Adherence – what is state of the art now?

Interview with Lina Eliasson

How does patient adherence affect the results of clinical trials?
Are there ways to improve patient adherence to medication and treatments not only in clinical trials but also in real-life situations?
What is the future of the value of clinical trials in terms of inclusive technological innovations?

Clinical trials are designed to test whether a medication would be best for the target population. While these approaches are considered critical to healthcare development strategies, their value for applicability still remains dependent on how the participants cooperate with the process of treatment which involves their attitude towards adherence to the trial.

In this podcast, join me and Lena as we talk about the most effective ways to get patients to adhere to treatments they are offered in clinical trials. With her background in psychology, Lena’s insight is on point especially when it comes to determining the role of human behavior in terms of determining the applicability of the results garnered from clinical trials.

While there are several problems that arise from the lack of patient adherence, this podcast highlights some of the most effective ways that are available today for researchers and statisticians to consider when handling patient-centric clinical trials-therefore ensuring a high rate of patient adherence.

Here are some of the important learnings you can get from this episode:

  • Patient adherence is affected by different surrounding factors in the lifestyle and personal perspectives of the patients involved in a clinical trial
  • Technological innovation makes it easier for patient adherence to progress; however, implementing these technological inclusions may present challenges to researchers.
  • Hearing the voice of the patients is critical to determining strategies that can help improve patient adherence in clinical studies.
  • Patient-centered goals could drive patient adherence to increase fast especially because the participants the benefits that they can get from strictly following the schedule and dosage of their medication.
  • Addressing personal fears and barriers through proper communication with the patients is an important aspect of successful clinical trials. It can only be achieved through the involvement of personally invested researchers who are more than willing to reach out to the participants and hear out their concerns.

To be a better statistician, learning how to influence patient adherence positively can help improve not only your capacity to reach your goals but also your capacity to motivate the implementation of change in different fields of healthcare.

Reference: How the EMERGE guideline on medication adherence can improve the quality of clinical trials

Learn more about adherence and other topics that will help you in becoming an effective statistician.

Listen to this episode and share this with your friends and colleagues!

Lina Eliasson, PhD CPsychol

As Founding Director and Partner at Sprout, I specialize in understanding, measuring and improving treatment adherence and other behaviors that impact health. I also have experience in identification and validation of clinical outcomes assessments (COAs) and in patient preference studies. My background spans both academic research and the commercial world. Following completion of my PhD on adherence to oral oncology drugs from UCL School of Pharmacy, I worked as a post-doc researcher at Imperial College London. I then joined a behavior change agency, where I oversaw the development, implementation and evaluation of patient and caregiver support programs delivered by multi-disciplinary healthcare teams, which I trained and supervised. Before founding Sprout with Dr Christina Jackson in 2017, I led the European COA team for one of the world’s largest clinical research organisations. Throughout my career, I’ve collaborated with numerous leading global pharmaceutical and biotech companies in UK, European and US markets across a wide range of chronic disease categories.

Transcript:

You’re listening to the Effective Statistician Podcast; a weekly podcast with Alexander Schacht. A niche piece designed to help you reach your potential lead, great science and serve patients without becoming overwhelmed by work.

Today I’m talking with Lena about adherence and what is state-of-the-art null. And before we dive into this, I want to mention that currently, the Effective Statistician Leadership Program with the Mastermind is available for enrollment. We offer this program only once a year. Otherwise it’s only for companies that want to purchase tens or twenty slots in the program.  But now, you as an individual can enroll. It will only open again at the end of next year. So head over to theeffectivestatistician.com to learn more about that and the leadership program, which are exactly designed for people like you; and see whether that is something for you. I’m sure if you haven’t had a chance to look over it, this will be interesting because there’s over 300 people that already went through the program and really had a lot of success with it. So check it out on the effective statistician.com.

 …And now some music…

Alexander: Adherence is such an important topic and today I’m talking with Lena, who is an absolute expert in this area. She’s a psychologist by training. This is so important because if you think about estimates and all of these other things- for anything that is related to treatment – and that is not just a policy estimate that is really important. Because if you don’t know whether people have taken the treatment, well, how can you do any kind of treatment at the most?

So stay tuned for this really nice episode. I’m producing this podcast in association with PSI Community dedicated to Leading and promoting the use of Statistics within the healthcare industry for the benefit of patients.

Join PSI today to further develop your statistical capabilities with access to the video on demand Content Library. For your registration to all PSI webinars and much more, head over to psiweb.org and learn more about PSI activities. Become a PSI member today.

