public-private collaboration to advance the use of … · ed that might involve large sample sizes...

October 10, 2019T R A N S C R I P T

PUBLIC-PRIVATE COLLABORATION TO ADVANCE THE USE OF REAL-WORLD DATA

Jacob Plummer

KEYNOTE

MODERATOR

Robert Califf Vice Chancellor, Health Data Science, Duke University & Former Commissioner of the FDA

Jacob Plummer General Manager, Health Systems, Datavant

Dr. Robert Califf is a former FDA Commissioner and he is concluding his tenure as the Vice Chancellor for Health Data Science at Duke University and transitioning to now become the Head of Medical Strategy and Policy for Verily Life Sciences and Google Health. Dr. Califf has extensive experience bridging and creating partnerships between industry, government and other policy groups. One such group is the People-Centered Research Foundation where he serves as Chairman of the board. The Patient-Cen-tered Research Foundation, or PCRF, has a mission to advance patient-focused clinical research through the use of networks of health systems and payers that are connected by the curated electronic medical records and claims information that they hold.

I want to begin this conversation, Dr. Califf, by having you set the stage for us, for people who are not familiar with PCRF: What is it, why can it do what industry or government could not do separately?

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F U T U R E O F H E A LT H DATA .C O M

Jacob Plummer

Robert Califf

Robert Califf I think a lot of us were very excited when PCORI decided to fund a network. And the history is I think as most people know, PCORI was founded as a public-private partnership. I call it quasi-governmental because it’s not a government agency, but it’s chartered by government and funded via tax on the Medicare trust fund and the insurance companies.And the idea is to advance patient-centered research. But the question is, how do you logistically get the kinds of studies done that are really need-ed that might involve large sample sizes or might involve the need to sift through large sample sizes to fi nd, for example, enough people with rare disease?

Janet already mentioned today that often, external control groups are used just because you can’t generate enough people with a rare disease. I think there was a question about how to deal with that. So there was a meeting, which I still regret to the day, that I was invited to that occurred out at Stan-ford where apparently, it got very heated and the patient groups were un-derstandably pushing to get more done. And there was a consensus reached that we needed a national network that would try to get this done. And that the big technical advance that had occurred of course was that everyone now had an electronic health record. But the problem and the challenge was that no one had curated electronic health records across a scalable set of health systems, beyond what Kaiser and some specifi c entities had done. So the purpose of PCORnet, the network, really was to do scalable clinical research focused on patient centricity, now called “people centricity” for reasons we could discuss, and taking advantage of the fact that we all have electronic health records. And you know, that’s been quite an effort over the last five years.

As part of that initiative in bringing data together, you and I have discussed the positive aspects of insights that were not available before, but there’s al-ways this question of patient privacy. And we’ve already heard this morning how central that is to getting right in order to be able to do more research. What was the experience with PCRF like? What sort of learnings were there that future consortiums should be aware of?

I think we’re all learning about patient privacy as we go along. And I’d have to say from the point of view of public policy, this is an area where a lot of work needs to be done to fi nd the sweet spot. And what I’d say is that the system that PCORnet used ... just to clarify one thing, PCORnet is a network and then a foundation was created to transition this over to a sustainable en-

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tity. Of course, I think everybody knows PCORI funding is in the balance this year. Congress has to vote affi rmatively to continue PCORI. I’m no longer a government offi cial, so I can weigh in and say, “I sure hope that happens.” And I hope people that are concerned about their illnesses will let their Con-gress people know that this needs to be continued.

But the system was developed based on the work that Janet and et al had funded from FDA and Sentinel, which is a beautiful way. And many other things are being done this way, of federated analysis where the data stays in places where it already is, where there are a set of rules that already exist that none of us are completely happy with, but at least are functional now and then whether an analysis needs to be done. The analysis is taken to the data rather than centralizing the data in a place where it raises new ques-tions about privacy and confi dentiality.

And I’d say that system works, but yeah, there are nuances that are being worked through. For example, the push for data transparency. If the data never moves and you don’t actually have a dataset, how do you make the data available for other people that might want to analyze the data from a different perspective? And there’s a lot of work being done on that.

There are also times when you have to centralize the data. For example, if you want to submit your results to the FDA, the FDA can’t say, “Thank you for your hypothetical dataset that exists out there somewhere that we can’t put our hands on.” But if you’re going to import and centralize electronic health record data, you don’t want to import the entire electronic health record data for 20 reasons that we can all think of.

