Open Science in brief, September 2022

      Open Science in Brief: A Focus on Real-World Evidence

      Not all research is conducted in the laboratory. Real-world evidence comes from across the globe in settings with real-world context, usually from observational studies, hospitalization data, electronic records databases, surveys, public health records, and much more.

      In our most recent Open Science event, we saw Dr. Angela van der Plas, Manager Real-World Evidence & Epidemiology, present some of the data we have gathered based on the real-world evidence around our leading heated tobacco product, the tobacco heating system (THS). Angela has worked on many aspects of real-world evidence including how the data is analyzed and has focused her research on several markets including Japan and South Korea.

      Angela discussed a range of statistics that we, and independent researchers, have gathered looking at topics such as: What is the impact of the introduction of THS? Does the introduction of smoke-free products affect cigarette sales? And are there changes in hospitalization trends in diseases such as COPD?

      Former journalist, Sukhi Hayer moderated the event, and during her presentation Angela answered many of the questions we have received during previous Open Science events, and others that are often asked. Additionally, Angela was available during the session to answer in a live chat any further questions viewers had.

      You can watch the recording of the Open Science event below, or read through the transcript of the video.

      Open Science event transcript: Real-World Evidence, 20th of September 2022

      Narrator: Hello and welcome to our eighth Open Science event. This event is pre-recorded and is around 30 minutes. One of our leading scientists, Dr. Angela van der Plas, Manager of Real-World Evidence & Epidemiology, will be giving a presentation on some of the data we have gathered based on the real-world evidence around our leading heated tobacco product. Angela has worked on many aspects of real-world evidence including how the data is analyzed and has focused on several markets including Japan and South Korea. She will be discussing a range of statistics that we and other independent groups have gathered as well as studies including ongoing ones looking at topics such as: What is the impact of the introduction of the tobacco heating system? Does the introduction of smoke-free products affect cigarette sales? And are there changes in hospitalization trends in heart and lung diseases? 

      Former journalist Sukhi Hayer will be moderating the event, and during her presentation Angela will be answering many of the questions we have received during previous Open Science events, and others that are often asked. Additionally, Angela will be there after the session to answer in a live chat any further questions you may have. Thank you for joining us for what will be another informative Open Science event. 

      Sukhi: Welcome everybody to this eighth Open Science event. This is a pre-recorded session that will go out on the 20th of September and of course Angela will be available for those questions after this recorded session. It is a specialized session. Angela van der Plas is an eminent scientist with Philip Morris International. I'll get Angela to introduce herself and then I'll ask her a question about real-world data. So, Angela if you may. 

      Angela: Thank you very much Sukhi. So, my name is Angela van der Plas, I'm a manager of Real-World Evidence & Epidemiology. Taking my title, real-world evidence is the study of data that has already been collected and repurposing it for other purposes. So, for example, when people talk in general about real-world data they're talking about data from registries, data from electronic health records, and data from health insurance databases or claims databases, and even data coming from already finalized clinical studies. And the fact is that this is very rich data that can be repurposed for studying other endpoints. 

      Sukhi: Excellent and I presume now you're going to go through a presentation where you reveal that study and the data etc. etc. So, I think without further ado let's get into that and then at the end I'll ask you some questions. I'll probably, during the presentation, I'll be asking you questions as well so without further ado over to you. 

      Angela: What we're doing at PMI is, we're trying to build evidence on the effects of the commercialization of the Tobacco Heating System or THS (In the video, Angela refers to THS as IQOS, which is how it is marketed in countries where it is sold.), both at the population level and at the individual level. So, in order to build this evidence, we have first asked ourselves what kind of questions we can answer with the studies that we're planning. So, what is the impact on population? And we see that we can answer for example: Are smokers switching more successfully to THS, and other reduced risk products? Are switchers to these products more or less likely to relapse into smoking? Is the introduction of RRPs [reduced risk products] affecting cigarette sales? And also, if there are already some changes in hospitalization trends for smoking-related diseases before and after the introduction of heated tobacco products. When we are discussing the impact of individual-level effects of the commercialization of THS, we are looking at what changes are there in risk to those who switch to reduced risk products, in particular heated tobacco products, including THS. 

