the consent forms will be posted after the trial is over. So it is not the intent that that posting will directly affect what happened in that trial. It was intentionally designed that way, the intent behind the proposal, when I gave you the overview is that, we're more and more trying to make aspects of research transparent and the goal is that transparency is a good thing. We often discover aspects of the system that aren't functioning very well when we learn about them and open up so many people could see them and comment on them, and that's done in terms of registering clinical trials.
It's done in terms of making data from clinical trials more available from the U.S. and European Union, they're moving in terms of this, so we're saying what about the core document that gives the heart of the information that underlies the ethics of these clinical trials, namely what’s in the consent form, why shouldn't this be made public too, so much of the other aspects made more transparent and public if these documents are made more public? People will look at them, comment on them, will say what's good, what's bad, and hopefully the mere fact that somebody knows when they write a consent form that this is going to be made public, they might pay greater attention to make sure they're doing a good job because they will know people will be seeing it, it gets back to whenever something is secret, where are they busy hiding this thing. Why are they so unwilling to let people see it?
So that is the premise. People could comment and whether they think this will work or not in terms of that goal, that is indeed the premise.
So could the public contact the investigator to give comments? Absolutely. Nothing preventing the public from doing that now if they got access to it, but they will have more access through time.
I have a somewhat similar, little different but the same theme. This is from Emily Eld from the Dana-Farber Institute. In the preamble it states that examples will be provided to investigators, but since consent is posted online it doesn't mean that are complying can regulations, please explain. Again, same premise, all out there, various people including experts and commentators will look at these and get a sense of what's better and what's worse, from journal articles, from reviewing posted ones, and gradually hopefully consent forms will get better and people understand what makes a really, really good consent form. I think it's similar to other aspects of clinical trials that have been made more transparent.
Some of those discovered clinical trials are not very good, the analysis of the data was not very good, and this occurred precisely because the data was public and various people had analyses that were different than those of the original people who originally conducted the study so it's opening it up to more comment. And that's the premise and again, more people can disagree if this will do that.
Our third question about posting. This is from Monique Lanz from Bridge Clinical Research. The Federal Register notice proposes making consent forms available on federal agency sites for public access, will the public have the ability to submit complaints or issues with the consent forms? If so what sorts of actions will be taken to address public concerns?
Basically as is true now, anybody could file a complaint with any of the oversight agencies about any trial they want. They will have to allege appropriate facts indicating there's a likelihood of the regulation not having been adequately followed. But yes, certainly if there's new information from the public, from the consent form that's posted, somebody could see something there and bring it to the attention of the regulatory agency as to what would be done based on that. It would be no different under our current rules. We have rules about an investigation, what takes place, what actions that happen, and that would happen here, except the person may allege that based on what the informed consent itself says.
So that's it in terms of posting consent forms.
There are three other questions about different aspects of the informed consent.
One was from Charles Hendrickson from the Oregon Health and Science University Center for Health and Healing. This is about boilerplate language. So the question is: one of the goals system is reducing unnecessary burdens by streamlining regulatory requirements for low-risk research. Current consent forms have mandated sections for each research study that state, quote, in case of injury contact et cetera. For low-risk studies such as registries there is no discernible risk of injury, however, patients who read the consent form will decline participation as they don't want to be injured. What plans are there to ease template language to make it more customizable to individual studies?
So he's raising questions on issues we're dealing with on the current rule, but not what the NPRM proposes changing, but under current rules the need to write consent forms that don't overstate risks that don't exist. And the current regulations don't require discussions, for example, what happens in the case of injury where a study involves no more than minimal risk. Some part of this could be just writing forms and are not aware of the requirements of the current regulations. In addition to that, there are ongoing regulations in the federal government, including involving the Secretary’s Advisory Committee on Human Research Protections, both groups have actually been spending a lot of time, and then reach out to the SACHRP members and members in the audience, and great to see them here. So there have been extensive discussions about ways to clarify these rules and consent forms, that risk studies do not have studies that say something that is irrelevant to that type of study so you do not have to discuss risks when there are no risks or what will happen in the case of injury, if there's a study where there's no possibility, or serious injury, so the question is right on track in terms of wanting to make sure consent forms are appropriate and we're just noting not so much NPRM change as recognizing the current rules allow this and let's make sure everybody appreciates the full flexibility of those rules including regulators being out there and giving more guidance on this.
Another question, this is from Emily Eld from Dana-Farber Cancer Institute, and she asks the question about interaction with section 109, current section of regulations, with section 116 in the new consent provision proposal. And just to highlight this because this is a somewhat obscure point even on our end. Section 109, which is about IRB research, and 109(b) has a provision that allows the IRB to acquire information in addition to that specifically mentioned in 116, the major consent provision. So IRB has the authority to say additional information should be required to given to subject under section 109, and so she's raising the question of what if an IRB uses section 109 how does that fit in 116 rules about having certain information in the core short consent form and other information in the appendixes and it doesn't seem that the NPRM is addressing that interaction. Up to now we're not aware of the circumstances which IRBs in fact are making the contextural underlying determination, our sense is it's probably rare but it's an interesting question and we welcome comment in terms of how these two sections should interact.
Very interesting question.
