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DSMB Training Academy: Preparing the Next Generation (Part 2) · Cardio Pod: Heart of the Matter

• 0:00
  Well, welcome everyone to Heart of the Matter podcast.
• 0:09
  I'm Chris O'Connor, principal investigator of the Heart Failure Collaboratory, and we're
• 0:13
  very excited to be talking about data safety monitoring committees, why they're necessary,
• 0:19
  how do we get people engaged in the participation and the training of the next generation.
• 0:25
  And I'm here with three of my favorite distinguished colleagues.
• 0:29
  I'll let them introduce themselves.
• 0:30
  David Demetz.
• 0:31
  Hello, yes, I'm Dave Demetz.
• 0:33
  I'm professor emeritus of biostatistics at the University of Wisconsin in Madison.
• 0:39
  And I've now gone through my 50th year of clinical trials in various capacities, but
• 0:44
  I still find it interesting and a very worthwhile exercise.
• 0:47
  Thanks.
• 0:48
  Tom Fleming.
• 0:51
  And Dave, approaching your middle age, we need you for another 50.
• 0:54
  I'll try.
• 0:57
  I'm professor of biostatistics at University of Washington in Seattle.
• 1:02
  And it's a real pleasure for me to be here with Janet and Dave and Chris to talk about
• 1:06
  these really important issues around monitoring committees.
• 1:09
  And Janet Wittes.
• 1:10
  Janet.
• 1:11
  Hi, I'm Janet Wittes.
• 1:12
  I'm delighted to be here and I'm really happy to be part of our failure collaborative.
• 1:17
  I am right now simply a statistical consultant, but I've been involved and realized my first
• 1:24
  CSMB was in 1976, so it's been a long, long time.
• 1:30
  Well, data safety monitoring committees are, there's a mystique about these committees.
• 1:35
  They've been run and chaired by a small group of people that as clinicians and clinical
• 1:42
  investigators we've had the utmost respect for, but it's a committee that has this cult,
• 1:52
  it has this culture of maybe a narrow inclusion.
• 1:58
  And so David, I'm going to ask you to start off the conversation.
• 2:02
  And why do we have data safety monitoring committees and why are we here today talking
• 2:08
  about the challenges of the next generation?
• 2:12
  Thank you, Chris.
• 2:13
  Well, the history of a data monitoring or sometimes called data safety monitoring boards
• 2:18
  goes back to the mid to late 1960s.
• 2:21
  The Helsinki agreements talked about you shouldn't conduct a trial any longer than necessary
• 2:26
  and always monitor the risk to benefits.
• 2:29
  That was followed up by an NIH sponsored report called, which we refer to as the Green River
• 2:34
  Report that took place in the late 1960s.
• 2:39
  Wasn't published for 20 years, but nevertheless everybody knew it was around.
• 2:42
  But it also called for the PAC to keep an eye on clinical trials and not let them run
• 2:46
  longer than necessary to monitor the risk to benefit ratios.
• 2:50
  So we've been doing this process since the late 1960s, certainly in the early 1970s when
• 2:56
  they began to become the standard way of proceeding across different NIH institutions.
• 3:01
  But I think many of us have become aware in the last five years or so that the number
• 3:07
  of clinical trials that are using data monitoring committees has simply exploded.
• 3:12
  And we became concerned that the number of people who had the experience that we were
• 3:16
  fortunate to have was not keeping up with the demand.
• 3:19
  So there's a big supply and demand gap that we have to recognize and pay attention to.
• 3:25
  And there are issues if you don't have properly trained data monitoring committees as Tom
• 3:30
  and Janet can attest to.
• 3:32
  Janet, what are those issues?
• 3:34
  I mean, this is part of the why.
• 3:37
  What are the issues that David is alluding to?
• 3:39
  Well, I think there are many issues.
• 3:42
  And I want to think about three kinds of people.
• 3:46
  There are the people, the sponsors.
• 3:48
  There's the people who present to the DSMB and the DSMB members.
• 3:52
  And all of them have to really understand what the purpose of the DSMB is and how best
• 4:00
  to perform as DSMB members in this whole culture.
• 4:05
  In my experience, there are lots of sponsors who don't really understand what the committee
• 4:11
  does.
• 4:12
  And they're actually, they don't trust the committee because there's this silent body
• 4:18
  outside, and therefore are low to give the committee the information it needs to make
• 4:24
  intelligent recommendations.
• 4:27
  And then there's the people who are presenting the data to the committee.
• 4:32
  And some of them don't know that you have to present data in a way that allows the committee
• 4:37
  to make recommendations during the course of a trial.
• 4:41
  And those reports are different from the reports that you see at the end of the trial.
• 4:47
  And then finally, there are the DSMB members.
• 4:50
  And I just had an experience very recently where a DSMB member not understanding the
• 4:57
  difference between the DSMB member who has to keep things confidential and a consultant
• 5:04
  just spill the beans what the DSMB was saying, spill the beans to the sponsor, and therefore
• 5:12
  jeopardizing the integrity of the trial.