      Now, in order to respond to these questions we'll come up with a study plan and we include many types of studies. The simplest ones are those that relate to sales data analysis. So, what happens once heated tobacco products are introduced in a given market. Are they affecting cigarette sales? There is some limitation to this analysis of course because there are many variables that can affect cigarette sales and we don't always have the complete picture in different countries. Now the other type of study that we can do to assess the impact at the population level are ecological studies. And ecological studies or time trend analysis look at the hospitalization rates before and after the introduction of heated tobacco products for cardiovascular disease and certain lung diseases. So, what we want to see is if there is a temporal association of the introduction of these products and a change or shift in hospitalization rates. 

      Sukhi: If I may interrupt there, briefly. You look at COPD in particular. Why just that, why not other sort of cancer-related diseases etc. etc.? 

      Angela: What we're looking at is, we're not looking at risk in these studies, we're looking at hospitalizations. So, we include cardiovascular disease such as ischemic heart disease, and also COPD [chronic obstructive pulmonary disease] and COPD exacerbation. So, these are endpoints that we can use because the hospitalization for both of these types of diseases can be seen within this time frame of the introduction of heated tobacco products. For cancer, if somebody is going to be hospitalized, this is going to either be a new diagnosis or receiving treatment, and cancer is a very long latency disease. So, it wouldn't be appropriate to use malignancies as an endpoint in these types of studies. 

      Sukhi: Right. 

      Angela: So, when we look at the individual-level impact we have different types of studies planned. The first one is a repeated cross-sectional study where we will collect using one of the databases that we have used for our ecological study in Japan. We will administer a questionnaire and we will assess tobacco and nicotine product use in this population and then we're going to be able to see if we can do a retrospective analysis. Meaning that we would see in those who have a disease to see whether the disease prognosis differs between those who have switched to heated tobacco products compared to those who have continued smoking. We are also going to follow these people up for at least one year to see any incident or no diagnosis of different diseases, in particular cardiovascular. And this is a sort of pilot to see if the follow-up is doable in such a setting. The other study that we're doing is probably the most important one, is a longitudinal cohort study. The longitudinal cohort study is a study that is following people for about five years. We're going to collect information and enroll 20,000 participants in four different countries and follow them up for five years and see the difference in developing certain smoking-related diseases, in particular ischemic heart disease and other cardiovascular endpoints. 

      Sukhi: And again, I presume that these people that you're going to select are, you know, smokers, ex-smokers, people who just use e-cigarettes, a mix of people, I presume. 

      Angela: What we are including in that is 20,000 participants that are either heated tobacco product users or smokers. Because we want to see what the difference is between those who continue smoking and those who have switched to heated tobacco products. But also, we want to see the patterns of use of these two types of products, and this is going to help us. 

      Sukhi: And age, sex, ethnicity, all of that built-in? 

      Angela: Exactly. The distribution of age and sex is going to depend on the country that we are including. So, we're planning this study and then I will detail this in the next slides. So, we're thinking: we have started the study in Japan, in Hungary, in Greece, and the Slovak Republic. The composition of each population is going to depend on the population of the general population in these countries. And the next and the last study that I'm going to talk about today is a longitudinal biomarker study. This study is going to look at whether smokers who switch to THS and other heated tobacco products have better functional endpoints and biochemical biomarkers of potential harm than those who continue to smoke. We are also going to see whether smokers have better disease risk or disease progression markers than those who continue smoking.  

      Now, I would like to present to you some of our results for the sales data analysis and I'm going to talk about the case of Japan and South Korea. So, if you look at the screen, you will see this slide presenting both countries. In the case of Japan, you see that there was already a trend of decreasing sales of cigarettes. And once THS and other heated tobacco products were introduced in that market there was a further decrease in cigarette sales. These types of studies can also evaluate what is the impact, for example, of different legislations or laws being introduced such as the cigarette price increase that happened from 2010 to 2016 as you can see in the slide. And also, what is the impact for example of other variables such as COVID-19 which happened at the at the end of 2019, at the beginning of 2020. 

      Sukhi: So, it's quite complex then the result of decrease in cigarette sales. 