And then one more informed consent question: this is from Monique Lanz from Bridge Clinical Research. Talking about transparency and introductory paragraph to section 116, how will consent forms be drafted in a way that is comprehensible to a range of literacy levels? And basically in terms of the issue of consent forms being comprehensible to people, this really is not a new change, the current regulations do in fact require the consent forms to be comprehensible to subjects. In fact there's lengthy discussion about how you do that and whether or not you formally test the concept form by running it through various consent forms in terms of various educational levels and so, absolutely, it's an important thing, it's an important thing that people are struggling with and will continue to struggle with even after regulations will go out, but the NPRM basically is not altering this requirement. It was there and it's still in there. So that's it in terms of the informed consent.
NORMA K. JONES:
Thank you Jerry, back to audience time for the microphone, and while you're gathering yourself together to come to the microphone to ask yourself a question I will remind you we're reading abridged versions of the questions, the full text is available on the web site. We're trying to capture the idea so we can focus time on the answer. But the full text is available. Seeing no volunteers right now. There will be another time. Get your questions ready.
Let’s get back to you Jerry, you have six questions on cooperative research.
PRESENTER: JERRY MENIKOFF
Yes. Thank you, Wanda.
Yes, here's a question from Mary Jane Welch, from Rush University Medical Center, College of Nursing. This is the question: it is only logical for reviewing IRBs to be held accountable for their reviews. I do not understand how this mandate achieves this goal. Please explain.
So she appears to be talking about the new mandate that gives the federal government basically authority to directly take action against one of these IRBs, instead of going against the institution, if the IRBis unaffiliated with the institution. Basically if we're understanding her question, we fully agree with her point. Currently to explain why this change is being proposed, currently under the Common Rule, there's no explicit authority at least on OHRP’s end to take action against an IRB that is not part of an institution that has an assurance with the federal government. And what the NPRM proposes to do is to clarify the federal government's authority to do what she says is logical. Namely if some problem happens in this the study because an IRB doesn't do what it's supposed to do, we would prefer to take action against that IRB, not blame the institution but blame the IRB or at least work with the IRB. Let's not talk so much about blame, work with the IRB to make sure it goes forward and is doing the right thing in terms of future use. So I think we're basically agreeing, absolutely, let's hold the reviewing IRBs accountable and we just want to clarify the rules that makes it clear that we can in fact do that.
The next question is from Nofa Proseta at the Tulane University School of Medicine, and it's a question about the multisite research study and the use of a single IRB, and the basis of the question is, it seems to be concerned by what if you do a study in which there is some sites within the U.S. and some sites outside of the U.S., and for example overseas, and how will the rules deal with it? So to clarify these rules, the NPRM single IRB requirement only applies to the activities of U.S. institutions that are conducted at U.S. sites. So those are the only places that have to be accepting this single IRB in terms of being their IRB of record.
Now if the study involves some U.S. sites and some foreign sites, then the foreign sites are not bound by this requirement. So it's perfectly acceptable to have a study that has U.S. sites and foreign sites. The U.S. sites, to the extent the government institutions, would in fact have to follow this one single IRB, and it would be serve as the IRB of record, but for the foreign sites this requirement just does not apply there, so those foreign sites could have an IRB of record that's a local IRB or an IRB for their country or whatever they want. So that's how that would work.
This is an anonymous question and it's raising issues about sometimes a particular institution has specific local concerns that are part of their culture or part of their sort of other requirements which I guess can be regulatory too. So for example, they're talking about the ethical and religious directives for Catholic health care and go on in this case, the institution could certainly require additional administrator review that the institution to address this, they also may need to include or exclude language from the consent form or other study documents or processes. One example would be to not include the requirements to use specific birth and birth control, I guess, or outline birth control methods with the IRB of record and issue different consent forms or other documents for each site, how might this affect the informed consent documents? What if an institution made a determination that is not in line with other local context issues for this institution?
Specifically, regarding the posting requirement, note that the posting requirement only requires one version of a consent form for an entire multisite study, this should not be an issue, there should be no additional requirement here. At the outset I should note, notice that nothing in the NPRM, requires whatever, forces any institution to participate in any clinical trial. So as are currently the rules, a particular site may in a particular clinical trial what is required as the protocol is inconsistent with the internal values and for that reason it may not want to be part of this particular trial. The single IRB requirement doesn't in any way change that option on the part of an institution. In terms of the example of birth control methods, which is an interesting issue, it would seem that the heart of that issue is initially not so much about the informed consent and what the consent form says, but the ability of various sites to alter the protocol in ways that may be different than the original protocol. So the question would be, to what extent can any site impose requirements on not being allow to use certain birth control methods that are part of a protocol at certain sites?
Even under the current rule this is a negotiation that would have to be worked out with the people working the study, the sponsor or the lead institutions. There obviously are scientific and other questions that come up with you change the terms of the protocol and reverse the entire protocol to change the birth control methods available at all the sites or changing it so that a particular site has different criteria. Assuming the birth control methods would change at one particular site as the question notes, yes, certainly the consent form should be appropriate for that site, ,that certainly is something that could be dealt with through conversations with the single IRB, which would in fact have to approve that change. Whatever the consent form says is appropriately describing what is in fact the protocol requirement at that institution.
