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Today I'm very excited to be able to interview Ruth Tal-Singer. Ruth is the vice president and medicine development leader at GSK Respiratory Research and development. She's also a GSK senior fellow. What's particularly most interesting is that she was an integral part of the ECLIPSE project as well as the COPD Biomarker Qualification Consortium. And we're going to step into that a bit later, but I've known Ruth for some time. We worked closely together on the COPD MAP project as well as the ERICA COPD project.
Welcome Ruth. And thanks for being here.
How are you today?
I'm doing great. Thank you.
So, what I like to do in these, I start off with a very open and broad question, which is why do you do what you do?
That's a good question. As a scientist, I've always been passionate about understanding biological triggers of disease and translating scientific and technological advances that we pretty much here about almost on a daily basis and really translating it to the development of medicines for patients who need them. So, this has really been a lifelong passion and I think that although we should celebrate the increasing number of effective treatment options for respiratory patients, many individuals continue to suffer from symptoms that impact their daily lives. And I think we see the evolution of this belief that treatment approaches should be more personalized. And today there are no medicines that are available that address the disease progression of COPD, for example. And it's really a hard fact for patients to live with and some of them actually feel quite hopeless about the management of their disease. So, what we're looking for is a way to identify patients with early signs of COPD and figure out how this disease can be prevented or slowed, or who are the patients that we should pay more attention to as we intervene or ask for lifestyle changes.
So, it's a long answer, but I feel encouraged that we got to the point that COPD is no longer considered a disease of smokers. And that although smoking is a key driver, we're starting to understand that there are other causes that we need to explore, such as environmental pollution, occupational exposure, poor lung development in childhood or infancies is a major contributor. And we're starting to know more and more about genetic factors beyond Alpha-1 antitrypsin deficiency. So, it was a long answer, but I do feel that what we do really matters.
I think I can say that you've been part of a lot of that advancement, so I think that must be very satisfying to have seen some advancements, but yet there's more to do. Is that, I guess that's what you're saying.
Absolutely. There's a lot more to do.
The next question that I always like to ask is what is the best example of a successful consortium-based project that you know of and why?
So, I can think a lot of successful consortia and we noted some of what has been fun. But I have to highlight the COPDGene Consortium in the United States, which is led by Professor James Crapo and Ed Silverman. COPDGene is now on its third phase and what they're doing is following many of the original 10,000 participants 10 years from their baseline visit, which included detailed genetic and clinical assessment. And when you asked me why, I can think of one word, which is collaboration. But I'll give you a longer answer if that's okay, is that COPDGene resulted in hundreds of highly cited publications including some with data from other consortia. And continues to provide really important information to better understand COPD and how it impacts patients. From its inception, patients were fully represented on COPDGene, which to me is a really key factor for a successful consortium and COPD Foundation were there at the time of its inception.
There as a strong atmosphere of collaboration and partnership among all investigators and industry participants and as a member of pharmaceutical industry, I felt included in investigator meetings, working groups, that resulted in important insights and a lot of opportunity for young investigators to work on different questions and publish new insights. I think to really reiterate the fact that the patient's aspect that working with COPD Foundation on these consortia was really the highlight of my job personally. And when we discussed the emerging data, like the presence of emphysema or the burden of disease and people were not defined the COPD the moment because their lung function is normal. We hear the patient's perspective that we're intervening too late and how important it is to diagnose COPD early and start preventive treatments. And I think that this patient perspective makes our scientific work more meaningful.
If I were to summarize that what you were saying, is that what really set that project up and made it so successful is that there was early on, co-creation, co-development by the different stakeholders.
Do all consortium projects unfold that way or is that a unique feature of a few? Maybe that's a loaded question?
Yes. I think that it's mixed. I think some consortium we're more driven by clinical interest or by scientists. And although everybody thinks of patients, it was less of a patient voice. So, I've worked on consortia where I felt that we took a lot of time to set that up the academic requirement for publications and how we're going to deal with data sharing. And with COPDGene I felt that there was never a question and this from the inception COPD Foundation at the time during John Walsh were there at all times the NIH, the National Heart and Lung Institute, the funders of COPDGene were there. So I felt that it wasn't hard work to figure out what we're going to do with the data, how we're going to share information. People were pretty upfront. And that was something that I felt was unique and maybe we always speak about shadow of a leader. The leadership of James Crapo and Silverman really mattered in this case.
Yeah. So, you mentioned a few key people, and I think you also mentioned there the disease foundation, which I think that's a great example. And as you know, it was about a year and a half ago in New England journal article mentioning actually detailing, not the COPDGene, but other similar projects including the cystic fibrosis work that highlighted the key role of the disease foundation. But I think you also highlighted the key role of a few connectors or key people that kind of drive everything. With that I want to shift to a project that I knew something about and that was the ECLIPSE project which you mentioned in your recent Linkedin article. And I guess the question, and maybe you've kind of already answered that, but was it hard to convince others at GSK to take part in the ECLIPSE?
