Office of Research Oversight (ORO)

Bi-Monthly Teleconference Minutes
Wednesday, July 14, 2004, 12 Noon to 12:50 P.M. EST

ORO Staff Participating:	
ORO Central Office	ORO Regional Offices (ROs)	
Dr. David A. Weber, Chief Officer	Dr. Min-Fu Tsan, Mid-Atlantic RO	
Dr. Joan P. Porter	Dr. Karen M. Smith, Midwestern RO	
Priscilla A. Craig	Richard D’Augusta, Northeastern RO	
Peter N. Poon	Dr. David J. Miller, Southern RO	
Paula Squire Waterman	Dr. Paul S. Hammond, Western RO	
Shannon B. Williams		
Lisa L. Franklin		
Cheron Cole		

Introduction (Dr. David Weber):

 Dr. Weber welcomed everyone to the bi-monthly ORO nationwide teleconference and reminded listeners that the hand-out related to the topic of discussion had been distributed via e-mail previously.  Dr. Weber introduced Bernard A. Schwetz, DVM, PhD who was appointed in April 2004 as the Director of the Office for Human Research Protections (OHRP) in the US Department of Health and Human Services (HHS).  OHRP leads the department’s efforts to ensure the responsible conduct of research involving human subjects.  

Prior to his appointment, Dr. Schwetz had served as OHRP’s Acting Director since February 2003.  Previously, he held the post of Senior Advisor for Science at the Food and Drug Administration (FDA) and during that time chaired FDA’s Institutional Review Board (IRB), which is responsible for ensuring the safety and well-being of participants in HHS-funded research carried out by that agency.  

In addition, he served as FDA’s Acting Principal Deputy Commissioner, Acting Deputy Commissioner, and Director of the National Center for Toxicological Research.  Before joining FDA in 1993, Dr. Schwetz was Acting Director of the Environmental Toxicology Program at the National Institutes of Health’s National Institute of Environmental Health Sciences and Associate Director of the National Toxicology Program there.  

Dr. Schwetz is an elected member of the National Academy of Science’s Institute of Medicine and a nationally recognized expert in reproductive and developmental toxicology.  He has served as a Distinguished Scientist at the University of Maryland, College Park; Adjunct Professor at the University of Arkansas for Medical Sciences; and Adjunct Professor of pharmacology and toxicology at Michigan State and North Carolina State Universities.

Enhancing Responsible Conduct of Research (Bernard A. Schwetz, DVM, PhD):

Dr. Schwetz began by stating that there are several elements of this topic that he will be discussing: 
(1) What should the Federal agencies be doing about the increasing amount of international research that we are engaged in?
(2) Issues related to the hand-out discussing the research enterprise in the United States.
(3) Discuss concepts with the listeners to get ideas about how to prevent another tragedy from happening within the human research community.  

Dr. Schwetz stated that he wants to reinforce his challenge to the VA to be leaders and role models within the whole area of human research.

#1.  Some thoughts about international research: Within OHRP a modest part of the budget is transferred to the World Health Organization (WHO) to support international conferences and training programs.  Dr. Schwetz stated that OHRP has a commitment to supporting activities within the international arena, but that he continues to be concerned about how to measure the impact that their investment makes.  Additionally, within the research enterprise, who should be providing the training, funds, and guidance to IRB communities all over the world?  For example, more than a third of the research studies that support registration submissions in the FDA now come from outside of the United States and that percentage is growing fairly rapidly.  Thus, a rather large percentage of the studies are being done outside the United States in places where we have much less control over how the IRBs review the research.  FDA is developing some guidance, but foreign research is not managed as closely as in the United States.  In addition, when something goes wrong in a foreign study, such problems can have high visibility in the US press and lead to the conclusion that what was done was unethical.  Some listeners might remember the series of articles in US newspapers a couple of years ago dealing with some terrible things done to subjects in US-sponsored research being conducted in foreign countries.  Dr. Schwetz asked the listeners who have a growing level of activity of international research for input on training and monitoring international research.  There has been a lot of discussion within OHRP about what it means to be HHS-supported or conducted because that definition itself, for example, drives the need for a research institution to have a Federalwide Assurance (FWA).  There is a lot of confusion about how to manage research being done by collaborators or people who receive funds outside of the United States, whether it is funds from HHS, VA, or from a pharmaceutical industry.  Dr. Schwetz welcomed questions or thoughts about how Federal agencies should be handling this.