Alexander: Welcome to a new episode of the effective statistician today. I’m talking with Lina Elliason. I hope I pronounced that correctly. Hi Lena, How are you doing?

Lina:  Hi Alexander. Yeah that sounds pretty good. But the pronunciation, it’s Lina Eliasson.

So I’m a chartered psychologist and the founding partner for Sprout Head Solution- a specialized agency that supports pharma and biotech companies and clinical lab assessment strategy for clinical trials as well as development of patient services.

Really, everything we do is about the patient voice; you know, bringing that to the forefront of drug development in the real world.

Alexander: So what did you study actually?

Lina: As I actually studied psychology.  And in my PhD I specialized in adherence to oral oncology drugs at the UCLA School of Pharmacy. So yeah, that’s really where the interest comes from.

Alex:  Cool. Yeah, I’m really interested in Psychology for various reasons. One of the things is I worked in the Psychiatry space for quite a long time. And since then, I thought every well-known psychiatrist says, “I don’t know about statistics” But psychologists, they do know about statistics. That’s why I always felt like there is always a really nice connection between psychology and statistics. And the other thing is, whenever I think about leadership- there is so much psychology in there.

So maybe in the next life I will study psychology instead of statistics- I don’t know.

Lina: Yeah- that’s right. Really, studying psychology, I say to any young people that speak to me about it- that it opens so many doors. There is so much you can do beyond being the classic therapist. So, it’s a really exciting field.

Alexander: Yeah. And so you already started very early on thinking about adherence- that’s the topic today. Where does it come from? Do you have an initial story that kind of triggered that

Lina: Yeah. My PhD started in 2006, I do not know if I just said it, at the UCLA School of Pharmacy. This time, there was not a lot of research in adherence in the oncology space. There are some studies on maintenance strategy for breast cancer but that was about it- and from it was the first golden bullet medicine that hit the market a few years earlier. It was a kinase inhibitor to treat chronic myeloid leukemia. And there was this curious situation that patients who did respond to the medicine, which was, you know, most of them I think some 80% or so- but they tend to plateau on different levels.

So, some had CML disease. They were undetectable; others had some detectable disease and yet, others didn’t do really well at all. You know, all over the world research teams were looking into what my course is, especially the difference in response and the team that I collaborated with, which was led by David Maureen, who at that time, was at Imperial College London. He had this idea that perhaps people plateaued at different levels because some of them didn’t take the drugs as prescribed. And you know this was hugely controversial. People were saying “of course all the patients take the treatment as prescribed- they have cancer”. And you know, this is an oral treatment. It’s easy to take. Side effects were mostly low grade. You know, clinicians said that people should just accept-you know, it was a golden bullet. But then we tried to monitor patients for three months, and sure enough, the adherence rate was at a strongest predictable response.

It was quite interesting that the expert community responded by saying, “Oh! Look at them at the Hammersmith Hospital, which is where the trial was run- they have a problem with adherence but we don’t.” 

You know, it was quite amazing, but the body of evidence proves the extensive impact of non-adherence to matinib and also other oral oncology drugs. And, you know, the community had to accept that non-adherence was indeed a pervasive challenge- even when we look at life-saving cancer therapy. And it got me hooked. 

Alexander: Yeah I can completely relate to that. In the early 2000s, I was working on HIV and it was, you know, the protease Inhibitors drugs. It really changed the kind of life expectancy for HIV patients. It was introduced just a couple of years earlier and also working on such a drug- and so I got more into the HIV community, and all these drugs are also, you know, our world- it’s more or less easy to take.

AIDS is really a severe disease. It also has a 100% mortality rate and there is no cure for it. So you would think like, “of course, patients would take the drug”; but no, there is a problem with adherence and there’s some studies that were done in prisons where people are directly observed on how the patients were taking the pills- each pill. And in these studies, response rates were dramatically better than in usual studies where the patients take the pills at home.

So, adherence plays a big role in these severe diseases like in oncology or HIV. So, even if we think about it like you said, what about the side effects? Well, your life is at risk, yeah? Worrying about these side effects is kind of related to all the other things. And of course we know from our personal lives, we know what a healthy lifestyle looks like- do we adhere to it?

Lina: No

(laughter)

Alexander: So, tell me a little bit more about adherence in clinical trials and what research you have come into?

Lina: Yeah, well, we often hear that adherence is critical in clinical trials. That evidence shows that suboptimal adherence is common in this setting too- and it’s a huge problem. Non-adherence in a trial setting affects the quality of the trial, the cost of the trial- the lost opportunities, because we have unduly large samples in the trials; and there are even some trials that have been discontinued or seen as failure since treatment has not been shown. But post op analysis indicates that this was because many participants did not actually take the drug as intended. And if you do not measure adherence, but instead measure the assumption that adherence is more or less perfect in your analysis- but it isn’t- this affects both efficacy and safety of the data. It can become a source of wrong estimation often resulting in over estimating dosing requirements.