So I’d say there’s still a lot of work in progress. But I really think the funda-mental issue that we all need to be talking about and thinking about is, in what circumstances do we trade off privacy for the benefi ts of getting bet-ter healthcare? I think Janet articulated it well. I hope we are nearing the end of the era where... I’ll just pick on my own institutions, Duke and Stanford, where I’ll soon be adjunct at Duke and I’m adjunct at Stanford where health systems advertise, the nice-looking doctor in the white coat saying, “We can cure your disease,” when in fact is for the most part, the doctor is guessing about what to do because no one knows what to do.

The guesses are not uneducated guesses. I’d rather have a Duke or a Stan-ford doctor than someone who knows nothing about the problem. But the fact is, whenever we do prospective studies, we found out that we’re wrong about half the time, but we don’t know which half we’re right about and

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which half we’re wrong about. So I hope we’re nearing the end of the time where people don’t understand that their diseases are going to be taken care of better, their medical problems, their staying healthy problems, if they collaborate and share their information so they can be studied in a systemat-ic way to fi nd out what really works. A great example two weeks ago was the red meat controversy, which I’m sure most people saw. We still don’t know, is it okay to eat eggs or not? Is it okay to eat red meat or not? If so, how much? And the data are contradictory because good studies haven’t been done.

And another one to point to, I personally love because it shows how little we actually know about both drug development and therapeutics. That is a class of drugs called the SGLT2 inhibitors beautifully developed to lower hemoglobin A1c for people with diabetes, the target for diabetes. And I still have bruises on my back from when a delegation of us went to FDA and said, “We have to have long-term outcome studies for diabetes therapies.” The guise was safety, but really, what a lot of us were thinking is, “If you’re going to give somebody a pill every day for the rest of their lives, knowing how complicated biology is, you ought to understand the risks and benefi ts over the relevant period of time.” And that was not happening.

So lo and behold, in controlled clinical trials with SGLT2s, every single trial shows this miraculous effect on heart failure. Totally not a target for the drug, completely unexpected, replicated in multiple trials and then now, we have specifi c trials done in heart failure, replicating the fi ndings from the secondary fi ndings of the diabetes trials.

So unless we systematically study things, God only knows how many bene-fi cial therapies there are out there that we don’t even know about because we haven’t had the discipline to study them with an adequate sample size, with an adequate degree of rigor.

And then to tie this together with PCORnet, when I’m teaching interns and residents now, I remind them that when I started running coordinated care units, we didn’t know what caused heart attacks and we had almost no treatment. There was morphine, nitrates and prayer. That was basically it. We didn’t know that aspirin was benefi cial. We didn’t know that statins worked and there were many other therapies we didn’t know about, reper-fusion, et cetera. But then aspirin was shown to be effective but it always bothered me that we don’t actually know the right dose of aspirin for sec-ondary prevention of ischemic heart disease, the leading cause of death in economically advanced society. So this has been bugging me for almost 30

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Jacob Plummer

Robert Califf

Jacob Plummer

years. And when we had the bake-off for the first clinical trial to do PCORnet, we needed something that was a safe enough that people could tolerate, all of the trial and error we needed to do to figure out how to do a new type of pragmatic trial where they would answer an important question. And we actually had voting done by the patient groups and the clinicians involved in the network, trying to figure out the right dose of aspirin. So we’ve now enrolled over 17,000 people in a randomized trial of baby aspirin versus full strength aspirin and we’ll soon know the answer.

But this is 140 years after aspirin fell in the market. We still don’t know the right dose. And if you tell me the right dose or duration of almost any drug today, I would tell you, “We’re sort of approximating.” But it’s possible to know a lot more than we know if we just have the discipline to admit un-certainty. And if the patient groups themselves drive the questions that are really important to them, that means we have to be honest with the patients about what we don’t know.

So I think in that trial, what’s so interesting about it is that the participation rates were very high. Is that correct, compared to other trials?

Yeah.

And it underscores the power and the benefi t of patients having an un-derstanding of what will be done. You raised a couple of points when we were talking and I want to highlight: fi rst, for people to get confi dent to get involved in these kinds of studies, that’s a benefi t of the federated structure today, that people don’t feel that they’re shipping off their data for it to be used for any purpose whatsoever. The analysis can come to the data. And I suspect that that’s why some groups have come to the table that otherwise they might not be interested in. And I want to just to call that out, something I’m excited by and we’re excited by with PCORnet and the way it’s designed.

