 Caleb came to the University of Chicago about a dozen years ago to be a Robert Wood Johnson clinical scholar as well as the McLean Ethics Fellow and he subsequently upon graduation joined the faculty of the McLean Center in the section of general internal medicine at the University of Chicago and rapidly developed a reputation nationally as one of the experts on pharmaceutical drug utilization, determinants of drug utilization, quality of pharmaceutical use and then ways to think about improving communication between patient and providers about drug use. So to the University of Chicago's loss and Hopkins gain about a year ago Caleb went to Johns Hopkins to become an Associate Professor of Medicine and Epidemiology and he co-directs the Center on Drug Safety and Pharmaceuticals there. Caleb. Thanks Marshall. Thank you. I think Caleb's talk will be on Y59D67, are we clear? Thank you. It's a privilege to be here and great to see and I'm sorry how can we project it up there? Thank you. It's great to be here and to see so many friends and former colleagues, Mark thank you very much for the opportunity to visit and all of the other esteemed faculty and former fellows and others from the McLean Center so it's really a privilege. I want to apologize to some degree for such an opaque title and I've already fielded many many questions from you as to just what the heck I'm going to be talking about and the truth of the matter is that at the time that Mark invited me to visit I was 100 percent sure that I was all in but I had no idea what I was going to talk about and so I'll just give you a second to take a look here, here for possible foci of the talk. So let's see a show of hands, how many think this is number A, I'll be talking about a 64-year-old man in Tulsa and access to a novel oral chemotherapeutic, okay how about B, controversies regarding a new proposed supplemented NDC system, okay C, post-it notes, clinical trials and marketing and science and how about D, global variation and informed consent, well there are a few good test takers in the room although I think many of you didn't raise a hand but I suppose you have your ideas and in fact I am going to be talking about post-it notes among other things and the reason why is because there's a very interesting story here in 1968 3M was working on developing a super sticky adhesive and they bombed and instead they developed one that wouldn't stay stuck and this sat on their shelves for about six years and in 1974 they began developing a bookmark that could be used that would have some adhesive properties and this too didn't fly fully until as part of a final effort they conducted a research study and essentially they used secretaries within the offices of CEOs from large companies and they essentially recruited the secretaries to participate in this experiment and the secretaries were flattered to be involved in the development of this product and essentially help became champions for post-it notes and help transform this product to something that's probably in most of our offices today. So what on earth does this have to do with research? Well I think there's a pretty good continuity between the last two talks and this one because my talk is partly about institutional review boards and partly about conflicts of interest and partly about the conduct of research and clinical settings and it's about a phenomenon called seeding trials and so these types of research studies aren't limited to post-it notes alone and in fact during the past 10 or 15 years I think there's been an increasing body of evidence suggesting the importance of these types of research studies. So just what is a seeding trial? Well from information largely from discoverable documents that have been produced through settlements between the US Attorney's General and pharmaceutical manufacturers we have some window into the design and conduct and dissemination of these types of studies. In many cases these are studies of in most cases of drugs or interventions that have multiple competitors cases where the trial design itself may be unlikely to achieve its stated aim. There's evidence that investigators for example will be selected based on their role as opinion leaders in a field and clinical expertise rather than necessarily their ability to serve as site investigators and their scientific knowledge and these firms importantly are I'm sorry these these studies importantly are generally conducted by the marketing and sales arms of manufacturers and some of these are hard to discern from routine bread and butter phase four that is post-approval clinical trials. They may have they may they may be blinded trials and I don't want to suggest and I'll say this again at the close but I don't want to suggest that there's an absolute clear line between between a marketing trial and a scientific trial. These trials have elements of both and we can discuss and I encourage all of you to think about where this appropriate division lies but just so I'm clear the goals of of these types of trials or one of the important goals is to introduce a particular product in the marketplace and to generate loyalty and advocacy for the product and to gain support for the product from opinion leaders and the like. Now some of you may recognize this typeset if not the actual article and that's because it was published in the annals of internal medicine not too shabby for place to see your stuff published. So this was a study called the focused