I think about 20% or 30% of all drugs approved since the 1980s have been dose-adjusted post market distribution. And a huge percent of those went through dose reduction. It really needs a serious suggestion and it does speak out about what you mentioned about HIV- that its an issue

Well you often hear that adherence is perfect in clinical trials. evidence shows that suboptimal adherence is coming in this setting too and it’s a huge problem non-adherence in a trial setting, affects the quality of the Tri-C and affects the cost of the tries. You know, they lost opportunities because we have unduly large, Sample sizes in the trials and you know there are examples of trials that have been discontinued or seen as failure as treatment effect hasn’t been shown. But you know, post hoc analysis indicates that there is an issue of adherence because the patients are not following through their trial treatments.

Alexander: Yeah, and maybe it’s better to be adherent to the lower dose than to be non-adherent to higher dosage.

Lina: Yeah, absolutely. It’s interesting you say that because one of the patients at the Hammersmith, he was non adherent and we knew it. And we opened up a discussion with him about it and he was on 800 mg of matinib, which some of the patients who were in the trial of the matinib at 800mg- they would be kept on after the trial had finished during their trial period. And when we talked to him, he just said “look I just have to take a break sometimes because I can’t manage the side effects. Then they reduced him down to 400 mg- and he said to me “you know I am really trying to take it now, every day. Because I really wanted to work on this lower dose”. And 400mg is the standard dose for matinib. So, I think you can really make the difference and sort of adjust dosing to a lower dose which might be safer for the patient to take. And you should know that from all the trials.

Alexander: It’s also kind of just as a side note of course- that means you need to have some discussions about which estimate you are actually interested in. Like, what was the treatment policy for patients that are really taking it- really considering all these kinds of different things.

Capturing adherence is really a big topic. I know that when I worked on these HIV studies; we had two columns. So we had for each, that kind of [he should have taken 20 pills but he returned too many- and probably have taken 15 at the maximum. So 15 divided by 20, then it’s just 75% compliance. That was how we dealt with compliance. What do you think about that?

Lina: Well, I think unfortunately, you know, pill count isn’t a very accurate measure of adherence but it’s still the most commonly used measure in clinical trials. Of course like you say, it’s reliant on patients bringing back the packaging- and they might do that, they might dump the pills before- you know. Like we had some 110, 120, 130 percent adherence according to pinch hands because you know we had put extra pieces in the bottles and patients didn’t know that and so they just dumped the rest off with whatever other people had left over.

 So, I’d say that’s not a great measure. And I wish that was spoken about more because I think, you know, sponsors might feel like they have kicked the ball because people can’t see it in there.

Alexander:  Yeah. And it’s also kind of understanding how it’s collected, what kind of signals are sent to the patients? Do they get some kind of bias there? Do they have an incentive to throw away all the pills because then they are not yelled at by the physician?

These kinds of things play a role. So, what alternative ways are there to capture adherence?

Lina: Well, there really isn’t a gold standard for capturing adherence and the measure is recommended based on the specific situation in which adherence will be measured. I think perhaps there’s three sort of key steps, you know? The first step of course is to clearly define adherence and the outcomes you are interested in your trial and we always use the ABC taxonomy, which was published by S-Stat Convergence from Ireland. It essentially breaks down adherence into three key behaviors. So, the initiation of treatment is the maintenance of your prescribed treatment over time. And then the point of discontinuation. The time period between initiation and discontinuation is referred to as the “system”-and this definition really applies whether it is self- administrated; whether it is a supported administration- or if a parent is administering it to a child, or if it’s a healthcare provider administering the treatment in a clinic.

 Then secondly, you want the measure to capture the adherence outcome as intended to produce the data that you need for your analysis. And I am sure you will agree, but I would say it is best to speak with the lead statistician before you decide on what particular data points and what measures to use because they will have valuable advice on what they need and how they need to be structured to work for their analyses. And of course clearly define the objective of the data and how it will be key to the outset.

 I think that measure would be appropriate depending on the outcome of your trial, who your respondents are; [is the patient- who is that patient. Is that an older person; what is dexterity like? Is it a young person? What type of drug formulation and administration is used and so on- you know, the hundreds, if not thousands of ways of keeping record- like self-record technologies, smartphone apps, and dispensing data- it’s really about choosing the best for your particular purpose.