The second thing you called out is sometimes when you bring the data together, you can have insights that were not even part of your initial hy-pothesis. And there’s a public health case that I think illustrates that, that we discussed. There was a paper done last year that spoke about how Google Search and location data was able to be used in order to help health depart-

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Robert Califf

ments fi nd restaurants that were making people ill. And you’re familiar with the study. Could you talk a little bit about that?

Yeah. Among the many upsetting things that happen when you’re an FDA commissioner is that all over the United States every day, people are having nausea, vomiting and diarrhea because of something they ate in a restaurant somewhere, or something they brought home from the grocery store. And sometimes, signifi cant deaths and hospitalizations occur because of this.

So when there’s a “food outbreak”, what happened is the reports would come in and then you dispatch the CDC epidemiology group to do the gum-shoe war to fi gure out what was causing the food outbreak. And there are methods the CDC has developed that were really good, but it took days to weeks to fi gure it out.

And then the FDA had the enforcement, direct hands-on inspection of the restaurant issue. And of course, while things were occurring, every morning I would get up at 5:30 and get a fi ve-page summary of all the people that were attacking me on that previous day. And while this is occurring, people are saying, “Why isn’t the FDA doing its job?”, et cetera.

Well now, and this is published so it’s easy to talk about, it turns out probably the number one surprise, if you cross-reference purchasing data with searches on nausea, vomiting and diarrhea, we can see exactly which restau-rant is causing the problem in less than a day. And the factoid to remember about why this is so important, if you happen to have family in the restau-rant business, you’ll like this: thirty-nine percent of the time, the offending restaurant was not the last one the person ate in, it was the one before that. So a lot of really good restauranteurs have gotten bad press because of things they didn’t cause because people assume it was that last restaurant that did it to me.

But this is shaving days to weeks off of the time it takes to fi nd the source and do something about it. This was done as a pilot study with a number of communities. And there are now discussions going on about how to instan-tiate this. I doubt if anyone in the room would like to be throwing up tomor-row because of what they ate. So this is a case where sharing your data in a way that is not consented has a real public health benefi t. And it’s an exam-ple that I think we need to talk about and work through to fi nd where that sweet spot is for the American public

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Robert Califf Well fi rst of all, let me just say that a month from now, I’ll be in the belly of the beast at Google. And working at Verily, which is one of the sister Alpha-bet companies, all under the same umbrella, is not quite the same. So I don’t want to say too much about Google other than what David Feinberg, who is the CEO of Google Health just formed about six months ago, what he has said.

I think it gets back to the confi dentiality, privacy issue that we need to de-velop a method of being honest with people about how their data is used in an explicit way. And I personally think there’s government regulation that’s needed and that’s just my personal opinion, not Google’s opinion. And we need to square away what we now know, which is that your health record, unless you’re really sick or you have a rare disease where there’s a mutation or something that’s driving your disease, your social data is actually a bigger predictor of your health outcomes and what your doctor is recording in the medical record.

So I can predict better what’s going to happen to you over the next year from your credit cards, where you live, who you interact with, all that sort of stuff. There’s tremendous power in that data. But the rules that Google [has] to prevent you from using it, as a Google employee, identifi ed to an individu-al and I think that’s a good thing right now.

But on the other hand, I would argue as a cardiologist, if I’m advising you to

Jacob Plummer And I think that one of the things I like about it as an example of what’s been done is...Chicago Department of Public Health was one of the initial adopt-ers of it. And I think also the Nevada, the Las Vegas Department of Public Health. It was published in Nature Digital Medicine if anybody wants to learn more...but it is an indicative of what can come. So earlier this month, as you know, Walmart opened its fi rst health center and it was promoting everyday low prices. But for health services, CVS I think has plans to open maybe 1,000 health hubs over the next couple of years. And I think what’s intriguing is that these are companies that are pretty sophisticated in the use of data and the analysis of data.

We’ve talked about how Google has over a billion searches daily that relate to health-related queries. So thinking about what was able to be done with taking purchasing data and search data to improve public health, imagine for us, what might we see over the next couple of years with Walmart, CVS, Google?

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eat, let’s say a low-salt diet and lay off of the red meat, who knows if that’s right? But if that’s what I said, and if your credit card data could show me that you’re actually eating at Burger King, getting a Whopper every day, I’m wasting my time with information that could be useful. And we know that a lot of people have trouble just articulating what they’re doing in everyday life. So integration of that information could have tremendous benefi t to you if it’s done in the right way, whatever that is.