Q: How are you integrating this with the ICH, specifically E6 (Good Clinical Practice Consolidated Guidance), which, as you know, is modeled more closely on the FDA regulations, specifically the definition of research and the definition of human subject?

A: Dr. Schwetz suggested that the best way for OHRP to handle that is to make sure that FDA is involved because FDA is close to the ICH process.  OHRP has depended on FDA to take leadership in that particular area.  OHRP is following iCH closely, but has not taken a leadership role there.

The caller stated that the reason she asked specifically is that currently many of the institutions who are doing industrially-sponsored studies are being asked if they are in compliance with ICH-E6.

Q: In HHS research that you have overseen the last few years, has there been a consistent policy of handling assurances in foreign countries where the research is taking place?

A: Dr. Schwetz stated that this question is hard to answer because, from OHRP’s standpoint, the policies have been consistent, but there is a gray area of when an assurance is needed.  OHRP is trying to narrow down the width of that gray area by looking at examples.  National Cancer Institute (NCI) research has provided a series of examples in which it was clear that there was a requirement for a FWA, ones in which it was clear that there was not a requirement, and then a series of examples in between.  OHRP hopes to develop criteria on when it is necessary to have a FWA.  OHRP continues to receive questions about this, but how much work is being done in the field that should be under a FWA is not really known.

Q: My impression is that OHRP has required more in terms of FWAs in international settings and that some of the other Federal Departments and Agencies (VA included) are thinking about their policies and procedures in that area, but is that your impression?  Are all of the Federal Departments and Agencies asking for FWAs internationally, or are they doing it in different ways to assure that the protections there are adequate in international settings?”

A: Dr. Schwetz stated that he would suspect that the various Federal Departments and Agencies are assuring protection in different ways.  From the standpoint of a “first cut,” if they are providing protections that would be comparable to having a FWA, then at least it is not an emergency that is waiting to create a big problem, and whether or not that that is something that should be cleaned up/checked out is, in addition, a question of resources.  Dr. Schwetz further stated that he would guess that there is more of a tendency for Departments and Agencies to be doing to assure protection through whatever means that they think will accomplish the same level of protection as an FWA.

Dr. Weber added that in a typical case where it might involve some relatively low-dose radiographic procedures or perhaps even high-dose radiographic procedures, nuclear medicine procedures, or requiring multiple blood sampling, one could not assume that an assurance would be requested.  It would vary country by country.  Dr. Schwetz concurred that it would vary country by country and would not necessarily be related to risk of the procedure.  It would be more related to local practice and local culture.  It is similar to the discussions that the research community is having now relative to research in children, i.e. background risk varies from community to community.

Q: Is OHRP willing to maintain assurances for projects that may not involve HHS funding?

A:  Dr. Schwetz said he thinks OHRP receives a fair number of requests for assurances for institutions who want to be prepared for receiving funding from HHS sources.  He stated he thinks OHRP will work with an institution doesn’t currently have HHS funding that would require an assurance.  Since the assurance system is more automated now than it used to be, that question is less important to OHRP and (it is hoped) to the people who are looking for a FWA.  It’s easier to negotiate an assurance than it was a couple of years ago.  Dr. Schwetz said, for example, that he’d tried to figure out with the large number of FWAs that OHRP has outside the United States, what per cent of those institutions actually have DHHS-supported or conducted research.  He hasn’t an answer to that yet, however.