• 5:15
  So all three groups have to learn what the DSMB is and how to run it in an effective
• 5:21
  way.
• 5:22
  Tom, what are your thoughts here on the why?
• 5:25
  Well, it's, you know, but kind of before getting into a bit more of where we need to go today,
• 5:32
  just to expand a bit on what Dave and Janet have said about the why, the mission of the
• 5:37
  monitoring committee is to safeguard the interests of study participants.
• 5:42
  And certainly that includes overseeing and protecting their safety.
• 5:46
  But it's also to protect the integrity of the trial, to help enhance the sponsor's efforts
• 5:50
  in protecting trial integrity.
• 5:53
  And a bit of an anecdote about that experience from my involvement, as Dave mentioned, the
• 5:58
  Greenberg report in the mid-60s introduced the concept of data monitoring committees.
• 6:04
  And over the next decade after that, they became more frequently used in certain areas
• 6:09
  within NIH, cardiovascular area and the eye institute.
• 6:14
  But they weren't yet used widely elsewhere.
• 6:17
  In the oncology setting, we started to implement data monitoring committees for all of our
• 6:22
  studies in the Norocentric Cancer Treatment Group in 1977 to 84.
• 6:27
  And interesting experience I had when I then moved to the Southwest Oncology Group to the
• 6:31
  University of Washington in 1984.
• 6:34
  I approached Chuck Holtman and John Crowley, the head of that group, to say, we need to
• 6:40
  keep data confidential, motivated by what Janet and Dave have already talked about during
• 6:44
  the course of the study.
• 6:46
  And they both agreed that we should do this to protect trial integrity.
• 6:49
  But they said, you're going to need to have the leadership, the steering committee agree.
• 6:53
  And I'll never forget one of the thought leaders on the steering committee said to me, wait
• 6:58
  a minute, Fleming, you want us to not share all the data from our ongoing studies?
• 7:02
  He said, what are we going to do at our steering committee meetings?
• 7:05
  Play tiddlywinks?
• 7:06
  And I said, well, he said to me, if we're going to do this, you need to tell me scientifically
• 7:11
  why.
• 7:12
  And I said, absolutely on target.
• 7:14
  We should do that.
• 7:15
  And so we took the experience in the seven years from 77 to 84 when we had protected
• 7:20
  confidentiality in the North Central Cancer Treatment Group and only shared the data with
• 7:25
  the monitoring committee versus what happened in the Southwest Oncology Group from 77 to
• 7:29
  84.
• 7:30
  We matched them up by major colon adjuvant, breast adjuvant, lung adjuvant studies.
• 7:34
  There were 10 in each group.
• 7:36
  And in the cooperative group, in the group that shared data routinely, SWOG, there were
• 7:43
  five of the studies that ramped up and then trickled away.
• 7:46
  And many of them could never be finished.
• 7:48
  Whereas when the data were kept confidential in the North Central Cancer Treatment Group,
• 7:52
  they ramped up and they stayed.
• 7:54
  And so the North Central Cancer Treatment Group, by having confidentiality, avoided
• 7:59
  the prejudgment that protected the ability of the trials to be successfully completed
• 8:03
  and also avoided early data that were released that were misleading in those settings.
• 8:09
  And about three years later in the Southwest Oncology Group, after we implemented this
• 8:13
  approach, that steering committee member said it was the best thing that had ever happened
• 8:18
  to the integrity of the steering committee.
• 8:20
  We were now using our time, not talking about what happened in the first 11 patients on
• 8:24
  a study, but making decisions on reliable evidence and protecting the integrity of the
• 8:30
  studies.
• 8:31
  So this is just one anecdote of the why.
• 8:34
  What is so important?
• 8:35
  Yes, it's safeguarding patient interests, but it's also protecting trial integrity and
• 8:40
  avoiding breaches of confidentiality that Janet now is just talking about in her experience
• 8:45
  that was problematic.
• 8:46
  I can just quickly add to that experience a couple of recent experiences that I've had
• 8:51
  where people say, okay, Fleming, we get it.
• 8:54
  We're going to keep data confidential.
• 8:56
  But what happens in a study that is looking at early data for registrational purposes,
• 9:02
  but then for accelerated approval, for example, but then later data to give the true clinical
• 9:06
  endpoint results.
• 9:08
  And we continue to run into circumstances here where there's not an adequate understanding
• 9:15
  that the monitoring committee needs to keep, have sole access to emerging data, even on
• 9:21
  those long-term validation endpoints to avoid prejudgment.
• 9:25
  Well, that's such a great analysis that you did that just gives us the data, the information
• 9:34
  to say the why.
• 9:36
  The why is good.
• 9:37
  Right.
• 9:38
  It's not speculation, Chris.
• 9:40
  There's a lot of evidence that we have over time of seeing what happens when you have
• 9:44
  a monitoring committee and you're preserving sole access.
• 9:48
  And that's critical, especially for registrational trials to maintain their integrity.
• 9:54
  You know, one of the things...
• 9:55
  Oh, go ahead, Janet, please.
• 9:57
  But it's not sufficient to have the monitoring committee.