      Angela: That is correct. And the data about different variables is unfortunately not always available. However, this is the same methodology that public health experts will use to evaluate how successful, for example, a price increase or a smoke-free law will have on disease or health endpoints, and also the sale of cigarettes. So, if I can continue to South Korea, you will see that there were a few legislations introduced in the market and they had also a decrease, there was an observed decrease in cigarette sales after for example the tobacco tax and price increase. And we see also that there's also a coincidence of a further decrease with the introduction of heated tobacco products and THS in the South Korean market and a further decrease in the sales of cigarettes. We can also see that with COVID-19 there was an increase of cigarette sales. The case of South Korea is a bit different to Japan because they also have a good market for e-cigarettes, in Japan this is not the case. The use of e-cigarettes is very, very limited, and there are no nicotine-containing e-cigarettes for sale over the counter in Japan. 

      Sukhi: And why are we looking specifically at Japan and South Korea? I presume you're in many more countries where you have your devices and this heat-not-burn category. Why just these two countries? 

      Angela: The reason why we started with these two countries is, Japan for example is the first country where we introduced THS, and other heated tobacco products were introduced. And South Korea is also a country that is rich in data and real-world evidence databases. So, we wanted to start with these two countries. But what we're currently doing as well is that we're monitoring the sales data of heated tobacco products in all the countries where we are marketing THS. And once we see that the market has matured and there is a good enough market penetration of THS and other heated tobacco products then we can start looking at whether the introduction of this type of product has had an effect on cigarette sales.  

      Now, I will show you another example of cigarette sales data and this time for Europe. So, this is cigarette sales from the Czech Republic, and you will see that between 2016 and ’17 there were a couple of legislations introduced about the use of tobacco products and anti-smoking regulations that did not seem to have impacted the sales of cigarettes. And you see also that the introduction of heated tobacco products, and particularly once it started increasing, then you see that there was a decrease in the sales of cigarettes. Now the case of the Czech Republic is really interesting because you have a lot of cross-border sales and there might be other variables that could also be affecting cigarette sales. So, while these findings are really interesting and we're trying to repeat this in other countries the interpretation of this data has to be with caution.  

      Now I would like to present to you the results of our time trend analyses or ecological studies. As I said before this type of studies use real-world evidence from electronic health records and claims databases to look at the effect at the population level of the introduction of heated tobacco products, and whether there was a temporal association between the introduction of heated tobacco products and hospitalization rates for ischemic heart disease, COPD exacerbation, and COPD overall. So, we have data from two studies in Japan. The first one is a study from the MDV, or Medical Data Vision, database which is an electronic health records and claims database.  

      And we see that there was a temporal association between the introduction of heated tobacco products and a reduction in hospitalizations due to COPD. Important to notice here is that MDV is a very big database with information from about 20 million Japanese subjects. It spans the whole lives, the lifetime of a person, so from age zero to above 100, and it has a good balance of males and females in the database. Now, if you look at the right side of this slide you will see data from the JMDC database which is an electronic health records and claims database as well. And the first graph refers to all hospital records and the second graph will refer only to DPC data which means this is procedure combination, and this is data that comes from claims being given to insurance companies. So, the first graph shows a temporal association between the introduction of heated tobacco products and a decrease in the hospitalization rates for COPD meaning either hospitalization for general COPD but also COPD exacerbation.  

      And when we look at the bottom graph, we see that the introduction of heated tobacco products was temporally associated with a decrease in hospitalizations due to ischemic heart disease. Now JMDC is a quite different database to MDV. JMDC has only people until the age of 74, which means people that are still working, and their dependents, and also there is a higher percentage of females in this population. Now as you can imagine, this does not present a causal association but rather a temporal association, this is the type of results that we get. 

      Sukhi: Can you just explain what you mean by temporal association? Because, you know, looking at these graphs, it seems very encouraging, but you keep saying temporal. So, just explain what you mean by that. 

      Angela: So, temporal means that once and after there was an introduction of the heated tobacco products in the Japanese market it was followed by a decrease in the hospitalization rates for these diverse endpoints. But I cannot say that this is a causal association. 

      Sukhi: Right. 

      Angela: And the reason is because this type of study is not used to elucidate what is causing the decrease in hospitalization rates, but it can give us an idea. So, yes, these results are encouraging but we cannot say that there is a causal association. 

      Sukhi: Sure. 

      Angela: And then let me talk to you about the longitudinal prospective cohort. This is, as I said before, a very important study because we're going to enroll about 20,000 people in four countries: Japan, the Slovak Republic, Greece, and Hungary. The purpose of this study is to follow these 20,000 participants which are going to be either cigarette smokers or heated tobacco product users for five years and then look at the risk of developing incident health events, in particular cardiovascular disease events. 