#2.  Dr. Schwetz next said one of the things he’d been emphasizing is a better understanding of what the research enterprise really is – the enterprise that involves humans regardless of whether the research is supported by pharmaceutical companies or by HHS or by NSF or VA or other entities.  Dr. Schwetz noted that when he came to OHRP, he heard a lot of people talking about the research enterprise.  Because he could find no one who had defined what the elements of the research enterprise are, Dr. Schwetz suspected the term was being used differently by different people.  As he tried to figure out where were the risks associated with human research, he thought it was critical for him to understand the components of the research enterprise.

The second slide of the handout sent before this talk reflects Dr. Schwetz’s current thinking about what the components of the research enterprise look like.  Dr. Schwetz said he’d gone through the effort to define the components of the research enterprise because he thinks in the past too much blame has been attributed to IRBs as the source of problems within the enterprise and that there are people who think that if they fixed all the problems within the IRB system, they would fix all the problems of human subject protection, all the problems of the research enterprise.  Dr. Schwetz thinks that both those assumptions are incorrect.  So, in second slide, Dr. Schwetz identifies every party involved in the research enterprise - from the sponsors to the educators, to those who provide regulatory oversight, to the accrediting organizations and so on, throughout the diagram.  What he has found is that there are sources of risk to research subjects from every one of those components in the enterprise, or in the interfaces between one component and another.  He urged that we need to ensure that as we look at our own institutions, and the whole VA system to determine where risks to subjects are in the bigger picture of VA-related research.  This includes our collaborators, our affiliated institutions.  He urged that we not focus too heavily on either the IRBs or investigators because there are other components in the research enterprise that have a significant impact on where risks might be found.

For slide #3, Dr. Schwetz stated focused on preventable risks.  There are risks inherent in research and, although there the review process works with risks and benefits, people involved in research need to understand that research isn’t risk free.  When Dr. Schwetz refers to the risks of the enterprise, he means the preventable risks to subjects.  Dr. Schwetz feels he’s looking at a “background of harm” probably existing around a threshold that somehow lines up with compliance.

For slide #4, Dr. Schwetz noted that day-to-day risks to which subjects might be exposed has individual variation (e.g. slight errors in procedure, or misjudgments, missed readings of diagnostic information, or erroneous diagnostic information) that put a large number of subjects at risk.  Those risks, however, are found around a low threshold that doesn’t make the newspapers when something goes wrong.  Dr. Schwetz thinks about what new legislation could protect human subjects in terms of the low level risks that don’t constitute tragedies, but rather occur every day where there is a threshold of risk that is not necessarily serious enough to be reported as an adverse event.  Or, new legislation could rather be driven by another Jesse Gelsinger or Ellen Roche death.  It’s likely that there will be new legislation after the election; Dr. Schwetz is hearing signals from the Hill related to writing laws that have (up to this point) not gone any place.  He fears that if there is some kind of tragedy between now and the election, it would drive new legislation specifically geared to whatever that incident was, but not necessarily to protecting people against the day-to-day load of risk relative to the threshold of compliance.

In slide #5, Dr. Schwetz addressed how we can anticipate the next tragedy.  Dr. Schwetz says everyone tells him there will be one; it’s a question of under what circumstances and who/where/when it will occur, as opposed any doubts that there ever will be a tragedy.  Dr. Schwetz agrees that such a tragedy probably could be prevented.  Dr. Schwetz said that, as you look on the slide titled, “How do we anticipate the next tragedy?” he has talked about the risks to subjects that are the background around a threshold, as presented in slide #4.  He is not talking about a major tragedy, as with Jesse Gelsinger, but about things that happen in day to day routine research.  In contrast, we have the tragedies that Dr. Schwetz would put in a category of major “unanticipated” events, with some considered accidents that are somewhat preventable.  Some events are unanticipated because we haven’t given thought to the “low level” sources shown on slide #4.  When Dr. Schwetz asks how we might know these “unanticipated” events, he often gets the answer “We don’t know where they going to come from, and we don’t know how to anticipate them.  If we knew, we would do what we can to prevent it, but we don’t know where they’ll come from, so why are you thinking about it?  Why are you worried about it?”  Dr. Schwetz is not satisfied with this response, especially, for example, when he is sitting next to Paul Gelsinger.  Then, the issue becomes more personal, especially because Mr. Gelsinger feels the accident that killed his son was preventable.