• 10:00
  It has to be a monitoring committee that really understands what it's supposed to do.
• 10:06
  Well, and we're going to get to that because that's where my fear is.
• 10:10
  And that is that there's a small group that know this and we got a larger group that are,
• 10:16
  yes, raising their hand.
• 10:18
  They want to get involved, but they don't have the experience yet.
• 10:21
  But let's talk about some of the transitions of monitoring committees.
• 10:24
  I mean, David, in that beautiful introduction lecture you did on the website of Society
• 10:30
  of Clinical Trials and now on the HFC website, you talk about the monitoring committees during
• 10:35
  the Coronary Drug Project and you had six drugs and you stopped two and you continued
• 10:41
  two.
• 10:42
  I mean, it was unbelievable.
• 10:43
  I don't know if the stopping rules today would have been the same as the stopping rules back
• 10:48
  then.
• 10:50
  That's question one.
• 10:52
  But one thing you've done well as leaders of DMCs is that you've figured out that sponsors
• 10:58
  sitting in these committees is probably not a good thing.
• 11:02
  And you've been able in the private sector to put that wall there.
• 11:06
  But the NIH, you know, the last NIH trial I did, I had project managers sitting there
• 11:12
  and, you know, listening to everything and they're the sponsor.
• 11:16
  They're writing the checks to us.
• 11:18
  David, how come you haven't made any progress in that space?
• 11:22
  Well, I have experience of having sat on both sides of the table in my career.
• 11:26
  I spent 10 years at the National Heart, Lung, Blood Institute.
• 11:30
  I think we've become more sensitive over time about many issues.
• 11:34
  That's one of them.
• 11:36
  I think we've also had experiences where sponsors, whether they be federal or private, have not
• 11:42
  have intervened, if you will, in what we consider the monitoring committee's business and caused
• 11:47
  problems for the monitoring committee as well as themselves in the study.
• 11:51
  So we've learned over time.
• 11:52
  But I want to go back.
• 11:53
  The Coronary Drug Project was a great teaching venue.
• 11:58
  If people have not read those papers, they need to go back and take a look.
• 12:02
  The statistical methods that I, Claire, England, Tom, and Jack can comment and criticize, I
• 12:06
  think the philosophies are all laid out in those trials.
• 12:10
  We've added some statistical sophistication, no doubt, since then.
• 12:14
  But they laid down a lot of the principles that we still adhere to today.
• 12:18
  And so as we thought about the gap and how we were going to try to close that gap, I
• 12:24
  think we all realized that there was no organized process by which to provide that training.
• 12:30
  It was on-the-job training, which is not adequate in today's setting.
• 12:34
  And so fortunately, we were able to, with the blessing and help or support of the Stiflifer
• 12:39
  Clinical Trials, retrieve three or four workshops that had been put on that happened by pure
• 12:44
  chance, I guess, to be videoed.
• 12:47
  And so with a lot of help and volunteer work, we got those videos recovered.
• 12:54
  And the Stiflifer Clinical Trial was willing to put those up on their website and now accessible
• 12:58
  through the Heart Failure Collaborative.
• 12:59
  And in addition to that, we were able to record some of our clinical colleagues as to why
• 13:05
  they participate and what value they see.
• 13:07
  So we have several testimonies, if you will, of clinicians who participated in clinical
• 13:13
  trials and why people should want to train and do that.
• 13:17
  So we have now a menu of videos, the three of us on this Zoom recording.
• 13:23
  We're part of that, but there are others.
• 13:25
  So we have that available.
• 13:27
  And we also, in addition to the training, we said, well, we also need to have a registry
• 13:32
  of who has experience and who would like to get experience.
• 13:37
  And so you can raise your hand, declare your interest.
• 13:39
  It's not a certification process, but at least it provides people who are interested.
• 13:46
  And finally, we realized that we needed to have a mentorship program.
• 13:50
  It's one thing to have the didactic training, but also to have seen one live and get that
• 13:57
  experience.
• 13:58
  So we also call for a mentorship program.
• 14:00
  And that's, I think, a challenge we have written about and are talking about to have more buy-in
• 14:07
  on the issue of having mentorship.
• 14:09
  But in general, we are on the move.
• 14:11
  And I think we're moving in a positive direction to try to close that gap.
• 14:16
  And I think it's fantastic that the Heart Failure Collaborative has stepped in and provided
• 14:22
  a wonderful workshop.
• 14:23
  I guess it was last June 12, which you referred to.
• 14:26
  And we're planning another one, I gather.
• 14:28
  I'm hoping that that's good news.
• 14:31
  And even better news to me is that other groups that are hearing about this say, how can we
• 14:35
  get involved?
• 14:36
  That's exactly what we want to have happen, is that we get this training program widespread.
• 14:42
  So I'm looking forward to the future.
• 14:43
  We've got a lot of work ahead of us.
• 14:45
  It's so darn important, as Janet and Tom have said, if it isn't done right, you can actually
• 14:49
  do a lot of harm to integrity of the trial, actually to the sponsors, and of course, most
• 14:55
  importantly, to the patients who put time and their own bodies as an investment, hoping
• 15:00
  to get an answer.