Another question is from Nestor Gonzalez from the David Geffen School of Medicine at UCLA and this is about local context. There is one concern regarding some of the proposed methods to make more universal determination as an exemption of IRB review and mandate that U.S. intuitions engage in cooperative research for IRB, for that it's based in the U.S., the concern has to do with an essential component of the process of review in local IRBs in which members of the community, not scientists, present these idiosyncrasies or play a determining role in approval of language or role or consent what assurances have been made to preserve the local involvement, respect, social and cultural values in which the research is conducted.
So in terms of that, the account of what's necessary in terms of what's necessary in it the local area around the certain site and the populations are by and large not being changed in terms of the NPRM. There are certain requirements there now, subject to interpretation, they will be there afterwards in terms of making sure those requirements are adhered to and people take cognizance of the interest of certain populations in certain localities. There are a variety of ways of doing that, and even in the current rules, for example, it is the case that a fairly high amount of research is currently reviewed by some central unaffiliated IRB, probably more so on the FDA regulated side than the federally funded side, but there's a lot of experience with this. But what happens in those circumstances, is that single IRB reaches out to the local sites and tries to find appropriate information about what needs to be done to deal with these local context issues. So again, there's experience with this.
People should feel free to comment on whether they think that experience, you know, tells us enough in terms of adequately protecting the local interests. I also will just note nothing in the NPRM prevents an institution from doing additional review beyond what the central single IRB might do. So if an institution is concerned about these populations, itself, it can be very flexible in terms of this, it can have its only IRB review look at this, bioethicists look into this, so there's a great deal of flexibility here, but bottom line of protecting these interests, the rules that exist before pretty much are still there, we're just changing the administrative system for coming to an answer about what appropriate protection are.
Here's an anonymous question. One of the exceptions of the single use for single IRB for cooperative research, more than one IRB is required by law, the only example that's been given is the FDA device research, and are other examples that would apply to this? And we're actually not aware of other specific examples, but we certainly welcome people commenting and pointing out what other examples of this might be.
And finally, this is a question from Josh Leslie, and this is a fairly complicated question picking up on Wanda’s point, if anybody wants to read the full text of any of the questions it is on the web site. There's a separate docket for this, but basically the questioner is questioning whether or not the changes relating to this single IRB review requirement might be harmful in terms of appropriately protecting research subjects. Again he extensively discusses this and in particular points out that while the NPRM discusses there's no evidence that additional research ethics reviews add to the protection of research subjects, saying that doesn't reach the flip side of that just because there's no evidence that does that, doesn't mean that perhaps it is doing that and they quote, I guess a famous computer scientist, Dr. Dystra, who has a quote, program testing can show the presence of bugs but can never show their absence. So the commentator says, similarly I don't think it's possible to generate evidence that additional IRB reviews and additional sets of eyes and research studies show human protection or research oversight process, however there's a litany of examples of insufficient IRB review that have led to real harms to research participants. So the question raises interesting issues. We certainly welcome comments on how the single IRB reviewer requirement might decrease or increase protections to research subjects.
We recognize that there's only so much evidence out there and encourage people to look at the evidence that is discussed in this the NPRM, and we welcome comments discussing further evidence that we have not provided or what the lack of evidence might suggest in terms of it moving forward.
That covers all the question I was supposed to cover.
WANDA K. JONES:
Audience time again. Okay? Yeah. There we go. You can tip that microphone up. There we go.
Just a question about the new proposed exemption at 104 (e) (2) that would allow the use of identifiable information collected for nonresearch purposes, and it says that there would be prior notice of people to whom the information pertains. And the questions in the NPRM are pretty broad as to what that notice might look like, so I was curious what thoughts you might have on what the notice might mean. It seems it can be interpreted very specifically to be like a consent, or it could be type of interpretation where it's just not a burdensome requirement. I was curious if you had a direction.
PRESENTER: IVOR PRITCHARD
Yeah. It's an open issue for us.
We recognize this would be something that would be something short of informed consent because the person would not have to actively do anything in order to participate in the research, but we recognize that there are a variety of mechanisms for notice. It could be up on the wall or it could be delivered to people individually. It could be in the newspaper and what the content of that notice could be, could very considerably, just say be aware there's research going on with your information or it could say something about what it's for and what safeguards are in place, et cetera. And it might or might not include things like, if you want to opt out contact so and so to opt out of whatever research we might be doing here.
So we think that it's not as demanding if you will as informed consent and so, not as protective presumably. However, it's something more than just nothing and it is open question for us, both exactly how it ought to be operationalized or whether there should be some flexibility in how notice is operationalized.
Please comment, all of you. You're on notice.
The multisite single IRB review, in the consent form that that IRB approves, which of the institutions should be listed for contact for questions about rights? Should it be the central IRB that reviews it? Or the local IRB? And if it's the central IRB, will that create a problem with individuals who have to actually pay a long distance call?
PRESENTER: JERRY MENIKOFF
Interesting question. I don't think the NPRM specifically addresses that level of detail, so feel free to comment and indicate if that's something that should be spelled out in terms of regulations in terms of giving an answer and what the answer should be. That sounds like a good thing to comment on.
WANDA K. JONES:
Another question here and then we'll swing back to the presubmitted.
Elisa Hurley in Public Responsibility and Medicine and Research. So I just wondered if you could shed a little more light on how and why the NPRM treats biospecimens and private identifiable information so differently from each other.