And what convinced you and your colleagues to do that project? Maybe I should put a little bit of detail in there. ECLIPSE really was at least as far as I understand, one of the first real projects to go out and really try to deeply phenotype patients with COPD. So yeah, how did that go? I mean, how did you get into that?
I can't say it was easy. We were asking for a major investment or financial as well as people resource to study COPD for three years. This was not an intervention study and the reason we selected three years because we wanted to from the onset or from the outset to make sure that we had the minimum duration the regulators expect for assessing disease progression and we wanted to make sure that the ECLIPSE study would support future clinical trial designs and conversations with regulators. So, it wasn't easy, but there were strong advocates who helped us with a proposal and as it evolved and convinced all the GSK stakeholders that this would really make a difference to patients and that we had to improve the way we discover medicines, but also how we conduct clinical trials.
So, as you said, studies like ECLIPSE were at the time in 2005 were really changed the landscape of our understanding of COPD. We've seen a lot of important disease understanding consortia come out. You mentioned COPD Map. We talked about COPDGene, SPIROMICS, ERICA there are a lot of consortia that you've been involved in Europe, the IMI work. So, I really think that this is a remarkable activity that we started and generating momentum and many other partners have done to support COPD patients.
So, it really changed the way innovation has been done in this field. Another interesting one that I wanted to bring up and you mentioned in your comment just now that you wanted to really make sure you could be able to go to the regulators and there is the COPD Biomarker Qualification Consortium, which I think has had some success in the past few years in actually qualifying a biomarker. So, what role did the patient stakeholders have in that effort? And in particular, how do they help to get biomarkers qualified?
So, that's a great question. The COPD Foundation is really the heart of the Biomarker Qualification Consortium, or as we call it CBQC and it leads this international consortium that has a lot of stakeholders. We established it in 2010 to evaluate a range of biomarkers or drug development tools that are meaningful to patients and clinicians. And obviously we had lung function. We already had biomarkers that were used, but we work with tools to measure individual's quality of life, which led to the acceptance of the St. George Respiratory Questionnaire or SGRQ by the FDA, exercise capacity. We're working on constant work exercise with the FDA right now and looking at physical activity, lung imaging, blood tests, and one of the biomarkers that was the first biomarker or prognostic biomarker that was accepted by the FDA is plasma fibrinogen. And it was the first one to be qualified and the only one of two prognostic biomarkers qualified for use as drug development tools. So we're really trying. I think that the patient role is critical here in lending a voice saying that we need tools that report disease severity or are associated with the risk of disease progression. And I think the fact that we created this integrated database that includes data from industry members and from government studies is really important. But to get back to your question, COPD Foundation brought us all together, brought us to the table and are lending this patient voice to this.
So, was it that they were expressing a need or is it just sort of the energy or the drive of the COPD foundation that really made a difference?
Yes. I think it's all of the above. Expressing the need to regulators was really important to various stakeholders or pharmaceutical companies that came in. I think the fact that patients asked for the information. They asked us all to sit together, made a difference. Although some of us organically, were already collaborating it brought us to the table in this atmosphere that ‘this is about patients’. This is not about the competition. And I've mentioned before collaboration, it's when you think about the way we work in academia, the way we work everywhere else we compete. Here when we sit at the CBQC we're not competitors, we're partners, and I think the fact that the patient's lead that really made a difference. Is that making sense?
Yes, it does. Actually, it makes a lot of sense. I've done some work on Lupus with stakeholders in Lupus and, what we were talking about quite a bit. Is that really for the regulators to accept a new way of doing a study or a new biomarker, they wanted to see that the community around the disease area was together and aligned. Is that pretty much what your experience was in this as well?
And that alignment's not always easy to achieve, I'm sure that was a big challenge. And so, this is one question. What I often find is that having a biomarker qualified, sometimes people don't understand the value of that. So that's the next question is what's the value of that and how does qualification accelerate innovation?
Great question. Biomarkers when we talk about biomarkers that could be drug development tools or clinical assessment measures as well, but they play a role in every aspect of drug development. And we do use them from initially demonstrating proof of pharmacology or selecting an effective dose in dose ranging studies, up to identifying subgroup of patients who might be more likely to respond to treatment because a biomarker represents a biological mechanism that we're targeting like blood eosinophils for example. So, biomarkers are already being used. They're really important but what qualification does is it means that within a stated context of use or as a regulator say context of use is the way we apply the biomarker. It's considered by the regulators to be reliable assessment that supports its application in drug development. And once a biomarker is qualified, the information is publicly available. People can see why it was qualified and it can be used by any program without reevaluating its use in the context of use.
So, it's not that people don't use biomarkers today, but study sponsors don't have to take a risk with each trial that they will bring a study that includes a biomarker either as a selection criterion, or an endpoint that regulators will not accept the data because they won't accept the biomarker or the clinical outcome measures. So, the fact that the scientific community accepted is okay, but the fact that the regulators accept it reduces the risk in clinical trial and drives innovation. Because it gives us a broader set of tools of biomarkers that are accepted by everyone and it's really essential to transform the way we develop medicines and get medicines to patients sooner and more efficiently than we're doing right now.