• 15:01
  And if we mess it up, then their investment is also wasted.
• 15:05
  So everybody has a stake in this game to do it right.
• 15:08
  Great thoughts, Dave.
• 15:11
  Training the next generation is really critical.
• 15:13
  We need you, Arthur.
• 15:15
  Data monitoring committees, as Dave and Janet have indicated, have now been widely implemented,
• 15:21
  and we continue to need people that will be involved, that have the background, clinical,
• 15:28
  and quantitative expertise, and then can bring those skills forward and be involved in data
• 15:34
  monitoring committees.
• 15:36
  And Dave's really laid out the aspects here of what he refers to as the didactic and mentorship
• 15:42
  or apprenticeship aspects of this.
• 15:45
  And as he's indicated, the didactic is important.
• 15:47
  There are many aspects to it.
• 15:49
  There are many articles.
• 15:51
  There's Elmer Plumbing of the Met's textbook and other textbooks.
• 15:54
  There's the short courses that Dave just mentioned that the Heart Failure Collaboratory had just
• 16:00
  organized on June 12th, and we'll be having another one in the future.
• 16:05
  And as Dave mentioned, there are now these presentations, these lectures that are online.
• 16:12
  As he's indicated, though, if I often say, Chris, if I'm going to go up on a small plane
• 16:18
  with you and you're the pilot, I'm going to ask if you've actually been involved in doing
• 16:22
  more than just reading a book about it, that you've actually been involved going up with
• 16:27
  an instructor.
• 16:28
  That experience, that actual real experience matters, and Dave refers to that as the mentorship
• 16:33
  aspect.
• 16:35
  But if what we're saying is we want everybody to be experienced on monitoring committees,
• 16:40
  then we're not growing the number of people who will be involved.
• 16:43
  And so we want the committees to be collectively experienced in the DMC practice, but to be
• 16:49
  heterogeneous in that so that some are new to the DMC process.
• 16:55
  Everybody is a full member on the monitoring committee, even if you're coming in without
• 16:59
  experience on monitoring committees.
• 17:01
  You're bringing in important clinical and quantitative expertise, but you are then in
• 17:06
  a group with others who've had the experience, you're going to be part of a process and learning
• 17:13
  from your colleagues about those DMC processes.
• 17:17
  So it's a really important step that sponsors need to be thinking about.
• 17:21
  And we can do this if we have a study of a COVID vaccine and we have a cardiologist and
• 17:26
  infectious disease doc and a pulmonologist.
• 17:28
  Oh, okay.
• 17:29
  One or two of them have expertise in DMCs.
• 17:33
  But often we have a single biostatistician.
• 17:35
  Well, I'm not sure why that is.
• 17:38
  We should have committees with two, where one of them is a Janet Wittes, who knows a
• 17:42
  great deal about the data monitoring committee process, and someone else who will be there
• 17:47
  as a full member, but learning a great deal from Janet and others on the committee.
• 17:51
  And so this is the process that Dave's talking about.
• 17:54
  And Dave has been leading an effort with Society Clinical Trials in being able to facilitate
• 18:00
  the ability for people who are interested to put their names in and to be able to be
• 18:05
  known to sponsors who are setting up these committees.
• 18:08
  That's really a terrific point.
• 18:10
  We've talked about young clinical investigators, seasoned and clinical investigators, but we
• 18:15
  assume that the biostatisticians magically have all that knowledge when they graduate
• 18:21
  from their programs.
• 18:23
  And that's not the case.
• 18:24
  So Janet, I like the idea of two biostatisticians, a senior or junior, just like we're talking
• 18:30
  about with the clinical investigators and clinicians on these committees.
• 18:34
  What are your thoughts there?
• 18:35
  I think it's really important.
• 18:38
  One of the words we haven't said today is that on a DSMB or DMC, what you have to use
• 18:44
  is judgment.
• 18:46
  Expertise is really important and you need it.
• 18:49
  Experience is important, but there is this element of judgment that comes from discussion
• 18:58
  in the committee.
• 19:00
  I think it's very important for young statisticians to see how the interaction works with everyone
• 19:11
  and how each person trains the others in their areas of expertise.
• 19:17
  I was fortunate enough in the CDP, in the coronary drug plot, I was a postdoc for Jerry
• 19:22
  Cornfield, who was one of the people on that committee, and he said to me, I've got this
• 19:28
  really interesting committee, would you come and just come join me?
• 19:32
  And there was an informality about it in the old days.
• 19:35
  Anybody could come.
• 19:36
  You were just told, keep your mouth shut.
• 19:38
  Now it's much more formal and we have to have, given the decades of experience, we can't
• 19:46
  just say to somebody, come to this interesting meeting.
• 19:49
  We have to have a structure for training and for mentorship, but I think it's really important
• 19:55
  for statisticians as well as clinicians to have experience and therefore to be, for the
• 20:01
  committee to have more than one statistician on.