So we heard a lot of talk about autonomy interest and there's a lot in the preamble about autonomy and biospecimens specifically, and I'm curious why we do not have same statements in our identifiable information. So can you speak to the asymmetry in the way they're treated?
PRESENTER: JULIE KANESHIRO
Well, I'll begin the conversation, although my colleagues may have more to say about this.
You know we recognize the asymmetry here, and so I take your point, and we do point out this distinction in how specimens are proposed to be treated in the NPRM in contrast to information, and it could can well be that our premise is mistaken. But you know of the data that we looked at or had accessible to us, it seemed that people in general now, they seem to have more of an interest in controlling the use of their biospecimens, perhaps in part due to the fact that there can be so much more information often generated from a biospecimen than information that already exists.
But this is something we want your comment on, tell us whether you think this is an appropriate distinction, whether it's in fact true that people have less of an interest in controlling their information.
And I guess your comments could go in at least two directions, right? One would be to say that no, there are similar interests that people share with regard to their biospecimens and information and therefore all of it should be treated in the same way, such that all of it should be treated as human subjects research irrespective of identifiability, both specimens and information. Or the flip that no, people don't have any more interest in their biospecimens than their information and we shouldn't treat biospecimens specially and instead, you know, we should maintain the status quo with regard to biospecimens or a different line and only if it's identifiable, you know along with certain spectrum, and tell us what you think that might be should it be covered or should they be covered under the Common Rule. But very good point and something we look forward to getting a lot of public comment on.
WANDA K. JONES:
Okay, let's go back to questions that were submitted ahead of time. Julia, you're on deck and we've got six questions related to exclusion.
Exclusions. Right. Okay, the first one is from [no audio].
WANDA K. JONES:
The mike died. Just give her the red one.
Okay, red mike, red mike is good.
Lee Stober at University of Virginia, and I'm not going to read the question, the question's rather long, but in essence what she's asking for is a clarification regarding the definition of intervention as that's used in the exclusion 101(b)(2)(i), and whether or not our interpretation of intervention is different in that exclusion than it is currently, and the straightforward answer is no, the term as used in in the exclusion is not intended to be any sort of conceptual change from how intervention is currently intended, it was intended to reflect the status quo and the movement of what was the exemption can now be the exclusion of that.
And so the next question is from Emily Elb from Dana Farber Cancer Institute, and she writes, please explain the exclusion that excludes research on identifiable private information that is subject to HIPAA to be outside of IRB oversight. This appears to create an enormous bucket of research on identifiable bucket of information without IRB oversight. Yes, we understand that, but the proposed exclusion is intended to affect only certain activities that involve secondary data collection and analysis involving use of identifiable health information. So the only concern here is for privacy and confidentiality risk. So the rationale was, the idea was that yes, the HIPAA protection and safeguards would be sufficient in this domain. But if you feel otherwise, if you feel that the safeguards are indeed insufficient, we of course invite your comment, and I would note that there is one of the questions framed in the NPRM directly on point, it’s question 22, and we invite to you comment on it.
The next question is again from Lee Stobrin from the University of Virginia, and she writes the NPRM provides a list of activities that are excluded on grounds they do not count as research. These include journalism, history, and biography. Among the reasons given for exclusion of these fields is that they focus on particular individuals and are generally carried out by practitioners of disciplines who have their own codes of ethics. On what grounds was this exclusion made?
And the rationale here really hinges on the concept of generalizability: the line was what activities do not create generalizable knowledge, ethnographic field work, at least as we understand it when we discussed it, generally would involve drawing conclusions from groups were from communities and not from individuals. However, knowing that OHRP was willing to put themselves forth as experts in the field of ethnography, we would invite your comment on whether this or other fields of scholarship should be included inside or outside of this exclusion. Next question.
Question 31. Question from CeliaHagan, Association of Public Health Laboratories, she's asking is newborn screening public health surveillance excluded from public oversight, and our answer is that newborn screening is a clinical activity rather than a research activity and therefore it would not fall under the NPRM. It would be a clinical activity.
Okay. The next question is anonymous. The source is anonymous. The exclusion for quality assurance intervention states that it does not cover the evaluation of an accepted practice itself.
Is this a change from the current OHRP view on quality improvement? It seems to be contradictory to the OHRP FAQs on quality improvement activities that describe implementation of accepted practice and evaluation of if that's standard practice worked. And our answer would be no, there's been no change in OHRP’s perspective and we do not feel this is contradictory with our current FAQs in this domain. And in the FAQs themselves, implementation of an accepted practice for the purpose of evaluating it is considered to be research.
So the key here is really to ask why a change in care is being implemented, and if you're implementing that change in care for quality of care or clinical care purposes, then implementing the change itself is not human subjects research, although perhaps evaluating the change may be.
So the next question.
Edward Liebow, from the American Anthropological Society, and he is asking: the NPRM makes no mention of ethnographic field work, such as conversation, interviewing, collection of life history, participant observation in everyday settings by means of which the investigator is seeking to understand social and cultural particularities. Where does ethnographic field work fit in in the categories of review?
