When the Regs Come a' Knockin': Nuts and Bolts of 45 CFR part 46



greetings this is Elise summers and I'm the director of the division of education and development at the office for Human Research protections welcome to our second educational webinar when the regs come a-knockin nuts and bolts of 45 CFR part 46 as many of you know in February we launched our webinar series with when the feds come a-knockin how to prepare for an HR p compliance evaluation of your program featuring dr. christina borer director of OHRP x' division of compliance oversight this maiden voyage was a huge success with over a thousand listeners on board buoyed by our success the first go-round we are back for more today I will be discussing the history and requirements of the US Department of Health and Human Services regulations for the protection of human research subjects this webinar is a basic offering well suited to those of you who are new to the field of human subjects protection and those of you who are not so new but wish to refresh and reinforce your understanding of the HHS regulatory requirements at this point I'd like to take a few moments to cover some of the logistical aspects of our program first things first I'm going to launch a poll asking whether or not you can hear me so here goes Oh Key dokie so there it is can you hear me and the things are rolling in the numbers are rolling in and it looks great over 97 percent of you can hear me so I'm going to close the poll and I will share the results I close the poll and I think I shared the results and now I've hidden the results okay most of you can which is the most important thing if you happen to have difficulty hearing the presentation you may want to switch your audio selection from telephone to voice over internet provider or VoIP or vice versa also during the webinar your control panel will read speaking Samantha Smith this is just an unavoidable idiosyncrasy of the software as many of you know samantha is one of our division of education colleagues I guarantee that in the not-too-distant future when you see the words speaking Samantha Smith it really will be Samantha speaking for now I'd like to take this opportunity to thank Samantha and Lynette Myers who are our wizards behind the curtain today next I want to mention that in so far is there maybe a thousand or more of you out there in cyber-land listening to my presentation it will not be possible to take questions at any point during this session some of you noticed that your reminder email contained a request for questions we did receive questions in advance and I will make every effort time permitting to respond to those within or after my presentation as always you may of course send along any questions you have related to this presentation to the general Oh H RPE M email box OHRP at HHS gov and we will answer them promptly in our normal course of a tivities also if you would like to review this webinar and/or share it with colleagues the recorded presentation will be posted to OHRP x' youtube channel within the next several weeks you will find the link on the OHRP website at that time many of you undoubtedly know that our first webinar on compliance activities is already available on YouTube now now before I get started in earnest I'd like to get a sense of who's with us today and I'm quoting liberally from Jimi Hendrix here are you experienced and so I'm going to launch another poll to see to see what we have out there so in terms of your experience in human subjects protections you are brand-spanking-new less than one year getting there but still a lot to learn one to five years looking to reinforce my understanding five to ten years or by golly I could teach this webinar ten or more years in this field and we see the results rolling in and you all are a very helpful and compliant group because I see that 90% of you have voted so I'm going to close this off now and this gives me a good sense of who you are with us here today I'm going to close the poll and share the results with you so that you can see that and I as I say that shows you're kind of all over the place which is good those of you who are very experienced in this field and you find this repetitive I will not be at all offended if you play some solitaire or take care of some other important work while we're going through this and now I will turn to the nuts and bolts of what we're here to do today I will hide this pole and return you to the presentation what I'm going to cover today includes some of the important historical precedents and ethical principles that got us to where we are today in terms of human subjects research I'm also going to talk about sort of the overarching area of regulated human subjects research and protections the applicability of the HHS regulations which of course are the regulations that OHRP enforces and then I'm going to spend the bulk of my time talking about the actual substance of the regulatory protections for research subjects within the regulations I'd like to spend a few minutes talking about some important historic precedents in the development of human subjects protections as you can see on this slide the three that bear the most relevance to the regulations that we work with every day are the Nuremberg code the Declaration of Helsinki and the Belmont report and I'll spend a little bit of time with each of these in turn during World War two as you may know Nazi doctors and others perpetrated some unspeakable acts of experimentation upon concentration camp inmates and these came to light at the conclusion of the war and the Nuremberg war crimes trials were held in which 23 German doctors were charged with crimes against humanity and they were charged with performing medical experimentation upon concentrate concentration camp inmates and other living human beings without any of any permission and the informed consent and notably there was of course no opportunity for individuals to withdraw if they wanted to so as part of the verdict from those trials we got the Nuremberg code and the court in its verdict enumerated some rules for permissible medical experiments now known