on the gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis and these are survival curves and were essentially cumulative incidents on the y-axis and this is from zero to 10% and this essentially demonstrates that with respect to this outcome there was early separation and and and distinctions between rofecoxib and naproxen in terms of these event rates and at the time that this was published you know the annals included the potential conflicts of interest of the investigators. I think all of them were either employers or consultants or received honorary or had stock ownership in the pharmaceutical manufacturer that was responsible for rofecoxib but what what they didn't disclose was further information that only become became available based on one of these settlements between us attorneys general and the pharmaceutical manufacturer. I don't know if any of you know how stocks or Christine Lane or Cindy Mulrow but you can be assured that they were interested in internal company documents that became available and were able to be scrutinized by scientific academic investigators about the specific trial and in fact they were interested enough to publish this which was entitled the advantage seating trial a review of internal company documents and this included this slide here is from a the marketing division of the firm and includes the responsibilities of the marketing group with respect to the trial and you see that it's essentially soup to nuts I mean it's designing the protocol it's overseeing the execution it's selecting the investigator sites running the meetings managing the CRO the the clinical research organization performing data analyses and preparing publications. Now if you were designing this trial what kind of outcomes would you be interested in studying well it depends on what your objectives are right and so I've shown you some data on cumulative incidents of adverse GI events but there's some other outcomes that were of interest too to the investigators or the sponsors I should say namely the prescribing volume for the drug that was under study as well as its main competitor so this is a graphic that essentially grades each investigator from a grade of A plus to D on their prescription volume for rofe coxib versus sella coxib rofe coxib was the drug under study the study had nothing to do with sella coxib at all and yet this was closely tracked among these investigators I should say there were several other features of the study that suggests that it was a seating trial including the fact that it was operated in 600 sites and this is not terribly efficient and not the type of site selection that you would imagine or one sees and generally in pivotal say phase 3 randomized clinical trials or even phase 4 studies where there's such low number of participants at each site. This isn't the only example so another example that we have is from Noronton so here again there were settlements between the U.S. attorneys general and the manufacturer I think it was to the tune of 540 million for allegations of off-label marketing and promotion of this drug and Mary you've already heard from Mary about Risperdoll I remind you that was Jim Johnson and Johnson that was last week that was 2.2 or 2.3 billion with a B for similar practices and so here this was a study of Noronton titrate to affect the profile of safety trial and what I've highlighted here are some clips from communications from someone within the marketing branch of the firm about the conduct of the study. The data is dirty there are several factors contributing to this and the like and you can read for yourselves their their report. Here again these this is from another memo from the marketing group within the firm I'll be meeting with health care communications when we get back from San Francisco greatest leverage we have is to ensure that the team managers are following up with our step stocks to ensure they're enrolling patients right now steps is the best tool we have for Noronton and we should be using it wherever we can. So some of you may be wondering what we know in fact that there was a question and response to Mary's talk I believe about the effect of various factors on on physician prescribing and some of you may be wondering how does participating in a clinical trial affect the likelihood that a physician is going to use a specific medicine and regrettably we know far less than we might about this as you can imagine most of the data on this is proprietary not in the public domain. There are a few exceptions though so this was a study that looked at the effect of participation in a trial on physicians prescribing and showed what what might seem obvious that is yes there's a non-trivial and clinically important effect this was accompanied by a very good editorial by drum and reny and Bruce Saudi discussing this and this broader phenomenon and I know that I'm in the room with you know some of the world's top bioethicists so I don't have to convince you I hope that there are some ethical concerns that are raised here I've highlighted just four here for you to consider although I think that there may very well be others this you know the phenomenon of seeding trials undermines the integrity of the clinical research process I think the questions about informed consent are even arguably more compelling because whether or not you believe that there is some scientific rationale and laudable objective of these studies and I think in some cases that's certainly