And this is a hard question to answer. It really depends on exactly what the activities are that are encompassed in that ethnographic field work, there's certainly portions of it that could fit in this the exclusion at 101(b)(2)(i) for research not involving interventions that also involves survey procedures or interview procedures or observation of public behavior, but it's also very likely that some of this research could be exempt under 101(e)(1) for surveys or interviews if the subjects can be identified. So without knowing the specifics of what's going on here, it's hard to be very granular in the response other than to say there's different pigeon holes where the research could indeed fit.
I think that's it for questions on exclusion.
NORMA K. JONES:
Great, Julia, thanks. And who in the audience can tell me what time it is? It's audience time again: that was such as easy question. You know I got a few smiles.
So just, you know. This is really hard, sitting here as you all are doing, but please come back to the microphone. Ask questions if you have questions. You have another chance.
I think that mike also went dead. We're really hard on batteries.
Sort of readdressing those last two questions, the NPRM is providing exclusions for particular research activities which may include research into a particular individual, it may include things, just throwing things against the wall here, like reidentifying things through genomic research to identifiable public databases like 23 or me or ancestry.comwhere the research may not have been intended to learn about a person but may learn new information about a person. Going back to about how the core of the human research subject as to whether or not there's new information about a person, how can we say that type of research is going to be excluded?
PRESENTER: JERRY MENIKOFF
I need more details – if someone is identifying someone from a deidentified biospecimen?
PRESENTER: ALLYSON BEACH
It isn't from a specimen, but I can go into a database and do research into my family name and somehow then learn more information, or you know, an investigator can decide to look into certain family lines or other research processes not necessarily with the intention of finding new information about a person, but then does and what this is suggesting is that that type of research would be exempt, which is really contradictory if the human subject research is about finding new information about a person, that research has found new information about a person, so that would therefore be human subject research.
PRESENTER: JERRY MENIKOFF
So let me just make sure I understand what you're saying. So the point about generating new information about a person is only about the exclusion relating to research using a biospecimen, so if we're not talking about biospecimens that's basically not effecting whether you're doing research that's under the Common Rule or not. That would only be relevant to a researcher who's using a deidentified biospecimen, and in some cases they would be able to continue to do that if the new rules are imposed without any consent, as long as they're not showing new information about a person.
The current rules relating to data by and large require consent if you are using identifiable private information, so a researcher who starts out with some information, it's not identifiable, they cannot identify the person who's they're doing the research about, but if they then learn the person's identity, at that point if they're doing their research, they before did not have a human subject, in the rules now would have the human subject and would be under the rule, so the notion whether or not you're generating new information is a different aspect.
The reason the regulations control the use of identifiable information is because of their privacy and confidentiality risk, and the notion is that researchers shouldn't be doing that unless the appropriate protections are there, and the new rules would in fact allow that to be dealt with in more scenarios than currently, so long as the privacy and confidentiality protections are built in and it builds those in in the new section 105. So if you could -- you want to go back to your scenario and – ?
Well, I'm concerned that certain researchers may use that as a loophole, if they start out maybe with the idea that I'm not looking for information for a particular person, I'm looking at maybe an ethnographic study and maybe I reidentify people, and maybe I have now information about a person so now we've switched. Now we're not in an excluded category anymore, so – ?
So I would say, that is how the system and I think some of the questions we discussed earlier in terms of for example, possible prohibition against reidentifying, in which we recognize there are legitimate interests to want to identify people but in these scenarios, the researchers should be aware if they reach a point where they went from not using identifiable private information, to using identifiable information, they're then in violation of the rules. Assuming they are using federal funds and violating the rules, it's not in their interest, I assume most researchers don't think it's a good thing to be violating the rules and then be subject to punishment or whatever bad things can happen to them, so this may be partly an educational process, but even the current rules without the ban on reidentifying do impose restrictions on the ability to be identified. The research initiative is not doing anything wrong but they will be the moment they have identifiable private information. The solution is they should have gone through an IRB ahead of time and said I'm doing this, it looks like I'm going to be generating identifiable information, please IRB go through the rules and make sure I'm doing the appropriate thing. I would think it's not in interest of a researcher to proceed under that line, thinking there is then going to be in violation of the rules. So it's not clear to me you would have the hole that you're talking about.
Okay, thank you.
WANDA K. JONES:
Other questions from the audience? We're hitting that post-prandial slump. Okay, we have three more buckets of questions and exemptions. We had four that Ivor will answer.
PRESENTER: IVOR PRITCHARD
Thanks. So the first question about exemptions is actually pretty much, pretty close to the first question that Michele Russell-Einhorn asked earlier, it's asked by anonymous, so maybe the question came from Michele Russell-Einhorn, and it has to do with notion of recognizing that at an institution that doesn't focus on research, isn't it true that the broad consent provision is going to create an administrative burden that it heretofore didn't have if it does want to participate in making biospecimens available to larger institutions that want to carry out research? The answer is yes it would, and hopefully they would do it in this a way that didn't involve a large use of administrative burden and resources.
The next question is from Lisa Dobrinfrom the University of Virginia, and the question is about the exemption decision tool, and the question says that, basically says that the value of the new exemptions depends on being able to review the exemption decision tool. The exemption decision tool hasn't been presented yet. Would we be willing to extend the comment period until such time as we presented the exemption decision tool for public comment so that people can understand how the whole system would work.