as I said as the Nuremberg code and these rules include the notion that the voluntary consent of subjects is absolutely essential for the ethical conduct of research that benefits must always outweigh risks and that subjects should be given the opportunity to terminate their participation or withdraw from research at any time and for any reason and the Nuremberg code as I mentioned came out in 1947 moving more toward the modern times and into the further along into the 20th century in 1964 the world Medical Association gave us the Declaration of Helsinki and one of the notions within the Declaration of Helsinki which was really a refinement of some of the ideas in the Nuremberg code was the idea that concern for the interests of the subject must always prevail over the interests of science and society and there are several examples of the notion of the Declaration of Helsinki at work in today's research context and in the interest of time I will give you just one in 1993 researchers were looking at the use of AZT which at the time was kind of the only known treatment for HIV status and AZT was being looked at by researchers to prevent vertical transmission from an hiv-positive pregnant woman to her fetus and later baby and in the context of that study when the results came rolling in and data came rolling in the use of the AZT was viewed as quite effective and it really did help prevent vertical transmission and so the trial was stopped so that every individual woman were given the opportunity to speak with her provider and determine what was the right course of events for her even though if the trial had continued surely more scientific data and information would have rolled in so again the interests of every individual subject must always prevail even over the interests of science now moving along even further in 1947 we had the Nuremberg code 1964 was the Declaration of Helsinki yet in 1966 Henry Beecher published an article in the New England Journal of Medicine where he documented 22 published studies that presented risks to subjects and that were taking place without their knowledge or approval and these studies were published in prestigious journals at very well-known highly regarded institutions across the country and some of these studies you may be familiar with they involved mentally disabled children deliberately infected with hepatitis virus hepatitis virus that was the so called Willowbrook study of the 1950s live cancer cells were injected into 22 senior adults with dementia and many meant more examples of that exist well when that article came to light the Public Health Service finally took some action regarding that and the director of NIH and the Surgeon General requested that the National Advisory have council review human subject protections and the council recommended prior institutional review for PHS supported research to protect the rights and welfare of subjects and to assure appropriate methods of informed consent and to determine the acceptable balance of risks and benefits for subjects and this policy was adopted by the Public Health Service in 1966 and this was the beginning of the IRB system as we know it today that the beginnings of the IRB system so 1966 the Public Health Service policy gave us all of those things on this slide however at the very same time as if in a parallel universe the horrific Tuskegee syphilis study was ongoing in this country it was a highly unethical American medical research project conducted by the very same US Public Health Service for almost 40 years and in that study researchers were looking at the so-called natural natural being that the the syphilis was allowed to continue unabated looking at the net so-called natural course of untreated syphilis in African American men and the subjects were all impoverished sharecroppers from Macon County Alabama many of them most of them were unknowing participants in any kind of study they were never told that they had syphilis nor were they offered effective treatment even when the advent and recognition of penicillin as a widely available and effective cure for syphilis was available in the general community so that was going on for 40 years in this country and when that came to light the government finally took the steps the federal government finally took the steps that brought us to the regulatory framework that we have today you'll note on this slide there's a picture of President Clinton and Vice President Al Gore it was not until 25 years later that through the President of the States the government formally apologized to the tuskegee survivors and their families and he acknowledged the profound wrong that was done during the course of that study in the intervening years between 1972 when when when sit when the conclusion of the study and and it's the fact that had taken place for all those years came to light in the press in 1973 Senator Edward Kennedy called hearings on the quality of health care and human experimentation and out of that we got the National Research Act which established the National Commission for the protection of human subjects of biomedical and behavioral research and for the first time I Arby's were required at institutions receiving support from our predecessor agency which was the Department of Health and Health Education and Welfare and so that institutions again would need to have I Arby's reviewing research at those at HHH e W supported institutions and the Commission gave us what we know today as the Belmont report and unlike many government documents which probably are sitting on your shelf collecting dust the Belmont report is very much a dynamic and still living document and it forms everything we do in this area every single day and we at OHRP a fond of saying that it should be required reading for anybody involved in research involving human subjects it gave us three basic essential ethical principles the first is respect for persons whereby we recognize individual autonomy and at the same time balance that with protection of individuals who may have reduced autonomy the second is the notion of beneficence by which we try to maximize