I think we also need to acknowledge something. There’s a great article by Larry Summers in the New York Times this morning about the fact we’re increasingly in the U.S. living in two worlds. One, representative of people in this room, who are living like Scandinavia, take care of themselves, exercise, can pay a personal trainer to help us out, generally congregate in urban areas together, are highly educated. And then rural America, which is see-ing a dramatic decrease in life expectancy and isolation and despondency evidenced by extraordinary suicide rates, opioid overdose rates and now an uptick in good old cardiometabolic disease, obesity, diabetes and vascular disease.

And of course, almost everyone in the U.S. lives within 10 minutes of a Walgreens or a CVS. And I’ve recently learned that if you look at where people congregate and hang out socially now in rural America, it’s Walmart. The number is astounding and I don’t remember exactly, but the number that sticks in my head is like 65% of rural Americans are in a Walmart at least once every two weeks.

So I actually think less important than the data at those places is the like-lihood that they will do what we failed to do in the big health systems in the U.S. They will actually start developing very low cost clinics because if you’re say, a typical man and yeah, I realize that men can be different than this, but... on average, while the wife is shopping, the man is hanging out smoking cigarettes outside of Walmart, or doing something, whatever they do. And you could use that time to check the cholesterol, get some advice about smoking, et cetera. And I think that’s going to happen because if you live in rural America now, just getting a doctor’s appointment can be a major ordeal, not to mention the transportation. So I think these things are really in a rapid state of evolution now. I think it’s a good thing, but at the core is solv-ing the issue of how to make sure that people understand what’s happening with their data.

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Robert Califf Right. Right.

Jacob Plummer So while we’re doing this now, I wanted to get your sense moving into this new role, what prospectively we should be thinking about the CVSes and Walmarts, but I want to ask you a question looking retrospectively, having been a commissioner at FDA, and you made a comment once, you said, “The FDA is all about interpreting data. And where we have really good data, there still are arguments to be had but they’re relatively civil. And the big deal is helping the whole ecosystem generate better evidence.” And so this may tag onto the last discussion a little bit, but what evidence do you wish FDA had, and what are the opportunities with industry partnerships to be able to gain that?

Robert Califf There a lot of opportunities. I’ll just put it that way. I think what worries me the most right now is that most new treatments, drugs and devices, biolog-ics, almost all our food changes, nutraceuticals, sunscreens... are getting on the market with no understanding of actual clinical outcome, benefi ts and risks. So I think it’s a good thing that we have the accelerated pathways for diseases where there’s no effective treatment, and there’s a great need or where the effective treatments are not very good, but the accelerated path-ways by defi nition use unvalidated biomarkers for the basis for approval.

And then the expectation was in the post-market phase, there would be structured evidence generation, that would actually tell you what really matters to people, which is: how long do you live, how functional are you and how do you feel? And those things are just not being measured at the rate they need to be measured.

And the consequences are, I think, potentially profound in terms of total chaos in the therapeutic world. We already have it in some areas. People that knew me when I was at FDA, my favorite one is wound care. There are 1,500 combination products on the market for wound care. Two have been studied in adequate clinical trials.

Jacob Plummer Yeah. I think on the point you made about access to care in rural settings and then also treatment that’s attractive to more men, I was talking with an RN at a CVS and I asked her, “Why did you take this role?” And she said, “Well, I used to work in a health center, but what’s different here is that I actually have male patients and I never had any of them before.”

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Robert Califf They’ve all gone through the 510(k), which by defi nition means that you say, “I’m as good as a predicate, but I’m not really better because if I was, then I’d have to prove that.” And you can cool a wound, you can heat it, you can ultrasound it, you can even put a little cup over it... there’s a name for this, like geospatial healing. It’s just like putting a cup over it, and that’s all paid for by CMS.

So now, we’re going to fl ood the market potentially with promising thera-pies, but no one really knows how to use them or combine them or how long they should be taken. And just to exemplify, you know...we talked about a lot when I was at FDA. My mom had multiple myeloma. She fi nally passed away after 11 years with multiple myeloma at age 91, which was remarkable, and was the benefi ciary of accelerated approval of a drug with almost no side effects, that was helpful.