And our answer is, first of all that we think that the merits of the specific proposed exemptions stand on their own regardless of what your view is on the exemption decision tool, whether you think these are categories of research activities that ought to be exempt with the identified conditions is something that we think people can provide meaningful public comment about regardless of the existence or nonexistence of the tool.
We do welcome comments on the content and function of the decision tool. We also note that the NPRM indicates that multiple federal agencies may develop exemption decision tools, and that any decision tool will be made available for public comment and that public comments will be taken into consideration in the development of that tool but the public comments on – [banging ].
WANDA K. JONES:
Everybody's okay in the back?
On one or more of those decision tools will occur at a separate time. Was it something I said?
WANDA K. JONES:
Could have been, could have been Ivor. You never know.
Sara Goldkind asked a series of questions more or less along the same line as David Forster’s question in 104(e)(2)(i), prior notice is required. Is prior notice meant to address the ethical principle of autonomy? If so how does it accomplish this? No opportunity to opt out is required. What information is required as part of the prior notification? Why should data be treated differently than biospecimens? In some cases use of private information could be more damaging than the use of a biospecimen. For example accessing the mental health history of a person could be associated with more harm than checking for a protein on a blood.
So our response is that, as you already are aware, the provision of prior notice is related to the idea of respect for persons and informing them of activities taking place. Under the current rule, IRBs may approve many such research studies without either informed consent or notice. Public comment is sought regarding what information should be included in the notice and whether the notice should also be used to offer the ability to opt ut. The NPRM does presume that in general people have a greater interest in what happens to biospecimens than what happens to data. We recognize that in some cases that identifiable information unrelated to a specimen may be more sensitive than information derived than from their biospecimen, and we also note that the privacy safeguards that are the default are meant to protect both kinds of information, biospecimen information and nonbiospecimen information.
Then the last exemption question is from Monique Lanz about the proposed exceptions to IRB review. How will it be made clear to the participants that the research study will involve no IRB oversight due to the limited risk?
Which prompts a question, show of hands, at your institution, does your informed consent form routinely include that first of all, does it include that the IRB did improve and approve the research study?
How many do not routinely include that research information in their informed consent forms?
At your institution for a research study that was determined to be exempt, do those studies routinely convey to the subjects that no IRB oversight occurred in this study? Show of hands.
How many do not include such information regularly for exempt studies?
There are a lot of paralyzed people.
In any case our...that was less informative than what I had hoped.
The NPRM preserves the status quo with regard to this issue. It is unclear how aware subjects are currently aware of whether there is IRB oversight still. Public comments may be submitted about whether and when this information should be conveyed. Well, I'm done answering exemption questions. Audience time again?
NORMA K. JONES:
Get your questions ready. We're running out of these segments of time. So don't let her be the last one.
I'm not the last and definitely not the best. I'm Jennifer, I'm from the Center for Applied Linguistics and I have a question about the new exemption category. A lot of the work we do is on testing and I notice it says research on testing would be exempt. There are a number of stages that are involved in testing development process, so there's a lot of cognitive labs, small scale trials that are working individually with students and collecting data would that be exempt as well as the data comes from the larger text?
Okay, so everything we do is exempt?
At least in that area.
Remember that the definition of research in the current regulation is unchanged and includes research development testing and evaluation. That means that for any given research activity, if it's covered by the regulations, then the pilot testing is also covered, right, and needs to be reviewed for the protection of the pilot-tested subjects, right? Whereas if it's a research study that is exempt, the testing development part of that activity, if the main activity is exempt, then the pilot testing would likewise as part of that activity be considered exempt.
Okay, so the new tool you're developing would help to eliminate that or help determine which category it falls into?
The new tool you're developing will help make that clear because sometimes it is very hard, it's a gray area as to whether it fall under this research or not
Remind us in your public comment we need to make sure this is clear.
WANDA K. JONES:
One last call for this segment. Okay, then let's move on to Julia again to address six questions on IRB operations.
How about three questions on IRB operations.
WANDA K. JONES:
I'll take that.
Let's go babe, all right.
All right, the first question I had submitted by Sara Goldkind, bioethics consultant. Section 111(a) (9) circumscribes a limited IRB review to considerations germain to broad consdient procedures and privacy protections. Why are these matters more important for the IRB to review rather than the scientific value research and minimization of risk for example?
The rationale here is that these are studies where we already know the nature of the risk because they involve secondary data or biospecimens, so there are privacy protections that have already been built in. In addition, if there is any change to the way the specimens are stored or maintained, the IRB is required to go back and reassess those protections.
So in this context the process of limited IRB review really turns its focus to ensure that the process of informed consent is conducted adequately, that obtaining that informed consent is appropriate because in some circumstances, the subject may not be able to make his or her own informed decision.
Now Sara Goldkind also submitted the next question asking per 111(b), why is there no explicit requirement that an IRB or other appropriately constituted committee consider group harms and risk minimization referent to families or communities as part of its review of secondary use of biospecimens or information?
As I think we already answered at some point earlier in the day, we recognize this is true. The NPRM simply maintains the status quo regarding consideration of group harms in this respect but we do invite your public comment.
The next question is submitted by Elisa Hurley from PRIM&R. Why are pregnant women still included on list of populations vulnerable to coercion or undue influence? The CIOMS guidelines, for example, removed pregnant women from the list of vulnerable populations in 1993.