• 20:06
  There are other constituents that need to learn about DMCs that we've touched on in
• 20:12
  our June 12th meeting, but one I've seen emerging, and I like to get the opinion of this group
• 20:18
  is patients.
• 20:21
  Should patients' voice be on a DMC?
• 20:24
  David?
• 20:26
  I had the privilege of serving on a VA clinical trial operation, and they were very insistent
• 20:35
  on having a patient representative on the committee.
• 20:40
  And I think that they did add, they obviously didn't have the technical expertise, but they
• 20:43
  too learned, just like we all learned from each other, they learned from what our statistical
• 20:47
  issues were and clinical issues.
• 20:50
  And so they were very sensitive to how a patient would actually view what was going on.
• 20:54
  We all worried that somehow they would not be able to keep the confidentiality of the
• 21:01
  data and so forth, but I didn't see any particular case in my experience that was a problem.
• 21:07
  The NIH, for example, sometimes added ethicists to the committee who are supposed to represent
• 21:13
  the ethics of the trial as well as the patient representative, probably as good a job as
• 21:18
  they do, they still don't represent the patient representative totally well.
• 21:22
  But I think hearing it from the patient's perspective is really important.
• 21:25
  You know, Tom and I served on the AIDS clinical trial group for a bunch of years, and it was
• 21:30
  a lesson of clinical trials 101 because all the issues we thought we knew were raised
• 21:37
  again in a different context, in a very sensitive context.
• 21:41
  But it turns out that the patients were absolutely critical, they did not sit on the DMC formally,
• 21:46
  but they became aware of what it is the DMC did and began to defend us as not being problematic,
• 21:53
  but being critically important to the integrity of the trial.
• 21:56
  And that was a 180 degree turnaround once they understood exactly what it was we did.
• 22:00
  So educating the participants, the patients who have something in stake here is important
• 22:05
  to get their support.
• 22:06
  John?
• 22:07
  I'd like to say something.
• 22:09
  Oh, Jeff?
• 22:10
  I want to talk about ethicists because I have learned so much from some of the ethicists
• 22:16
  on the committee.
• 22:17
  Sometimes you're faced with a real dilemma.
• 22:20
  The data are showing harms and benefits, and you don't know how to make judgments.
• 22:26
  So sometimes the issues are very complicated, and I have found it remarkably helpful to
• 22:32
  have somebody who's formally training effort to be able to walk us through how to think
• 22:38
  about what these issues are.
• 22:40
  So everybody comes with a different set of skills and insights, and as long as everybody
• 22:49
  participates, they're very, very useful.
• 22:54
  And just to add to what Janet and Dave were saying, when Dave and I were involved in the,
• 23:04
  it was from the late 80s for the next 20 years actually, on the monitoring committee that
• 23:10
  was overseeing the NIAID clinical trials and therapeutics for HIV AIDS.
• 23:16
  They were being conducted by the AIDS clinical trials group and the community program for
• 23:19
  clinical research and AIDS.
• 23:21
  And as Dave was describing, there was significant membership involvement and integration with
• 23:28
  ethicists and with patient advocates, and it was a real benefit to us.
• 23:33
  And what made it more possible was that the committees were somewhat larger, and because
• 23:38
  we were looking at it, we were overseeing a program of trials.
• 23:41
  I think in my 20 years on that, we monitored, I think, 60 trials.
• 23:46
  And so it allowed us to be a bit more efficient by overseeing a program, and it made it then
• 23:52
  more feasible to have a somewhat larger committee.
• 23:56
  And by being larger, Chris, we were able to be more inclusive, more diverse, and it was
• 24:01
  a real advantage.
• 24:03
  I would say though to sponsors in general, although our focus here is on getting more
• 24:07
  people involved in monitoring committees, that it's wise to consider putting a monitoring
• 24:12
  committee in place, not just specifically for a single trial, but if a sponsor is developing
• 24:17
  an intervention in their ongoing concurrent related trials, then having that single monitoring
• 24:22
  committee in place to oversee the program for that intervention is not only more efficient,
• 24:28
  but it gives the monitoring committee broader access to related studies as it relates to
• 24:33
  understanding safety and benefit to risk.
• 24:36
  It then in turn allows us to be a bit more inclusive by having a somewhat larger committee
• 24:41
  and bringing in more expertise, obviously maybe more in clinical areas or quantitative
• 24:46
  areas, but as Dave and Jenna were saying, on the ethical and patient side as well.
• 24:51
  You know, one of the things that I always liked about serving in that monitoring committee
• 24:56
  for the AIDS trials, we wanted our training to converge.
• 25:00
  If you were to eavesdrop on that committee at any particular time, it would take you
• 25:05
  a while to figure out who the statistician was, who the ethicist was, and who the AIDS
• 25:11
  physician was.
• 25:12
  They all knew enough about each other's discipline and respect that discipline that they could
• 25:16
  have a conversation that eventually led to a consensus recommendation, which is the goal.
• 25:21
  So that's the ideal.
• 25:22
  If you can get to that point, you've really done something.
• 25:25
  I think we achieved it in that network.