benefits wherever possible and minimize harms and also by the notion that physicians have of doing no harm the third is the notion of justice and that's captured with the idea that we always try to have an acute equitable distribution of research costs and benefits and I would just like to note that to give an example of the dynamism of the Belmont report when it was written we were of course just coming out of the the horrors revealed with Tuskegee and the notion was that individuals needed to be protected from research a lot of pharmaceutical research was being conducted in prisons where the populations were literally captive audiences for the research and so again the notion of Justice was protection from the costs of research however again in the mid eighties with the advent and recognition of HIV and AIDS research advocacy groups began to grow and viewed research participation as possible access to new and promising therapies and treatments and so the the goal with justice is to provide sufficient protections from costs of research but at the same time access to possible benefits and research now at this time I'm going to launch another poll about the developments in human subjects protections just to see if you guys are here and paying attention so here we go which of the following documents played a role in the development of the current regulations for the protection of human subjects and here I would ask you to just pick one just pick one and I don't know how it were actually how it works if you can chain if you choose one and you can change later but there are about about half of you have voted we'll give you another few seconds because we have a lot of material to cover here today let's see what we have here and I think I think you're saying what I am saying yes you are seeing the Poland progress so that's good all right we have this sort of magic okay that's great 87% of you voted that's good enough for me if 87 percent of the American electorate voted then that would be that would be participation we would all be proud of okay we're gonna close this all right we're just about at ninety we're gonna close this polls and as I suspected I'm gonna share the results here you all are a very very attentive and bright group 75% of you chose all of the above and that is correct I know I spent a long time talking about the Belmont report and in many ways the Belmont report really was as I said the philosophical parent of our regulations but at the same time those other documents also played important roles and informed where we are today so thank you for participating in that poll and now I'm gonna move along with the content of the presentation so with those historical precedents in mind I'm now going to talk about the overarching oversight of human subjects research and just give you a flavor of who's involved and our our piece of the pie so there are many federal departments and agencies 17 that are signatories to what we call the common rule and I'll talk about that in just a few moments FDA also of course has a significant role in the protection of human subjects research in industry sponsored research some of your states and localities may have further regulations or guidelines in place I know just by way of example that the state of California has its own statutory framework in place in this area and then last but certainly not least you'll each of your institutions plays a very important role in the protection of human subjects and indeed the regulations that our office enforces delegate a lot to the institutions and make it your institution's responsibility as a important role player in the protection really where the rubber meets the road so as I alluded to the office for Human Research protections we implement and enforce the HHS regulations at 45 CFR part 46 we owe a Charpy are the artist formerly known as the office for protection from research risks we used to play this role with this role within the National Institutes of Health and around the turn of the century the center of this most recent century we were elevated from within the National Institutes of Health to the office of the secretary to give an elevated view toward the protection of human subjects and also because our purview extends beyond just the National Institutes of Health to all of the agencies within HHS it was felt that the appropriate place for our office was within the office of the secretary as I alluded to the the main bulk of the regulations are what subpart a has come to be known as the common rule and you'll see on this slide the many other federal departments and agencies that have adopted it and the common rule is the rule that goes to the federal funding and support of research so for example if you're conducting research on pesticides involving people that's funded by the Environmental Protection Agency they have adopted the common rule they would implement it for that research now the HHS regulations as you hopefully are aware have additional protections in subpart B for pregnant women C for prisoners and D for children and one of our fine colleagues who put these slides together found this great picture which we believe is a teenage pregnant woman who appears to be incarcerated so there you go and if you happen to have somebody in your research study who is that person you would have to follow all of those additional protections because they are additive I just want to make a note you see on this slide also listed subpart E that's really an administrative regulation that goes to the formalities of IRB registration it is required now for IRB is reviewing HHS and federally and HHS and now also FDA regulated research and again if you have a federal wide assurance on file with us you also have a relationship with a registered IRB as I alluded to or as you may have noticed the Food and Drug Administration was not listed on that slide with the signatories to the common rule that's because they operate from a different statutory and regulatory framework the good news is that the requirements for IRB in terms of the membership and review of the IRB those requirements as well as the