Again as we discussed previously, it wasn't an intentional decision early in the NPRM process to not change the treatment of vulnerable populations as they currently appear under the NPRM right now.
That's all for IRB operations.
WANDA K. JONES:
Okay, very good. Probably the last audience question segment? Going once? Yet another.
I actually submitted this and I was waiting to see if it came around.
WANDA K. JONES:
We still have another bucket of questions but it's better that you're here.
This is a concern from a university. And basically regarding identifiable private information, that can typically waived for secondary use, but it indicates where the individual happened to be asked to sign a broad consent regarding information and they refused, it could no longer be waived. We assume that's specific to a particular study and not to future studies and other protocols but we wanted to verify that.
I think I understand the question to be related to the prohibition on waiving informed consent when an individual has been asked for broad consent and declined?
And to what extent would that apply to all future research and not just that study?
And yeah, and I guess since it's intended to be just that, broad and not for a specific study per se, you know I think that prohibition as it’s articulated in the NPRM would in fact be, you know carrying forward for any specific study for which the broad consent was sought for use of the information, right, that now would be proposed for use in a particular study. So I think that prohibition would be carried forward.
But just to add, this is not having to do with the broad consent provision. Even under the current rules one could ask someone to participate in a research study in which you get identifiable private information from them and they decline, right? Or you ask them to participate in the primary study and also ask for consent to participate in future research and they decline, right?
I think one would have to look at two issues. The first is, exactly what were they asked? Were they asked to participate in a specific future study, in which case if we're talking about a different study then one could ignore that refusal. Or if they asked generally, can we use your information in some future study, under the current and under the NPRM regulations, you would have to presumably either go back to the person and ask them again and have them change their mind or you would have to waive informed consent in order to use the data, and in order to do that under the waiver criteria, the IRB would have to find that you weren't adversely affecting the rights and welfare of the subject, which I think would be a rather steep challenge for the IRB in that particular circumstance.
One more thought here, I think. I just wanted to point out that the NPRM really doesn't specify what should count as a refusal, right, or a decision not to provide broad consent, so is the absence of a signed document sufficient if they were given the opportunity to sign? They were handed the form but never actually returned it? Should that count, right, as a refusal?
Should it have be documented in some manner to count as a refusal? So please provide us with your comments on that point.
Okay, thank you. I think there was concern about tracking and specificity with the right to refuse, thanks.
WANDA K. JONES:
Other questions from the audience? Let us get the last four questions if they haven't been covered yet, but I suspect they might haven’t been, Julia.
This last bucket is a miscellaneous bucket but we'll launch in. From Celia Hagan, Association of Public Health Laboratories, does the rulemaking apply to only federally funded research? The CDC requests specimens for assay development for CDC-requested stool samples for developing whole genome sequencing for foodborne illness investigation. Would that be considered to be federally funded research? Would the state public health laboratory get consent to send the specimen to CDC? Is method development in this generally considered to be research?
So here we have some embedded questions. The first, does proposed rulemaking apply to federally funded research? I think most people understand at the end of the day that the answer is yes except for the provision that expands coverage to the clinical trials that are not federally supported.
Now regarding the questions where the CDC is obtaining samples from, in this case, a state laboratory, I would just bear in mind that an institution that releases specimens to another institution is not engaged in human subjects research by virtue of that releasing.
So would the state public health laboratory need to get consent to send those specimens to CDC if they're not engaged in human subjects research? No, they wouldn't be required to get that consent.
And the final question here is method development in general considered to be research? In general, OHRP does consider method development to be human subjects research.
So go on to find the next question here.
Again Celia Hagan, Association of Public Health Laboratories, can states mandate without consent without consent uses of biospecimens that contradict the Common Rule, for example, new born blood drive spot for whole genome sequencing. Well, if a state is experiencing federal research activity, then it's bound by the Common Rule and if you're bound by the Common Rule, you have to follow the requirements of the Common Rule. On the other hand, if a state is not accepting any federal funds, then the state is free to go forth and exercise activities on its own terms.
And I will proceed now to a question submitted on the clinical trial expansion. This was submitted by Mary Jane Welch, College of Nursing, RushUniversity Medical Center. Please explain how mandating the applicability of the Common Rule to all research conducted at an institution will meet the goals to enhance and streamline the review process, reduce inefficiencies, and hold unaffiliated IRBs directly accountable for regulatory compliance without compromising ethical principles and protections. It is acknowledged that most institutions already voluntarily extend these regulations to all research conducted within the organization, thus making this mandate redundant. In addition, often only research that is neither funded by a federal department or agency falls within the oversight of other agencies, resident and student projects.
It seems this mandate would create barriers to developing future researchers. Well, first I want to clarify that the NPRM does not cover all research at an institution. Also I should clarify that under the current construction much resident and student proposals would likely fall out of the scope of the NPRM. The current NPRM does eliminate the option in the FWA to check the box. Now currently institutions have a choice as to whether they wish to check that box in approximate regard to all research regardless of funding while the majority two-thirds do, one-third do not.
The NPRM proposal is intended to ensure that those studies that generally pose the most risk to subjects, such as the clinical trials, are covered by the Common Rule, and the intent here is to further the goals of enhancing human protections and make those protections more uniform and standard across the research community. At the same time eliminating the check the box option allows institutions to implement greater flexibility for low-risk research that is not within the scope of the Common Rule.