      And the important part of this study is that we want to confirm the diagnoses that are reported by the participants. The participant as I said is going to be followed for five years. They are going to be interviewed through a self-administered interview online every three months the first year and then every six months, and we're going to gather also information about other important variables such as demographic variables, socioeconomical status, lifestyle assessment, diet, exercise etc., family history of disease, and also tobacco product use. This is really important also because being a longitudinal study, it’s going to help us find what makes somebody or what can make somebody switch for example, what can predict that somebody will switch, will take up another product etc. So, this is a very important study. 

      Sukhi: I was going to say that it will give you great insight, won't it, into the behaviors of people and also the relationship between the behavior and potential disease as well, I presume? 

      Angela: Exactly, yes. 

      Sukhi: Okay, thank you. 

      Angela: But importantly I wanted to add that we're going to have a continuous data analysis. Every year we're going to also look at signs and symptoms associated to smoking-related diseases. So, we might have some information before the five-year follow-up ends.  

      Lastly, I would like to say that even though we are presenting results from Japan and South Korea and we're planning studies in some other countries including European countries. I just wanted to show you that we plan to do our sales data analyses and ecological studies in other countries. As I said before, this is once the country is mature enough and there is a sufficient market share of heated tobacco products in that country. For the sales data analyses, we have Portugal, Greece, we have also Italy, the Czech Republic, to mention a few, and the same thing for ecological studies where we will be looking at hospitalization rates.  

      Now for individual-level health studies we are doing some Japanese database-driven prospective analysis using some databases, not only JMDC, but also some other databases that are already starting to collect smoking behaviors, and also, we should start a study in the Czech Republic, also database-driven. So, thank you very much and I'm more than happy to respond to your questions. 

      Sukhi: Thank you, Angela. Just on that database question. I wonder if other countries that you're looking at, you'll have access to those databases? With Japan, I think you've got a wealth of data but perhaps other countries, you won't be able to get access to that data, is that right? 

      Angela: So, as you said, it depends. It’s on a country per country basis. So, every time we do a sales data analysis, we want to then look at the possibility of running a time trend analysis or time trend study, and while the data might be available in some countries, it's not in some others. So, we're looking at, as I said, we're already planning in the Czech Republic, in Slovakia, and also Lithuania so there we can get the data and analyze it. But again, as more countries become more mature, we're going to be able to include them in our portfolio of studies as well. 

      Sukhi: Okay. Excellent. Thank you. There are questions as you have alluded to that have come in that we'd like to ask you. This is coming from the public, and also previous Open Science events as well. So, if you could answer these that would be very, very helpful. Now, it says here real-world evidence studies require information on the health status and nicotine product use over time. The latter is generally not collected, which prevents comparisons against smoking. How can collection of product information be promoted? 

      Angela: So, that is correct. The great majority of real-world evidence databases are not going to have the systematic collection of tobacco nicotine product use. However, there are some databases that are already collecting it, not only in Japan but also in South Korea. The other possibility is, like we're doing with a cross-sectional study, is that we are administering a questionnaire on tobacco nicotine product use to people belonging to a database, in this case JMDC. So, that is going to help us do an individual-level type of study. 

      Sukhi: Now in terms of epidemiological, a lot of people are saying, you know, when the Covid vaccine was discovered, it was discovered very quickly and put out there. And we were getting the results pretty much instantaneously. Why is it taking so long to get these results back, this real-world evidence back in terms of the relationship between heated tobacco products and potential diseases? 

      Angela: So, what you saw happening with the Covid pandemic is, it's an infectious disease. So, information for me comes really quickly, but it's also updated very quickly. If you remember, at the beginning of the pandemic there were some studies showing that there was fomite transmission- [i.e. disease transmission on object surfaces] of Covid whilst afterwards it was discovered that this fomite transmission was not as important as aerosol transmission of Covid. So, this is what happens when you’re talking about an infectious disease. For smoking-related disease epidemiology, most - all smoking-related diseases have a very, very long latency except for maybe cardiovascular disease which is a, it takes about four or five years to actually half your risk of developing cardiovascular disease after you stop smoking. So, that is maybe a bit less or not as long as other diseases as for example COPD or lung cancer or another more complex disease. Complex disease epidemiology takes time. 