requirements for informed consent are largely congruent between the HHS which are the OHRP requirements and the FDA regulations and again as I believe I've alluded to some what the difference is stem from applicable it applicability the HHS regulations are based on HHS funding or support of research and the FDA regulations kick in when there is a use of an FDA test are all so if the study involves drugs devices or biologics that's where the FDA regulations would come into play our regulations come into play where the funding or support is is there which is a good segue to exactly how our regulations do come into play now there are several prerequisites to determining whether or not you actually have to follow the regulations in 45 CFR 46 these are some threshold determinations that you need to make to figure out how and in what way the activities that you're conducting may or may not be covered by the regulations the first is research involving human subjects conducted or supported by HHS that is not otherwise exempt or non-exempt human subjects research that is covered by an assurance of compliance and I'll take each one of those and spend a little time with each of those with respect to the conduct or support by HHS you'll notice that there's just a sort of a cute little cartoon of money I want to note that support encompasses more than just money so for example if there's a study for which NIH has supplied in-kind support such as computers or microscopes or lab equipment that would also be considered HHS support so I just wanted to note that with respect to applicability derived from your assurance of compliance as you know and I'll talk about this a little bit more later all of you I'm guessing if you've signed up for this but perhaps not have or are thinking about getting a federal-wide assurance of compliance within that federal-wide assurance of compliance your institutional official has had to make an election as to which research you want your assurance to apply so it can either apply to all of your HHS or federally sponsored research because that's a requirement under the assurance or you could have you can elect to have the assurance apply to your entire portfolio of human subjects research regardless of source of support and I'll get into that a little bit more later now continuing into determining applicability there are four questions that we need to ask and it helps to ask them in this order the first does the activity involve research does it involve human subjects is the human subjects research exempt so you do have research you do have people involved but is it possible that it's exempt and last but not least is your institution engaged so again you might have research you might have people involved they may not be exempt but there may be an overarching activity being conducted which is non-exempt human research but your institutions particularly release of it may not constitute engagement and we have a human subjects regulations decision chart available on our website which I invite you to take a look at that helps you walk through those determinations and I will somewhat quickly in the interest of time move through each of these research is defined in the regulations as a systematic investigation designed to develop or contribute to generalizable knowledge and it's important to get underneath those words and underneath the labels that we might have attached to a certain activities such as program evaluation or quality assurance it's important to go beneath the labels and figure out exactly what activity is being conducted now happily on our website I'd like to point out that we have some frequently asked questions pertaining to Quality Assurance activities and what what constitutes Quality Assurance activities that may be researched and what may not be research and I would recommend to you that you take a look at those because again even though those are in the context of QA activities some of the information really transcends those activities and can be applied to other things that you may be doing at your institution the next important definition threshold definition is does the research involve a human subject under the American regulations a subject has to be a living individual about whom an investigator conducting research obtains data through intervention or interaction with the individual or identifiable private information now the good news is with respect to data through intervention or interaction is that hopefully we all know when we're poking or prodding a person or speaking with them or giving them medicine or hooking up an IV so that one hopefully is fairly straightforward the more tricky one is the question of whether or not we're using identifiable private information and I would here to recommend that you take a look at guidance we have available on on our website that relates to the use of data and tissue and in that guidance there are examples and frameworks that describe situations where what you're doing if proper safeguards are in place what you're doing may not actually constitute human subjects research may be research but you may not be involving a human subject now next okay you have a you have research you want research you wanted to gain some generalizable knowledge for the world and you're involving living people the next question is well is it possible that what I'm doing is exempt and time does not allow us to discuss these these categories in any kind of detail so I'll just make a couple a few quick observations about these exemption categories how they relate to these sub parts with the added protections good news is if you're conducting research with pregnant women under subpart B research with pregnant women can avail itself of these categories of exempt research the exemptions do not apply to research involving prisoners under subpart C so if you're conducting research involving prisoners under subpart C that would have to go before an IRB and follow all of the additional protections in subpart C in the area of research involving children under subpart D most of these exemptions do apply except the second category educational