• 25:27
  Great, great point.
• 25:29
  In the Alibari Philomaridibets textbook written by either Susan or Dave, not my B, my favorite
• 25:34
  paragraph in that book was exactly what Dave said.
• 25:36
  You know you have a great monitoring committee when you're a fly on the wall, you're there
• 25:39
  and you're observing, and there's a clinician, an ethicist, and a statistician, and at the
• 25:43
  end of the hour, you don't know which is which.
• 25:45
  Does it mean the ethicist doesn't know the most about ethics and clinical clinician and
• 25:49
  about the clinical stuff and the biostatistician, about the quantitative stuff?
• 25:52
  But we would like people to be broadly conversant about these areas, and as a result, as Janet,
• 26:00
  you would say the data monitoring committee is not a collection, it's a collective.
• 26:04
  Where we bring all of these collective experiences together into a common position that the committee
• 26:13
  that will then take in its recommendations.
• 26:16
  One issue I'd like to raise before our time is up is that we have become somewhat alarmed
• 26:21
  lately about the documentation of trials.
• 26:24
  There's obviously the protocol, there's a statistical analysis plan, there's an informed
• 26:28
  consent document, but the document that seems to get lost and is rarely ever seen is the
• 26:33
  DMC charter.
• 26:34
  And as you well know, the charter contains sort of guidelines, not rules, but guidelines
• 26:39
  as to how the committee is to operate and has a great influence on how we get to the
• 26:44
  end of the trial.
• 26:45
  But that document is rarely seen.
• 26:47
  And so we have been, we have a paper just accepted in the Journal of Clinical Trials
• 26:54
  calling for DMC charters to be made accessible through clintrials.gov.
• 27:00
  Now we were working on a solution that's not ideal, but at least it's a start.
• 27:04
  And so I think we will move forward and make that available now.
• 27:08
  Getting people to buy in is another matter, but we're hoping that we can shed some light
• 27:13
  on the DMC charter, which to date has not been the case.
• 27:17
  That's a terrific point.
• 27:19
  And another angle, as an editor I could speak to this, we could ask editors in journals
• 27:25
  to say as part of your acceptance to this prestigious journal, Jack Hartfiller, where
• 27:31
  I was, but New England or Lancet, the supplemental material must include the DMC charter, which
• 27:38
  I know they're including CEC charters now and CEC definition, but maybe that's one way
• 27:43
  we get at it also.
• 27:45
  That would be fantastic.
• 27:46
  I can tell it would be fantastic.
• 27:49
  We'll push that on the, I'm an editor emeritus, I'll push that on, and many of you are too.
• 27:53
  One last- This is a really key point.
• 27:57
  Yeah, go ahead, Tom.
• 27:58
  And Jenna was talking earlier about opportunities that we need to improve the DMC processes.
• 28:04
  This is surely one.
• 28:06
  And my sense, my own sense about this is that sponsors have often offloaded to contract
• 28:13
  research organizations the intermediary role, the role to basically facilitate the DMC process.
• 28:19
  And even if it's with best intentions, it's often without the depth of experience of understanding
• 28:26
  the critically important scientific and ethical considerations where the monitoring committee
• 28:31
  doesn't, as Dave was saying, we don't need a rule book.
• 28:36
  This is, and Jenna was talking about judgment as being really critical to developing recommendations.
• 28:41
  And so DMC charters are a really key aspect of what it is that outlines how we are going
• 28:47
  to proceed.
• 28:49
  And it is, as Dave said, not a rule book, it's guidelines.
• 28:52
  It shouldn't be specifically indicating restrictions on what the DMC should be able to see, or
• 28:59
  that we start with an open session rather than in fact allowing for a closed session
• 29:03
  to come first, or that we develop our recommendations by voting.
• 29:07
  And I've said to people, why are you insisting on an even odd number of people?
• 29:11
  Because you have to have a vote.
• 29:12
  We can't have a tie vote.
• 29:13
  So wait a minute.
• 29:15
  This is not a political process.
• 29:16
  This is a scientific and ethical process where we're not doing our job if we in fact take
• 29:21
  a three to two and say we're done.
• 29:23
  We need to work together, understand each other, develop consensus.
• 29:27
  And in my experience, that's always been achievable, to develop consensus.
• 29:32
  And so these documents, these DMC charters are critical that they are properly set up,
• 29:38
  as Dave said, as guidelines and not rules.
• 29:41
  And as David indicated, and through efforts with clintrials.gov, if there can be more
• 29:47
  transparency or visibility of these, it will be helpful in allowing people to see how they're
• 29:52
  done and also for accountability that these need to be done in a way that are respective
• 29:58
  and enhancing the quality and the integrity of the ethical and scientific consensus.
• 30:03
  The other challenge to me, and we've actually written about this, is that I've said a monitoring
• 30:08
  committee can only be as good as a report it gets to review.
• 30:11
  And we know from experience that we've seen the good, the bad, and the ugly in terms of
• 30:15
  reports.