      Sukhi: Now you alluded again in your presentation to this, and I think, you know, a lot of people are saying there's a lot of evidence in Japan hence why you're doing a lot of study in that area. But to get a more accurate picture, I presume of different people how they consume heated tobacco products and nicotine and tobacco, you know, are you planning on looking at a kind of cross-section of the world to get a more accurate picture? 

      Angela: So, yes, we plan to include more countries in our study portfolio. However, we have to let the market mature. As I said before, real-world evidence and epidemiology have to do with observational studies. So, if in your market, the market penetration is really low, you're not going to find users of your product and hence you will not be able to study them. However, in countries such as in Japan, in the Czech Republic, in South Korea where the market penetration is higher than in other countries then you can start thinking about this type of studies being run there and that is what we're currently doing. 

      Sukhi: Okay. Do you have an insight on sales data for cigarettes and heated tobacco products over time in Japan and other countries and what other factors can affect the sales? I think you mentioned some of those earlier on. 

      Angela: Yes. So, I did mention that there are many variables that can affect cigarette sales. One of them is for example Covid. There's also cross-countries, there is a high rate of sale in the Czech Republic for example. Germans come and buy the product there and this happens in other countries. Illicit trade is also an important variable and the data regarding illicit trade for example is not, it's not very detailed, you just have a calculation of it. The other thing is that e-cigarette sales are not tracked as sales as for example for heated tobacco products or cigarettes because also they don't have really consumables. It's a product that you buy, some of them you can discard, but some of them you just buy the liquid. So, it's really difficult to quantify the sales of electronic cigarettes. 

      Sukhi: Now again we talked a little bit earlier about the decline in cigarette sales and hospitalizations data on COPD and you said it was a temporal relationship. How do we demonstrate a causal relationship? 

      Angela: When you look at the time trend analysis that is when you look at trends in populations. When you want to study causality, you have other studies to assess, and these have to do more with the individual-level risk assessment. That has to do with, for example, the longitudinal cohorts where we are following people over a five-year period of time, and we will be able to assess and adjust for other variables the risk of developing cardiovascular disease between those who continue smoking and those who have switched to heated tobacco products. That gives you a better idea of a causal relationship of an exposure and an endpoint. 

      Sukhi: I'm coming to the end of the session here, but just a couple more questions. And one has to do with the fact that, you know, you're conducting these particular studies, epidemiological studies. But is there anyone else out there looking and trying to do the same? 

      Angela: So, yes, there are a few studies out there that have already started looking at differential risk of certain diseases, smoking-related diseases, and either continue smoking, switch into HTPs, but also stopping smoking. Probably the most interesting one is the Choi study that was run in South Korea in men in a big database, the National Health Institute database there. They have data for about five million people, and they show that there was definitely a differential risk of developing cardiovascular disease. So, at the top you had those who continued smoking, and then those who had switched to heated tobacco products, and of course even lower were those who had completely stopped using tobacco products. 

      Sukhi: And just finally, Angela, you know, you do a lot of studies, I presume. What are you most excited about? Which study would you say is the one that kind of you really are up for? 

      Angela: I think every study that we do is sort of a piece of a puzzle because you know evidence and claims come in stages. I like all my studies, but if you ask me which one is my favorite, it would have to be definitely the longitudinal cohort study where we are looking at differential risk of developing smoking-related diseases. And it will also give us a lot of information of what makes a person stick with smoking, switch to heated tobacco products, or completely quit, which is going to be really useful. 

      Sukhi: And a question you probably get asked numerous times. But why do you personally work for Philip Morris? 

      Angela: Working at PMI has really opened the door to new knowledge, to new types of study designs, to being open about how we want to answer a scientific question. So, this is really exciting. 

      Sukhi: Okay. Thank you, Angela. Your work is not yet done. So, just to reiterate. This is a pre-recorded session that's going out on the 20th of September. Obviously, people can ask questions off the back of this. You are live for half an hour, 30 to 40 minutes, to answer people's questions. So, this is the 20th of September. So, if you are willing to ask questions, please do. Angela is available to answer these live in person. But obviously after this date, you have your day job to go to, Angela, so, and get on with those studies, I think. But thank you very much for your time and that brings a close to this Open Science in Brief session, a look at real-world data with Angela van der Plas. Thank you. 

      Angela: Thank you very much.