tests and so forth is circumscribed when it comes to children children can be given education research involving educational tests under category 2 and that and that can be considered exempt research involving children and surveys and interviews is not exempt and the third prong is limited so when you're involving children in research involving observation of public behavior that's okay and only okay with children when the investigator does not participate in the activities being observed so that's the exemptions now the last question that you ask is is your institution engaged so again the overarching activity may be human subjects research which is not exempt but then the question is is your institution engaged and institutions are generally considered to be engaged when the employees or agents obtained for research purposes data about the subjects or identifiable private information or this is also important for engagement if your institution is obtaining informed consent and involved in an informed consent interaction with subjects then you and your institution are considered to be engaged again here we have some excellent guidance available on our website that details examples of one engagement exists and when an institution is not engaged and I invite you to take a look at that as well now finally if you have human subjects research that is not exempt and in which you are engaged then the full panoply of regulatory protections for research subjects comes to bear and the regulations are basically in three sections the first deals with institutional assurances the second IRB membership and review and the third informed consent and I will move through each one of those in fairly hopefully efficient and short order an institutional assurance is required when your institution is engaged in non-exempt human subjects research it's really a documentation of your institution's commitment to uphold the human subjects protections regulations and it is one method of compliance oversight it's it's how we establish our relationship with you and at the present time the federal wide assurance or FWA is the only assurance option for those of us who've been around this business for a long time you may recall the multiple project assurance single project assurance different alphabet soup melange of assurances now there is only one kind and it is within the four corners of the FWA that you have to designate a registered IRB as being responsible for the review of your research portfolio now I also want to note that it is in this first section of the regulations that pertains to institutional assurances this section of the regulations also describes the general over arching obligations of the institution qua institution in terms of human subjects protections so if you haven't taken a close look at the regulations here you might like to the next major portion of the regulations talks about IRB membership and IRB review the membership requirements are fairly straightforward you have to have at least five members the regulations talk in terms of you having appropriate experience and expertise represented on your IRB to review the research that will be coming in front of it before it the regulations talk in terms of diversity of members in terms of gender and ethnic background and the regulations explicitly state different categories of membership that must be on your IRB so you must have at least one scientist one non scientist and one non-affiliated member and I'll talk about each one of those in turn for a few moments in a few moments I also would like to note that if you are conducting research involving prisoners you need to have a prisoner representative on the IRB as a member and we make no distinction between voting members non-voting members the regulation is to talk about members and that's what we mean is a member with all the full rights of being a member and that person must represent the interests of prisoners so former prisoners perhaps a prison chaplain someone who would view the research from the perspective of a prisoner now turning back to the traditional categories of membership you need minimum one scientist one non scientist interestingly although quite reasonably when you think of the history of the regulations the regulations require that in order to meet quorum the non scientist must be present so no convened IRB meeting can take place in the absence of the non scientists and in determining who fits what role you want to look at the training background and occupation of these individuals and I would note that the regulatory language related to this talks about the primary concerns of the person so the primary concerns of the person are in scientific or non-scientific areas so a registered nurse by and large we would consider that person to be a scientist a middle school English teacher of a middle school English teachers primary concerns whereas a middle school English teacher we would say that this person is probably a non-scientist a member of the clergy also a non-scientist the biggest thing is that institutions make reasonable and rational decisions in this regard and I would note also that it is perfectly acceptable from OHRP perspective for institutions to take a twofer so for example it's perfectly possible that your non scientist and your non-affiliated could be the same human being so a middle school English teacher who has no other affiliation with the institution a member of your community who's a clergy member could conceivably be your non scientist and you're not affiliated one can certainly maintain they're not affiliated membership even with certain associations with the institution so for example a patient a subject a former subject or needless to say their service on the IRB if that's the only association with the institution they can still be considered not affiliated one of the things we like to stress from OHRP and we think it's important and useful for people to hear it from us is that we encourage the use of the flexibility and efficiency inherent within the regulations that's why we have the lady doing the yoga and the newfangled light bulb so the