• 30:16
  And so in a lot of the education and training of the sponsors about what's necessary and
• 30:22
  the members as to what they should expect, we need to also train the statisticians and
• 30:26
  be alluded to as to what really constitutes a good DMC report.
• 30:29
  A 3,000 page report is not helpful.
• 30:32
  An NDA submission is not helpful.
• 30:34
  Hey, Janice, you've talked on this.
• 30:37
  My job is going to lead to Janet as well.
• 30:39
  We're going to have another meeting here because I know our time is short.
• 30:42
  What Dave just mentioned is so important.
• 30:43
  reporting statistician group or the statistical, the SDAC, the statistical data analysis center,
• 30:44
  And as a person on monitoring committees who hasn't been a person who develops the reports,
• 30:50
  we're sitting here with Dave and Janet, who are absolute remarkably strong leaders in
• 30:54
  that generates the reports.
• 30:55
  As Dave said, you're only as good as a monitoring committee as the information that you obtain
• 31:00
  as a statistician.
• 31:01
  And so we're going to have a meeting here.
• 31:02
  And we're going to have a discussion about how to make sure that we're able to make the
• 31:05
  best decisions.
• 31:06
  And so we're going to have a discussion about how to make sure that we're able to make the
• 31:09
  best decisions.
• 31:10
  And so, I think, Janet, as a monitoring committee, as a Paulina talked over here, what is the
• 31:13
  key thing about monitoring committees when doing something so that I was going to add
• 31:16
  to our conversation?
• 31:17
  I think that the important thing to take into consideration, there are certain facts that
• 31:20
  are not something that I think will come into force, but it's important to look at.
• 31:23
  We've gone through significant things over
• 31:37
  years.
• 31:38
  Don't think, as we're very enthusiastic about DSMBs
• 31:42
  and how interesting they are and how much we learn from them
• 31:45
  and how much we enjoy being on them.
• 31:47
  Don't think they're not a lot of work.
• 31:50
  If you agree to be on a DSMB, you have a huge responsibility.
• 31:54
  And in my experience, people take that responsibility
• 31:58
  very seriously.
• 31:59
  Similarly, when you're doing, writing a report,
• 32:03
  you have to understand what the data are.
• 32:05
  You have to understand what the disease is.
• 32:08
  And you have to put yourself in the mind of somebody
• 32:13
  looking at a report who has to make a recommendation about what
• 32:17
  you do in the study.
• 32:18
  So it's a complicated process that you need to go through.
• 32:22
  You can't just roll out a report.
• 32:25
  And I think people need training in that as well.
• 32:29
  Well, we certainly have enough for another entire commentary
• 32:34
  on the podcast.
• 32:35
  But I want to just wrap up by asking the panel here.
• 32:39
  The importance of diversity in the composition of committee
• 32:43
  members.
• 32:44
  This came up at our June 12 meeting, Tom.
• 32:47
  And you brought up some really good points.
• 32:49
  Why is it important to have a diverse committee members
• 32:53
  and train diverse members of our community
• 32:56
  in monitoring committee activities?
• 32:59
  A study is very complicated.
• 33:02
  And we're talking about trials where people
• 33:08
  are the experimental animals.
• 33:10
  And we're talking about a committee that's
• 33:12
  looking at ongoing data and trying
• 33:14
  to make a recommendation about what
• 33:17
  should happen to that trial.
• 33:19
  So it's important to bring in diverse views.
• 33:22
  Diverse views medically, diverse views scientifically,
• 33:26
  diverse views culturally, diverse views intellectually.
• 33:31
  And that's because the trial itself
• 33:35
  is filled with diversity of all kinds.
• 33:38
  So I think of diversity in a very general sense.
• 33:41
  You want input from lots of different people
• 33:46
  who can bring different views, but not so many different
• 33:51
  people that the committee gets unwield.
• 33:56
  David?
• 33:57
  Yeah, I think I would amplify what Janet said.
• 34:00
  It's amazing how little you sometimes think you know.
• 34:05
  Until you get on in real life, all the different issues
• 34:08
  that arise that you didn't plan for and didn't prepare for.
• 34:11
  And so having that diversity of experience
• 34:13
  and intellectual background training really does help,
• 34:17
  really does matter.
• 34:18
  And so it's not like you're looking at a simple two
• 34:21
  by two table and trying to decide,
• 34:23
  is it significant or not?
• 34:24
  That would be unrealistic in a clinical trial anyway,
• 34:27
  but it's certainly not the case.
• 34:29
  We have lots of different issues and wheels in motion
• 34:32
  to deal with.
• 34:33
  So diversity is absolutely essential.
• 34:37
  Not many additional thoughts?
• 34:39
  Great points by both.
• 34:40
  Good things don't happen passively.
• 34:43
  They happen actively.
• 34:44
  We need to realize that there's so much gain
• 34:48
  that we get from diversity.
• 34:49
  There's so much gain in terms of the synergy
• 34:51
  and the strength of what we learn
• 34:54
  as we are working together with colleagues who are bringing
• 34:58
  diversity in their backgrounds, both in terms
• 35:01
  of what their scientific or clinical or quantitative areas
• 35:05
  are, but also in terms of sex and race
• 35:09
  and other aspects of diversity.