Looking back at slide #4, Dr. Schwetz tried to pull together what he thinks are some of the sources of risks to prompt people to look at their own environments, to see if one factor might be more likely than another to account for a tragedy, and what could be done to prevent it.  The potential tragedy could be related to inadequate training, or conflicting/competing interests that could lead to bias or blindness or noncompliance, especially noncompliance that increases the background variety of risk.  Other factors contributing to a potential tragedy include inadequate or poorly used resources of the Human Research Protection Program, where IRB staff spend time on burdensome tasks that don’t translate into protecting human subjects.  For example, IRBs don’t have enough time to ask questions about experimental design or whether risks have been minimized because they spend too much time on 100-page consent forms.  Some potential tragedies are related to errors in judgment.  Often, when OHRP visits an institution, the staff find flawed procedures.  Even sites that have already had a tragedy may still have a systemic inability to prevent the next one, so the risk continues.  Dr. Schwetz notes credentialing professionals and institutions, or accreditation, isn’t going to prevent tragedy from happening, as that situation is probably independent of accreditation.  On the other hand, if the accredited institution has an infrastructure that encourages people to anticipate and prevent situations that could lead tragedy, then, in the long term, accreditation would probably make a difference.

Dr. Schwetz has asked many people if credentialing investigators is something OHRP should be pushing to reduce risks to subjects, and he has received a wide variety of answers.  One common response to this question is that if you can’t drive a car without a license, why allow people to do research without the equivalent?  The opposite extreme maintains there are already too many requirements for doing research and there is a risk of driving good, young researchers out of the field by adding requirements.  Although Dr. Schwetz doesn’t know the extent to which an untrained investigator is a risk factor, he does know institutional indifference is a risk factor.  Dr. Schwetz says institutional indifference is obvious when OHRP investigators go to an institution, and the critical people (responsible for the institutional commitment) don’t show up at the meeting.  What’s even worse is that the institutional people at the meeting aren’t surprised the institutional official hasn’t shown up, or that upper level people didn’t bother because that’s the normal procedure within the institution when it comes to human subject protection issues.  So, institutional indifference is something OHRP picks up pretty quickly and is a significant sign for Dr. Schwetz that there is risk waiting to be expressed.  As for the source of risk related to gaps in regulations, there certainly are areas where OHRP hasn’t provided enough guidance or conflicting or confusing guidance and, to some extent, that factor could contribute to risk as well.

Stepping back from the list of sources of risk shown on slide #4, Dr. Schwetz asked the audience from where the next tragedy is likely to come.  He noted that he continues to think the likelihood of an IRB creating a situation that increases the likelihood of a tragedy is not as probable as those who are in contact with the subjects creating such a situation.  This means the investigator, or someone else.  Dr. Schwetz gave the example of a pharmacist compounding an agent to be given to a research subject. The pharmacist gives the prepared agent to someone to take to the research location, and this person notices the agent is a different color or volume than what was given to him/her earlier.  Still, this person thinks there isn’t have time to go back to check to see if the agent is correctly compounded, and takes it to be given to the subject.  Finally, the person actually administering the agent notes it doesn’t look the same as what was given 2 days before, but not wanting to question someone else, he/she give it, hoping nothing will happen.  That situation creates a chain of events where the likelihood of harm could be interrupted, and if the institution doesn’t give thought on how that chain of events could be interrupted or kept from occurring by detecting and stopping the potential harm, then it will happen.  The question needs to be asked “What could we do to prevent such accidents?”