regulations themselves talk about the use of expert consultants as part of the IRB review process so the use of an expert consultant is perfectly appropriate he or she cannot be is not a member of the IRB and does not vote but again just by way of example if an institution has never done research involving children before and a really interesting project comes along the institution can have a pediatrician help review the materials and provide their viewpoint on whether or not it's appropriate for children now similarly but distinctly OHRP and our predecessor OPR are have long recognized the use of alternate IRB members so in the first example the expert consultant helps the IRB not a member is in the regulations alternate members not in the regulations but yes we considered these people and these people are indeed in fact members alternate members can be listed on your IRB roster as people with appropriate expertise who can substitute for any other member of the IRB for whom it makes sense and would be appropriate in terms of background and expertise as it says here they can substitute for an entire meeting or any portion of the meeting so if you have an alternate sitting on the back bench and the primary member for whom they substitute has to leave for 10 minutes or for the rest of the meeting the alternate can step in for as much or as little as is necessary as long as that alternate is appropriate and I would also add that it's perfectly permissible for an alternate to be considered an alternate for one or more permanent primary members of the IRB moving along now in terms of IRB membership just want to note that interestingly perhaps for some of you the only place in our regulations where conflict of interest is mentioned is in terms of IRB member comfo and the regulations state that any IRB member who is conflicted may provide information requested by the IRB but must be recused from the review and the vote and importantly conflicted members do not contribute to the quorum so just as in the situation where an IRB may invite any investigator with a proposal to come before the IRB and answer questions about their proposal and then leave for the deliberations in the vote so too can an IRB member who has a proposal before the IRB stay to answer questions about his or her proposal however when it gets to the part of the deliberations they should leave and they may not be part of the vote and again it's important that to note that conflicted members do not contribute to the quorum so it's important for you to make sure that you'll have the appropriate numbers in the room that day to maintain quorum even if the conflicted member leaves the next portion of the regulations talks about IRB review and in terms of the types of IRB review the substance and the process of a review and this goes to the process of review the regulations pretty much default to convened meetings where the quorum requirements are met however the regulations also describe situations where expedited review is perfectly appropriate and OHRP encourages institutions to use expedited review in the appropriate circumstances this is a situation that if we were actually in a room and I was seeing you face to face I would ask you to show me your hands to see how many of you in your institution do expedited review and I would expect and hope that it would be a lot of you for expert review as I'm sure you may know it's allowed when there is minor changes to approved research whether or not that original viewers expediter or convened and also where there is research that is of no greater than minimal risk and it's a list and it's on the list the quote-unquote list that we have available that's not in the Federal Register and it's on our website that lists types of research for which expedited review is permissible and again if you're not familiar with what's on that list I would invite you to take a look at that IRB review is described in the regulations and again in terms of the content and process it is required prior to initiating human subjects research again non-exempt human subjects research it is required in the context of continuing review and the regulations speak about a continuing review and that in determining the frequency of continuing review it must be appropriate to the degree of risk but not less than once per year many institutions default to an annual review which in many circumstances is appropriate but there may be situations where an IRB would like to see research come back before it in in less than 365 days IRB review is also required prior to initiating any changes to approved research this is to be distinguished from the situation where change needs to be made immediately to prevent an immediate hazard to subjects but if there's going to be any type of ongoing change to approve research it needs to come before the IRB and of course the IRB needs to make what we call the 111 findings and it must have in front of it the sufficient information to make those findings the 111 findings that I'm going to turn to in a moment as well as the findings required under any of the relevant sub parts so very quickly the findings under 111 and I say quickly only because we've we've discussed these in other contexts already the 111 findings very much hearkened to the Nuremberg code the Declaration of Helsinki and the Belmont report the IR bees have to find that the risks are minimized that the risk benefit ratio is reasonable that subject selection is equitable these all ring of Belmont and Nuremberg and of course that informed consent is obtained and documented appropriately or or unless it's waived other findings that the IRB has to make is that where appropriate data is monitored this would come up in cleaner the clinical trial context the privacy and confidentiality what provisions are made for it how will things be protected as well as safeguards for vulnerable subjects if there may be situations where there are vulnerable subjects who are not those described in the subparts but may be economically disadvantaged or have other status situations which which would render them vulnerable it's important to note