• 35:11
  FDA and industry and government sponsors
• 35:14
  are properly becoming more aware now
• 35:17
  of more active attention we need to take actively in ensuring
• 35:22
  that we have proper diversity representation
• 35:26
  in the populations of the participants in the trial.
• 35:29
  Absolutely.
• 35:30
  And we should be doing the same on monitoring committees.
• 35:33
  And monitoring committee members should
• 35:35
  be attentive to these issues.
• 35:37
  And I think as we build in the diversity of monitoring
• 35:39
  committee membership, that will certainly facilitate
• 35:42
  the insurance that the committee in its recommendations,
• 35:45
  as it does.
• 35:46
  We have an organizational meeting
• 35:47
  at the beginning of every trial.
• 35:49
  And the monitoring committee, while it doesn't make decisions,
• 35:52
  the sponsor does, is in a position
• 35:54
  to acknowledge and recognize the importance of diversity
• 35:57
  and encourage the likelihood that we will have studies that
• 36:01
  are monitored by more diverse committees
• 36:04
  and that are ensuring that the membership participants
• 36:07
  in the trial are optimally diverse.
• 36:10
  Well, that's a terrific conversation, a terrific way
• 36:13
  to wrap up here.
• 36:14
  Because what we're trying to do is to encourage our colleagues
• 36:19
  to say, yeah, I'd like to be part.
• 36:22
  I'd like to be part of it, the monitoring committee.
• 36:25
  And gosh, the ability to learn, to understand clinical trials,
• 36:30
  to be around so many smart people,
• 36:33
  it's a wonderful experience.
• 36:34
  But share in one or two sentences, Janet,
• 36:37
  why a young biostatistician or a young clinical investigator
• 36:42
  should really reach out and try to become part of the training
• 36:46
  and participate in DMCs.
• 36:49
  I don't know any better way of learning about a trial, trial
• 36:58
  in general, a specific trial you're in, of being on a DMC.
• 37:02
  Because in a short period of time,
• 37:05
  you're distilling a huge amount of information and insight
• 37:10
  from people who are very thoughtful and very engaged.
• 37:14
  And so think of it as an intense learning experience
• 37:17
  where you learn and have responsibility at the same time.
• 37:22
  So it's a terrific experience.
• 37:23
  And that's why all of you who are listening
• 37:26
  should quickly run and join us.
• 37:29
  Terrific.
• 37:30
  I don't know if we can beat that.
• 37:31
  Tom?
• 37:32
  Well, I would just say whenever I have an opportunity
• 37:34
  to share the passion about the importance of the role
• 37:39
  in the mission of a monitoring committee,
• 37:41
  I always say to the people that I'm talking to,
• 37:43
  I'm thanking you.
• 37:44
  Don't have to thank me.
• 37:45
  I'm thanking you.
• 37:45
  You're the future.
• 37:47
  We need you.
• 37:48
  We need everyone who is listening here
• 37:49
  that has an interest to visit the website,
• 37:53
  to take the steps to become involved.
• 37:56
  Because data monitoring committees,
• 37:59
  the importance of the mission is critical.
• 38:02
  And we need to have continued interest.
• 38:05
  You're the future.
• 38:06
  We hope that you will be motivated
• 38:09
  to follow through on additional didactic training,
• 38:12
  and then basically to get involved in the mentorship
• 38:15
  aspect of actually serving.
• 38:17
  And it's highly rewarding to be able to be
• 38:20
  involved in this process.
• 38:22
  And it's incredibly important, the contributions
• 38:24
  that you're going to make.
• 38:25
  Thank you all.
• 38:26
  David?
• 38:27
  Yeah, I would amplify what's been said.
• 38:30
  I would say that it's intellectually
• 38:33
  challenging and satisfying to be part of it.
• 38:35
  And on top of that, it's very gratifying
• 38:38
  that the contributions you're making
• 38:40
  to patients in our particular role.
• 38:43
  I get a lot of satisfaction out of knowing that I've
• 38:45
  done something really good, either by helping
• 38:48
  a new drug or a product become approved,
• 38:51
  or keeping one that's not effective out of patients.
• 38:55
  Thank you very much for the opportunity.
• 38:57
  Well, I just want to thank you, Janet, Tom, and David,
• 39:01
  for a terrific conversation today.
• 39:03
  I can tell you that already a sponsor has contacted me
• 39:07
  in one of the three names of young women who attended
• 39:10
  the June 12 mentoring session to begin to participate
• 39:16
  as young colleagues on DMCs.
• 39:18
  So that's a success in and of itself.
• 39:21
  And we plan to do more here with that.
• 39:23
  So don't think that you are going anywhere near retirement
• 39:27
  in the next five to 10 years, because we got
• 39:29
  a lot of people to train up.
• 39:31
  So thank you today for being part of the Heart Failure
• 39:33
  Collaboratory podcast, Heart of the Matter.
• 39:36
  And we look forward to more conversation in this space.
• 39:40
  Thank you.