the case I would bet dollars to donuts while I've not reviewed them I bet dollars to donuts that the informed consent forms are not discussing the fact that there are marketing objectives as well and so I think that this question of the degree to which patients are fully aware and investigators as well mind you because the investigators are not being brought on board knowing that their prescriptions for Celebrex versus Vioxx are going to be tracked is a very important issue we've heard a little bit about the medical literature in these trials undermine that insofar as they're not based on sound science and importantly as well to the degree that these trials affect physician behavior and are designed to do so they undermine and in fact I think would violate not just ethical norms but legal regulations that would preclude manufacturers for essentially paying prescribers to prescribe their drugs and to the degree that they generously compensate the investigators for enrolling patients but also influence the physician's behavior at the same time I think that this is of note so I wish that these were easier to identify and prevent I they're terribly difficult and in fact if you think about these two examples that I've gave you it was only after the fact after we had discoverable documents that really showed us the inner workings of the firm that the seeding nature of these trials has come to light and I think it's anybody's guess that agree to which this is a terribly rare phenomenon or not I don't know I do want to say again what I've already said once which is that I don't want to suggest that it's a I think it's a bit overly simplistic to to suggest that that either a trial and it's a false dichotomy to suggest that either the trial is a marketing trial and therefore kind of bunk or it's a legit scientific study and therefore raises no concerns and I think that this blurred boundary is as a challenge with respect to how to interpret and identify actionable steps based on the information that's come to light through for example the annals paper that I shared or this the publicly available documents regarding the ronten that I've shared it is noteworthy 20 or 30 or some large number of IRBs reviewed the steps trial and only two declined to approve it so you know I think for institutional review birds there's an important set of questions I imagine that many of you are either experts on or grapple with with respect to the degree to which IRBs are and can able to adequately patrol the science essentially of these types of studies you know registration of clinical trials is necessary but not sufficient that's not gonna I think I think that's important but not necessarily something that will preclude the use of seeding trials and the what I've called the subordination of science to marketing there are many pushes on improved ethical standards for the pharmaceutical industry and we can discuss those some and you've already heard some about them and I think also you can use you know if you take just an example like hypertension during the past decade there've been hundreds probably thousands of fairly poorly designed short-term studies drug to placebo drug versus drug with surrogate endpoints such as blood pressure reduction that actually have provided very little a new fundamental scientific knowledge and so if you think about those types of studies some of which no doubt we're seeding trials although the exact number no one can be sure but if you think about those versus the kind of fundamental transformative knowledge and impact that studies like the WHI study have had or the all-hat study I think that one can make a good case that that these provide such a greater return on investment that we need to identify ways to to increase the number of these longer-term larger better-designed studies of course funding them is another question and a non-trivial matter so I thank you all for your attention it's wonderful to come back and I've really enjoyed seeing all of you and look forward to some discussion as well. Marshall had to leave so I'm sharing for the next a few seconds I guess we've got time for maybe one question Tracy. And my concern even goes farther I don't think as IRBs that we look well at the science of industry sponsored studies I think we're spending most of our time looking at studies that are coming from our own institution to look at the science but I definitely think that we are seeing evidence that a lot of these studies are fundamentally as much marketing as anything when ads are coming through that they're putting on Facebook pages and it's like well we don't like them but if we're one of 50 centers if we say don't put it up on Facebook that's gonna say nothing right we can say don't list our name as one of the 50 centers doing it but I'm not sure where that really goes in the long run either and they're doing Facebook pages and they're now sending out their pens and bags and t-shirts and coffee cups to the people in the studies since supposedly the physicians can't get them anymore and I have personal concerns about that as well. I appreciate the comment and don't disagree and I think you know the trials have to be closely scrutinized I wouldn't underestimate the impact of one center's actions in terms of you know not approving a trial or making some step to restrict the degree to which promotional materials can accompany trial but you know I appreciate and don't disagree with that comment and insight. Thank you.