that in the context of research involving pregnant women prisoners or children there are additional findings that need to be made unlike research outside of the subparts research within the subparts there are categories of permissible research and the IRB has to affirmatively find that the research being proposed fits into one of those categories similarly where research involves children informed consent is not the notion at work so much as a cent of children and permission of their parents although substantively again and I'll get to this in a moment it goes back to the substance of informed consent there are other considerations in the subparts that go to the composition the IRB secretarial panel process for research that is not otherwise approvable by the IRB use of expert consultants and so forth and I know I'm running up a little bit against time here so I will keep this moving we have a poll and I think we'll do the poll but I'm going to do it real quick and I'll see see which see you're still paying attention and this is actually a little bit of a trick question and we'll do it fast which of the following must be considered in determining the frequency of IRB review and I see that you are guys are doing very well on this also you can see the poll in progress and you're sort of moving along here I'll see what we got here all right there's lots of you still participating and that's good 72 percent so I think if we hit close this baby out at 75 percent okay this looks pretty pretty consistent here you said 72 percent of you said that it is which of the following must be considered in determining the frequency of IRB review and 3/4 of you got the correct answer which is the degree of risk to the subjects that is the regulatory requirement in terms of determining continuing review having said that 26% of you more than a quarter of you said all of the above and I would say that while that is not exactly the regulatory language it's certainly not inappropriate for an IRB to want to take a look at all these different things that are involved in a study to determine when and how the IRB wants to take a look at it I'm gonna hide this one now and keep moving along here let me make sure what you're getting is what I want you to get okay okay so now last but certainly not least is informed consent informed consent really is the first among equals in this whole in this whole business of human subjects research and protections and the key principles of the informed consent process really the atmospherics of informed consent involve full disclosure of the nature of the research and the subjects participation adequate comprehension on the part of subjects or their legally authorized representatives and again here we see Nuremberg loud and clear the subjects voluntary choice to participate and this slide shows the basic elements of informed consent that informed consent has to say that what we're doing here is research or an experiment or a study you'd be surprised that we still see informed consent documents that just launch into what's going to happen without actually telling the person informing them that they're being asked to participate in research risks and benefits should be described as closely as possible to ordinary normal events that might occur in the person's life so that they can understand it in that context alternatives where they exist confidentiality how it will be upheld and instances where it may be breached in the sense that they would understand it so for example if information would be released to a governmental agency that should be stated in the informed consent compensation for injury if it exists or if it doesn't exist whom to contact in three different situations one with questions about the research if a person believes that he or she has been injured in the context of research or if a person has questions about their rights and welfare as a research subject here we would suggest that these people be different people so that for example if the person has questions about their rights and welfare as a subject perhaps the IRB or an institutional Ombudsperson somebody who has expertise in that area somebody who is not closely tied to the research project itself the IRB also can insist on additional elements when appropriate although I skipped over that last one and shame on me for doing that because the last one is really Nuremberg loud and clear right to refuse or withdraw and/or withdraw from research at any time without any penalty or loss of benefits it has to be made crystal clear to subjects that their participation is voluntary and that they have an option to decline any procedure or to withdraw whenever they whenever appropriate whenever they wish to again the IRB can insist upon additional elements when appropriate such as the consequences of withdrawal so no a person can leave whenever they want but if a person let's say is in a study of an IRB of a high blood pressure medication it's perfectly appropriate to put in that informed consent you have high blood pressure if you withdraw from this study and discontinue any high blood pressure medication that could be dangerous for you so there are additional elements listed in the regulations that the IRB can insist upon the regulations also provide for a waiver or alteration of informed consent under certain circumstances 116 C we rarely see it has to do with public benefit programs 116 D is really sort of the classic waiver or alteration provision which I'll get to in a moment 408 just describes a waiver or alteration of informed consent in the realm of children's research and 101 I is a waiver of informed consent in situation where the research study itself contemplates on research in an emergency setting where it would not be possible for somebody to give consent the notes the slides little behind here it's interesting but I hope you're getting them oops informed consent the IRB must find and document so this has to be documented somewhere that the research itself poses no greater than minimal risk that the waiver will not adversely affect the rights and welfare of the subjects that the research could