That's a very great answer. The next question I wanted to ask it kind of tails into that is how do you see biomarkers being used in the future for managing disease? And I'd add into that. Have you seen where it's gone from qualifying a biomarker into clinical practice, so beyond just drug development?
Yeah, it's a great question. And I think what we're seeing today is that the world is moving towards digital measures. Almost everybody is wearing a Fitbit or a watch or some kind of a digital health assessment tool when we're moving to a way that clinicians and patients can manage their health better with tele medicine and with work. I think biomarkers, although they're used routinely in other fields, we're seeing in fields like the respiratory field, that we can use biomarkers to define therapeutic approaches and learn from other fields where we use Hemoglobin 1AC to define risk for diabetes or looking at blood pressure monitoring and hypertension. In the future, maybe we could use biomarkers that are accepted to allow physicians and patients to measure disease. And I'll mention the COPD assessment test (CAT) because we're involved in trying to qualify it. The CAT is often used by clinicians and patients to identify symptomatic individuals or to monitor disease burden. But you could see how it could be a widely accepted digital questionnaire tool. So, if regulators accept it as a validated measure, it could be something that everybody could use in managing disease.
I think what you speak to there is also what you start to see, particularly as you go towards precision medicine, this sort of convergence of research and clinical practice. It's like the convergence of digital but that's also driving this convergence where it's going to become that clinical practice is also about helping the research process as well. Now you mentioned earlier that you do see personalized medicine and precision medicine in COPD, but the question would be what needs to happen in your mind for that to become a reality?
It's a great question. I think that the vision that is starting to become a reality is that we can use these tools that we have already to look at precision medicine. But we still need additional biomarkers and further understanding of how to address treatable traits that a lot of people are talking about in respiratory disease and treatable traits are different facets of COPD that characterise the presentation of the disease in individual patients like cough, mucus, susceptibility to infection or exercise capacity, low step counts. And what we need is a panel of biomarkers and to continue our insights into this disease or other diseases and have what professors Agusti and Macnee called a ‘control panel’ to have a bedside accessible treatment algorithm. And I'll mention machine learning. Not that I'm an expert, but really having that algorithm to improve targeted or personalized treatment for patients with respiratory disease. And I believe the data integration and machine learning will be essential in simplifying this complexity of data that we currently have.
So, I'm going to bridge out just a bit on treatable traits to ask you, do you think treatable traits is also a concept that could lead to the development of a therapy that treats multiple diseases as well?
Absolutely. And I think that we sometimes when we think about exercise capacity for example, that's something that is associated with a lot of chronic diseases. And I think what I tried to do in my Linkedin article around COPD is more than the lung. It doesn't just affect the lungs. There are a lot of comorbidities with COPD. Some patients have cardiovascular disease, others have muscle dysfunction. The whole idea is that if we have a trait, which is poor exercise capacity and something that is associated with a mechanism, or with a genetic risk, I think we can be disease agnostic and say this is the trait that this medicine treats or this therapy treats. Is that making sense?
Yes, it is. Well it's actually interesting to mention those kinds of things because what you start to see is that exercise capacity or being able to function are more things that patients really care about. Right?
And so that gets to the next question, which is, why is it understanding that patient centeredness, maybe this is an obvious question, is important to innovation or any company or research or trying to innovate in a particular area.
So, there are a lot of ways I can answer the question, but although we work as a business, our customers are patients, we are patients or caregivers at different points of our lives and it's at the heart of what we do. So, we absolutely need to deliver medicines that patients care about because that's why I come to work each day. It's really, we're trying to develop therapies no matter what disease area to fix whatever needs the patients have. So, I do think that without patient centeredness, there's no point in doing what we're doing. It's just an academic pursuit otherwise. Does that answer your question?
Yes it does. And it brings us back full circle back to the first question, which is your why, which is a nice loop around. But before going, I want to give you the opportunity of if anything else that you wanted to bring up that I haven't asked you or something else that you've thought of as you've been giving your answers.
No, these are great questions, but I think you've said that many times thinking about bringing consortia together, thinking about big data and integrating it and I think one point that I wanted to make is to achieve it we need to start at the outset within the intent to integrate data globally. And when we set up studies, we need to think about how we harmonize methodology because technology advances all the time and technology innovators come up with new tools to assess the same type of data, or if we think about CT scans or reducing radiation in imaging. We have to make sure that when we work with technology companies that they have a way to translate the data that are collected so we can integrate with data collected with all their tools. So, what I mean with each new study we really need to think about how we integrate and gather the information to enrich the data we already have. So maybe that's a point that I wanted to add that is really important.
And, and I'm glad you made that point. That's a very important point and I've seen that recently in some work we've been doing around digital health where some of the providers hadn't even thought about making their data sort of a standard so other people could use it besides on your own device. And it's things like that, that really also really emphasize the strength of a consortium and I really liked your point about that technologies are changing all the time. So, there's a real need to have processes and ways of integrating data because the different data types are always different almost every half a year or so. So, very interesting. Okay. Well thank you very much for coming on. It's been very interesting. I've definitely enjoyed as always
Yeah me too. Thank you.