Dr. Schwetz noted that both the airline and railroad industries collect information on near misses and do something about it.  OHRP doesn’t have the authority to collect “near miss” information.  Also it seems as if in the current research environment, people are afraid to report errors because of fear of being reprimanded or fired. Thus, there is no way of collecting the information and no way of learning from mistakes unless something bad happens.  Dr. Schwetz is not sure how to collect information that will help us to anticipate what the next tragedy is.  He said there are many on the call today who are much closer to that situation of knowing how you, your institution, and your collaborators might collect such information and prevent tragedies.  Dr. Schwetz said he would welcome any thoughts on how we all could prevent that tragedy, not only because of the obvious harm to an individual or family, but also the harm to our institutions when it happens, including affecting the likelihood that an institution will be able to recruit subjects for other studies.

Dr. Weber called for comments and questions  

The listener agreed with Dr. Schwetz that the IRBs are not the prime problem, but research cannot be made absolutely risk–free.  Investigators often think that if they tell the subjects every small detail in that 100-page consent form, then they won’t get enough subjects.  So there is a tendency to soft pedal risk because a laundry list of risks might result.  It takes a much higher commitment to the details and understanding in presenting the consent form.  It is important that we change the culture that permits one to quickly accrue subjects, quickly get them through the laundry list, and not really emphasize what the probabilities are.

Dr. Schwetz stated that clearly one of the constraints to research and getting new drugs/medical products approved is the time it takes to recruit the subjects, and that is a function of how much information is made available.  It is clearly a balance between trying to anticipate what might happen as an adverse event or side effect versus not mentioning it and having it happen, raising the creditability question.  There are 2 things that account for the burden that makes this more difficult.  One of them is clearly that research is more complex, in many cases, today than it was 10 years ago because of all the additional information that we know, we can therefore predict the possibilities of what might happen with the mechanism behind the drug being tested.  Do you put all complicated biology and medicine in the consent form and try to get it to a level of writing that people will understand?  The greater complication of research today has made it more difficult to anticipate what we should be telling potential subjects.  But then there is the other complication that the consent forms have grown from 2-3 pages to 20-30 or more pages, and a lot of that extra information has to do with protecting the institutions, not the subjects.  Dr. Schwetz noted that a lot of people have commented to him in meetings we have all attended, saying that we had better protection of subjects when we had informed consent documents of 2-3 pages than we do when we have 30-40 page consents – and no one reads them.

A listener agreed with that.  I think if we streamline those documents and included the rest of the information for protecting the institution if the subjects want to take it with them, we would do much more good and less harm.

Dr. Schwetz said that for subjects who are impaired in their ability to read or understand or whatever, the idea of a short form and would depend on the consent process to convey information might help.  For those who can read and understand English, we have imposed on them the idea that by having 30-40 page consent forms if the potential subjects can read them, it’s better.  I think research shows now that’s not the case.

Many times the change of investigator is listed as a minor change to a protocol, but many times when research is passed from investigator to investigator, it invites problems.  How do you perceive that – a change of investigator is a minor change or a significant change that should be reviewed by the local IRB?

Dr. Schwetz said he thought it would be an error to assume that it’s a minor change.  He thinks the IRBs need to protect the researchers, protocol, and institution, because it’s a big problem if a change in investigator is not brought to the attention of the IRB and something bad happens.  There is work involved in notifying the IRB and having it understand what the change is and whether or not the new PI is also credentialed and trained and acceptable from the standpoint of being equivalent or better than the first PI.  That takes time, but Dr. Schwetz thinks it only reasonable to invest in that time to protect everyone.

I think the question is should it go to the full board or should it be expedited?  

Dr. Schwetz said he didn’t think if necessarily had to go to the full board, but it depends on the nature of the protocol.  If it’s a low-risk protocol and the PI is to change, and the IRB Chair (or designee) looks at the change and understands the new person is an equivalent leader for this research, that’s one thing.  But if it’s a fairly high-risk research project, Dr. Schwetz thought that an IRB Chair would want to give it to the whole board, or at least raise it to the whole board.

I would just like to observe that we’ve switched from a discussion of how to protect participants to a discussion of process, which may be one of the sources of your deep concern about our attention to protecting human subjects.