not practically practicably be carried out without the waiver and that when appropriate subjects will be debriefed after participation it's really this third prong that I want to just focus on a little bit to say that OHRP has always taken the position that mere inconvenience in terms of getting informed consent typically will not cut it it really the waiver without the waiver the research project itself would be very difficult to begin or carry out I just want to make a quick note because I see that I'm running out of time here that the regulations that we enforce include separate requirements for documentation of informed consent so it's important to note that the substantive requirements for informed consent live at 116 but that the requirements for how that informed consent has to be documented live at 117 and the and the regulations talked about the long form document which is the one with which I'm sure most of us are familiar which would embody all of the elements that the IRB would insist upon the short form includes it an oral presentation using a summary that the IRB has approved the short form also involves the use of a witness and it again the use of the short form is perfectly acceptable and encouraged by OHRP we recognize that use of the for short form sometimes involves a little more upfront work and work in terms of the informed consent interactions and so sometimes institutions are a little reluctant to use that short form but there's no regulatory prohibition from using the short form and in fact again I'd like to stress that we encourage its use where appropriate uh written documentation can also be waived and I see that I'm going over here just a little bit I hope you're still with me and I apologize for going over but I just have a few more slides the written documentation again it's a separate regulatory section and it's important for you to note that there may be instances where the IRB may still insist upon informed consent but can perfectly reasonably and acceptable e waive the documentation requirement and it can be waived where the consent form is the only record linking the subject to the research and that the principal risk of the research is from the breach of confidentiality so just something for you to consider also documentation can be waived where it's minimal risk research and the research procedures themselves do not include anything like informed consent if done outside the research context so again by way of example if the research procedure itself is talking to somebody then that typically does not involve written informed consent in the outside world so just to sort of close out this notion of the informed consent both the document and the substantive informed consent it is not to be viewed as a single event or just a form to be signed rather it should be viewed as an ongoing process that takes place between a researcher and the prospective subject and it's a good idea for your institution to have policies and procedures in place that really go to how the IRB expects this to be fulfilled now I'm going to take my last poll and I'll see if you guys are still hanging on here where's my poor my polls here they are okay just went away poll closed Oh new poll okay you still with me I hope you are okay I'm gonna launch this last baby here okay the Department of Health and Human Services regulations at 45 CFR part 46 included requirements regarding institutional assurances and institutional responsibilities institutional review board membership and review informed consent or all of the above let's see how you're doing here and this is great I appreciate your continued attention especially since I do recognize that I'm going over a little bit here okay I'm going to close this out 80% of you have voted and 96% of you have said all of the above and those of you who've said all of the above oh I have to share it that's why I have my wizards here behind the camera well it's not a camera behind the speaker um okay what do you seeing now let me see audience view okay so you can see that the vast vast vast majority said all of the above and you are correct so I'm gonna get rid of this poll here move along to my final slides the key points I hope you've gotten them Belmont report read it love it who regulates human subjects research well we of course at OHRP do but there are lots of different players and you play a very large role in it how and when did the HHS regulations apply and the basic protections afforded by the HHS regulations I hope you've gotten a sense of that today I just want to give one final slide here with contact information these are ways to reach us I want to ask your indulgence with regard to our website it is not the easiest website in the world to navigate but if you indulge the website and give it four or five or even six more clicks than you think you should have to do you will probably find lots of great information if in the words of bono you still haven't found what you're looking for please avail yourself of these other ways to contact us we are happy and proud to say that we still have a live human being answering our phone and trying to help you or get you to another live human being who can answer your question finally finally finally and I know many of you probably have to go I want to give a quick shout out for some other events we have coming up on June 22nd we are co-sponsoring with the University of Pittsburgh one of our research community forums on international research called building bridges research around the world we're going to have a focus as I say on international research also we will be holding one of our quality assessment workshops on July 17th in Seattle Washington and that course is a very basic course for those who have to implement the human subjects protections and work as IRB professionals every single day so if you'd like more information about those conferences please contact me or any of these contacts on this slide here and again thank you thank you very much for your attendance and we look forward to hearing from you soon thank you goodbye

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