Okay, getting close to the end. I think there's one more.
One more from a Monique Lanz, Bridge Clinical Research, and she says in light of the emergence of electronic record health systems and clinical research, how will consent forms and privacy safeguards differ from electronic health data and other clinical data. We were a little confused about exactly what the intent of the question here was, what was being asked, but the NPRM does propose that compliance with the HIPAA privacy rule would satisfy privacy safeguards and therefore these could be used to protect clinical as well as research information and of course, the Secretary’s safeguards haven't yet been developed.
But I would point you to question number 71 in the 88-question list that's embedded within the document, and it does request input on how the security measures should be calibrated to various degrees of risk and sensitivity of information that will be collected.
So with that I thank you very much but I think I'm done.
WANDA K. JONES:
Great, Julia, thank you.
Okay, so I misspoke, we will give you one more chance. This is truly your last chance. Wow.
David Borasky. Julia, on your last response, can you just say again what you were saying about the changes to the check box and the assurance process?
Well the current NPRM eliminates the check box option, that's gone. Part of the rationale, and I invite others here to help chime in, was to enhance human subject protection overall by providing a greater framework for uniformity and allowing greater flexibility for institutions to implement other ways to review low-risk research that was not covered by the Common Rule. But if you would like to provide more of a rationale, others here?
So the implication of, basic consequence would be that institutions would no longer have a choice about how far to extend the regulations, they would have to extend the regulations to cover clinical trials irrespective of HHS funding. And they would have to cover HHS or other Common Rule-funded or supported nonexempt studies and studies that have exemption conditions, but other than clinical trials, if a research study doesn't get Common Rule funding or support, the institution is not required to follow the regulations.
Right, and the extension of the subparts as well, I mean that would still be...Obviously all the agencies in the department have haven't uniformly adopted all those additional subparts so that would be some sort of an option, too, whether you extend those.
That's correct. I mean it is true, first of all that different agencies have or have not adopted various subparts. I'm not sure we have addressed the question of...
... we haven't.
...we will have to abide by the subparts or not.
I guess I will add one more point that may be obvious here is that while the proposal is that we would eliminate the check the box option outs assurance, there's nothing in our rules that would prohibit an institution from participating now from participating as a matter of policy applying the Common Rule and/or subparts across the board to all research carried out at that institution.
All it's doing is basically saying that that would be an institutional choice.
It would not make that research under our jurisdiction.
And now for something completely different, there's something I meant to say with respect to the broad information, and that is to draw attention the fact that while one could put into place requirements that you like whenever you choose, the effective date for compliance for the regulations identified in the NPRM is one year after the final rule is published. Plus, in the case of the single IRB requirement and the broad consent for biospecimens, they take their effective date for compliance is three years after the publication on the final rule. The expectation that with respect to those two provisions it would take some institutions more time to put those into place.
WANDA K. JONES:
Those are important points there, Ivor. When we release the final rule it's not just immediately effective, there are pieces that phase in that allow the work that you have to do on your end, allow your work to proceed.
Questions, last chance? Okay, this time it's for real then.
The public comment period remains open until December7th, so we're about to close this meeting, you have a bonus two hours. That's a chance to add public comments while it's still so fresh in your mind generated by the questions asked today and specific points. And you heard Jerry and his colleagues repeatedly encourage you to comment on particular points because this rule is only made better by participation and as are all federal rules, the public's participation is critical.
The full text of the questions that we read to you that were submitted in advance that full text is available on the docket that was set up for this meeting and this meeting itself will be posted to the OHRP web site at a later date and obviously will become part of the publicly viewable docket as well. So many people to thank right now and obviously it's the OHRP staff, those seen, those unseen, many of whom are in or have been in the audience throughout the day, they just really make life so much easier working as a team to get this kind of work done.
Our federal colleagues, the departments and agencies that have joined with us and have worked hard and in many cases been willing to trust the public comment process because we have to move forward to get this very complicated rule moving and cooking.
So, thank you to every single one of our federal agency partners, the departments and agencies who are going to help us make this real.
To the communications staff, Diane Gianelli, and her staff. We did hear from you all that the webcast is working great. That's always great to help that that piece of it does help enable public participation, but the work of our com staff is critical as well.
And of course we're the government and where we would be without our lawyers. So the Office of General Counsel has been here throughout the day as well, and it really is extraordinary teamwork that I have just been privileged to be in and out of throughout this entire process to watch this NPRM mature, to watch the language evolve, and it will still evolve based on your very, very thoughtful and real comments.
The video production team here at HHS, every time you do these things it's better and better and better so we're really grateful for you.
The time you've taken, the support staff, to make this meeting happen, and finally those of you who in the audience who sat through now close to six hours.
If you don't count lunch, five, because we like to eat and get out a bit, but to sit through this is not as easy task, but it I do commend each one of you because it reflects commitment, your personal commitment, and ensuring that every person who has the opportunity to participate in research has the opportunity to fully understand the risks and the benefits of that participation.
So thank you, we look forward to working with you.
We look forward to your comments between now and december7th and thank you all very much.
Safe travels home and thank you again.
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