But if you said, “How long should she have stayed on the treatment at the dose she was on as a 91-year-old person?” There’s not even anyone thinking about the answer to that question. But if all 91-year-old people with multi-ple myeloma put their records together and said, “Hey, let’s do a randomized withdrawal trial.” With things that seem reasonable, you can answer these questions very quickly and very cheaply now.

I think Janet did a really good job of saying basically FDA is going to fund things that bring structure to this. But I’m worried that in the push for re-al-world evidence ... you know, I’m a golfer, it’s sort of like you take as many mulligans as you want until you get the shot that you like. You can have a really good score when you do that.

Jacob Plummer Sounds like good advice actually. Last night we had a private session with folks from PCORnet, different networks, and I think OneFlorida highlighted that they have the largest dataset for patients over 90. So the type of study that you just spoke about I think now is actually in a position to be done. And I want to ask you as a closing question, we’re in Washington D.C. and we have an election coming up… There’s an opportunity for tremendous chang-es in public policy. You mentioned already your advocacy for PCORI, the importance of that. What would you like to see happen from a regulatory and policy perspective over the next 12 to 24 months?

Jacob Plummer Wow.

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Well, we all know we have this continuum now, if we’re just talking about medical products. We have this continuum from FDA to CMS. CMS really sets the tone with what happens with private insurance in the U.S. in terms of payment. I think the very most important thing is to really instantiate a comparative effectiveness system in the U.S. that would give patients and clinicians the information they need to know, which treatments are best. And we just don’t have that, and people are having to guess about things that are really important to them. And I don’t blame the industry because if you’re running a company and you do a net present value calculation, I wrote a paper about this about 10 years ago, it never comes out positive to do a head-to-head comparison.

But if you talk to people on a clinic, the thing they most want to know is, okay, we got these things available, which one is the right one for me? And we just don’t know the answer to that question almost ever. And when we do the trials, we often get very surprising results. So I think we need a sys-tem, and that of course feeds into value-based payment.

It was anguishing for me to watch Andy Slavitt trying to put in a value-based payment system at CMS when you’d never have the information you need-ed. Because you need to know what are the actual clinical benefi ts of the treatment relative to the risk over time to calculate what the actual value of the treatment is. So to me, that’s the number one thing we need.

And I think involving the patient voice, and this is critical, because I think another key lesson from PCORnet is, and I’ve seen this over the years — most Americans, if you honestly approach them and say, “We don’t know the answer, but your information will help”, there’s a lot of empirical evidence to say that people will say, “I will gladly participate. It might help me but more importantly, it might help my children or grandchildren or my friends.” We just need the healthcare system that I actually play ball with this for it to work. And I think incentives for that to happen are really important.

Jacob Plummer We’ll close now and I’ll say that in addition to setting up the framework that allows for collaboration, and I think that’s why everybody is here today, is to think about how to be involved with that collaboration... It’s as important to be able to message to the public about the outcomes that are happening so that there can be more confi dence of participating and by patients partici-pating, then they can expand the number of collaboration that are possible.

Robert Califf

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One thing I appreciate about you and in preparing for this session is that you have a very active Twitter feed. There’s many different publications that come out. I learned more in the last two weeks reviewing some of your papers on the subjects for real-world data and evidence that I had known before. And I encourage everybody to take advantage of that and to follow you online. Thank you so much for being here.

Robert Califf Yeah. Let me say two things about that quickly as I know time is up. Number one, I was tweeting before I went to FDA, but the administration told me I was not allowed to tweet. And then along comes Scott Gottlieb and Twitter is made for disseminating policy things and shorthand where you can then click on it and go to the deep thing if you want to go to that.

But then I had seen all along that Andy Slavitt was tweeting when I was told I couldn’t. So for some reason, I never asked him. And after we fi nished our terms, I asked him and he said, “Oh, they told me I couldn’t Tweet either. I just did it anyway.” So I really regret that I didn’t use Twitter at that time.

But also just in terms of help from the community, I will say about Google Health now: as I think everybody knows, almost every person in the world, if they have a health problem, they’re on Google Search. And the number one commitment of Google Health is to improve the information that people are getting at the very frontend when they ask a question. But that’s easy to say, exactly how to do it is going to be complicated. So I personally would wel-come a lot of feedback from people about what they’re experiencing either with yourself or your family or with patients that you’re seeing if you’re a clinician on the Google Health because we have a really major commitment to upgrade that. Obviously, it’s not terrible now because people use it. But I think any clinician will tell you there’s a lot that needs to be fi xed. Thanks.

Jacob Plummer Thank you.

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