And then finally, and just as important, is that it is convenient for the responder. It should not be too cumbersome- not too intrusive, or has some other adverse feature that can give you an accurate or missing data- or worse, if not responded well- this might result to discontinued trial; or perhaps decide that you not want to enroll participants in the first place because they know what it will take to respond to these measures.

Alexander: What are the kinds of ways we can encourage adherence in a clinical trial?

Lina: Well, I think it is important to highlight that it’s directly based on the patient to do something about it. And to support patients- to ask why he has discontinued the medicine. What were the challenges that they had if they discontinued with a trial? Why did they do that? And I think you know you could use questionnaires to capture quality of data and ask the why questions.

A newer method that we are increasingly using for our sponsors is exit interviews. And so you know, typically done at the end of the trial when the primary endpoint has been reached- and you spend, you know, maybe half an hour, an hour, just having a chat about- [obviously], you have a discussion guide with you.

Ask them about the experience during the trial, and it’s an opportunity to ask them about the treatment that they received. And I think once you start understanding the whys, that’s when and how you can help and support patients.

Alexander: That’s a good point. I think this getting first-hand experience about what the patients really care about, helps you a lot later on to follow up trials and see what specific points you would need to talk about, do you need to set expectations, what other things you need to do later on once you have launched the product- to increase adherence.

In the end, if the patients continue to not take it right, it’s better to stop the drug. It will not help the patient, yes?

And we need to kind of have a really open and honest discussion about this. I know that perceptions can be very, very different. I once was working on a drug that (inaudible) and it has this little side effect, that’s the injection were a little bit painful and several injection site reactions also not something that anybody in the safety department and FDA really cared about- because that’s minor. But in real life, it is a topic- and so don’t think like it’s the same as with the oncologists when they say that “oh, this side effect should be bearable or if it is life-and-death, don’t just assume that your point of view and perception is the same for the patient.

Lina: Yeah, totally agree.

Alexander: Yep, Very Good.

You mentioned kind of, digital things like smart phones; what do you think is in there in terms of capturing or improving adherence.

Lina: There are a lot. It’s a part of an evolving field; like in the early days, we have the microelectronic monitoring caps where we use medical bottles to record opening. Now, those kinds of technology have extended to blister packs, and there are dosing machines and the microchips that are embedded into the formulation of the drugs. You can be inside tablets that send signals when it’s ingested.

Obviously, if you have a delivery device, you know, an inhaler or like you mention an injection pen, you know. The digital monitors can be sort of embedded in there that sends signals when the drug is administered. And of course, some of those or many of those come with platforms, dashboards, or interfaces, for sometimes their patients. So they can see data- in a trial setting, the side staff has access. We also have smartphones and tablets that you can use to self-record. Or, video recordings- sometimes the video does not capture the picture but they capture the movement so you still have identifiable data of ingestion. People can use those interfaces on their smart devices.

Alexander: Yeah, that is the way you can directly connect, interact with the patient- like send them some reminders, and give some incentives so that when they take the drug, they can see how they are improving. There are probably lots and lots of opportunities to help patients be more adherent.

Lina: These are the more interesting ones and you just touch on those. And the best is that you can combine data and these trackers where patients can track their adherence- and that’s captured within the system. But you can also use them to feed in data-and sometimes, they can also be connected to digital health records that you might use manual entry to update. But to be able to see how your adherence changes over time and how your response changes over time, and record adverse side effects and how they change over time with the treatment; that’s surely interesting.

And of course, it is more motivating if the patients are going in the right direction. And if it is not going in the right direction then it is something that the patient and the healthcare team prescribing the treatment needs to know.

Alexander: Yes, and it’s kind of helpful in building a habit of adherence. And several books I have read about atomic habits- do you know about that one? It talks about the four parts of a habit from the trigger up to the reward. And you can think about these four things if you want to have patience and develop a habit of taking the medicine. And taking the pill every morning.

Helping patients establish these habits and have technologies that support that – that’s just really cool.

Lina: Yeah, absolutely. And I think these technologies also provide channels to deliver other information. So, habit formation is something really important. And there is the powerful, what we call behavior change technique; or, the active ingredients in the psychological interventions.

But there are also other behavior change techniques to be used. So say, it might be that the patient has certain concerns over side effects and some of that might be because of their experience, or it might also be that they have read something that’s accurate or not- If we have channels to connect with the patient to provide them with accurate information, which is addressing some of those barriers that they might have in terms of managing their treatment and their disease or other health behaviors that they want to stick with around. That could be diet or exercise or whatever it could be.