Dr. Schwetz has emphasized the idea of the research enterprise and looking at burdens to see where we’re putting our efforts, perhaps unnecessarily, and leaving gaps in other areas.  What about the  wax and wane of the idea of centralized IRB review or at least regional IRB review?  How do we know which is preferable and what are some of the trade-offs to going to going one way or the other?  That is, maybe eliminating unnecessary redundancy versus preserving the ability of the local community to make decisions about what occurs in that local community.

Dr. Schwetz noted that the benefits or concerns over central IRBs as a mechanism is an important topic to keep discussing because there are divergent view, and there may be the erroneous assumption that if we arrive at a central IRB process it will fit everybody.  Dr. Schwetz thinks that will never happen, that there will be some circumstances where central IRBs are probably helpful.  Dr. Schwetz would use the central IRB of the NCI as an example of where the NCI has highly experienced people review protocols for the research that they are sponsoring.  The NCI then gives the local IRBs the option of either reviewing the research in a minor way, and agreeing with the NCI review, or doing a full review by the convened board of the local IRB.  So an institution has the option of using the NCI review or not.  Dr. Schwetz thinks that imposing the central IRB process, without options at the local level, would be a mistake.  To assume that we are moving in the direction of having regional IRBs or a national IRB that would do a lot of the review means rubbing against the grain of so many IRBs at the local level such that this may never happen.  Dr. Schwetz is not particularly supportive of the concept of a regional IRB.  He thinks if you have expert specific IRBs (e.g. an IRB with expertise in pediatric cancer) where there are just a few experts in the country or in the world who really know all the medicine and the biology of that particular cancer, perhaps it might be good for such an IRB to review the specific types of protocols.  But when it comes to other kinds of research projects where there would be a lot of experts, Dr. Schwetz doesn’t see the benefit of channeling such research through one IRB that doesn’t have knowledge of the local conditions.

Dr. Schwetz thinks there are places where central IRBs can be helpful, however, there has been an expectation that if a university research site is involved in the central IRB process that things will go a lot faster, and the site will draw a lot more money from the sponsor to support research.  Dr. Schwetz noted the data are conflicting on that issue – some things are faster and some IRBs are faster than others within institutions.  So, to speed up the review through a central IRB process may work well at one institution, but not another.  Dr. Schwetz thinks it’s an experiment in progress, and that we should keep looking at it.  He also hopes that we will figure out ways to know what are the right uses for central IRBs and not have unreasonable expectations that it’s a broader answer than it really is.  But when a central IRB would work, Dr. Schwetz thinks that it should be used, as there clearly would be benefits to help reduce burdens and bring experts to the scene.

As a new AO at the VA, whose previous job was in patient safety, the person commented about the PowerPoint presentation distributed with the teleconference agenda.  He thought patient safety is everywhere, and it’s certainly an important aspect of research.  Dr. Schwetz’s comment about failure mode and perhaps not having a mechanism to be able to evaluate near misses “rang a bell” with the listener.  

One listener requested an ORO teleconference on data safety and monitoring boards.  There seems to be confusion about when we need them and how best to serve patient safety with a board or a smaller group of people.

Dr. Schwetz said he would like to hear such a discussion and recommended that Susan Ellenberg of FDA would be the person to do such a discussion because she is the expert from the viewpoint of the FDA-related product studies.

Dr. Weber then brought the teleconference to a close, thanked Dr. Schwetz, and suggested that teleconference participants e-mail ORO staff either in the Central or Regional Offices if there were other questions or comments regarding the presentation.  ORO staff would forward the e-mails to Dr. Schwetz.

Other Announcements (Dr. David Weber):
1.  The table prepared by Paula Waterman comparing 1200.5 policy with the regulations is now posted on the ORO website.

2.  The next teleconference will be Wednesday, September 8th.  Dr. Weber indicated tentative plans to have that call cover the ORO memorandum on “What to Report to ORO.”  Dr. Weber encouraged all teleconference participants to send an e-mail to him with suggested topics that they would like to have discussed on the teleconference.  Include the names of any individuals who might be likely candidates to present the topic on the teleconference.