That’s really valuable to us as well. And I think it’s important to sort of highlight that we should not forget that there are other barriers around that may hinder someone from doing something like dexterity issues- or it could be something in your environment or your support work- and what we can do to involve people there.

And you know the biggest motivation is the biggest one. The way we work, we look at motivation as the conscious ideas and emotions, and beliefs that you have that drive your behavior; that also automatically form habits – which impacts the automatic motivation that people have.

Alexander: I love that. There is so much kind of psychology in it, obviously.

Working with a psychologist will certainly be helpful to increase adherence. And maybe it is one of the things that have the biggest impact on the high probability of results for your study. And in the end, it could be just wasted. It is best to use it to really understand what the real barriers are in the real world.

There’s that- there are many companies that have this support system to help patients stay on treatment, and remove all kinds of barriers, especially when it comes to helping the more costly patients- patients who need to be treated with more costly drugs. Patients need to invest in these areas.

 With all the research and all the learning that you have gathered through your clinical trial; for example, working with Sprout, you can get so much knowledge into making sure that all factors work.

Lina: Yeah, absolutely. I mean I think there is no arguing that the care and the monitoring that participants get within a trial setting is different from clinical practice. You know, it’s often more comprehensive and that might influence patient’s treatment experience but there is still an opportunity to learn a lot about, you know, the challenges, they had the opportunities that they saw with the trial treatment, the clinical outcomes of importance to them and understanding that; and what they think might be helpful for people who have prescribed this medicine in the real world. Because, of course, they’re the experts on their condition and they understand what it’s like living in the real world with that condition and not having access to the treatment that they have just received in the trial.

So, I think that this is hugely valuable to support the development of support services that can be marketed alongside the drug and inform measurement strategies- also, for real-world studies. And yeah, I encourage people to take the opportunity to learn as much as they can from the participants in your trial. You know, it’s not always that the way you measure things fits or captures everything that they want to say. And usually, participants really value being able to share their experience in their own words with someone- and that is captured and beneficial for their community out there.

Alexander: So, this is where interviews really come into place?

Lina: Yes, absolutely. And they can be more open in the way that they discuss the outcomes. You know, we believe that exigencies also help interpret the results of the clinical outcome assessment of the patient’s outcome measures that we used in the trial.

 We can ask them what was different- it can help provide further validation [in a way] to those measures. And I think, one of the big differences between the real world compared to clinical trials is that it is short term and real-life treatment is often lifelong. So, over a lifetime, things change; not just physically and medically, but we spoke about the capability for opportunities to stick with prescriptions with recommendations as it changes over time. Ideas and beliefs also change over time and that really needs to be considered when applying trials in the real world- and from the perspective of each individual.

Alexander: Yeah, because if you have a lot of patients in a clinical trial, you can gain experiences from lots of different situations. From older people, from people that live in different circumstances, those who are living in life crisis- how do you deal with these kinds of situations?

And you can take these learnings and improve the cure and plan for contingency in the real world. Whereas questions are answered for the patients. You have a channel where patients can even ask these kinds of questions. As of this instant, I have one question about exit interviews. How do you capture the data from these exit interviews?

Lina: Yeah. Well usually recordings, you know, an interviewer, and sometimes the interviews are done by site staff. So then we would train the side staff to conduct the interviews. And so they prepare a structured interview guide and we train the side staff to do the interviews and ask the questions and they are then recorded- audio recorded, and that audio recording is sent for transcription. And during transcription, they make sure to remove any remaining identifiable information, and then those transcripts come to us for thematic analysis. And there might be specific research questions before.

Like I was saying, for example, if there isn’t enough evidence in terms of what meaningful changes on a particular measure have been used, we can explore that. We can then also ask them questions about their experience with the treatment if they miss doses, and then we will say, this is very common. Questions like what were the circumstances around mitosis during the trial?

And we can also ask them questions about the trial design and you know, how it was to actually participate in the trial. This can then be fed back to the sponsor so that they can use that to inform future trials to ensure that trials are becoming more patient-centric over time. Making it easier for patients to fit in with their life- and then, of course, supporting their patient in the trial and their adherence to the trial’s treatment.

 Alexander: Yeah, because one of the specifics about trials is also that they can come with a burden to the patient. And that can make patients stop the trial.

Lina: Yeah. I should have said that actually. With the exit interviews, sometimes we do the exit interviews ourselves so that the process would be safe.

Alexander: Awesome. That was an outstanding discussion about adherence; how we can capture it; how we can improve it both in clinical trials and in the real world- and how we can much more understand everything from the patient. Especially about what they are concerned about, and what their problems are. Obviously, this is a big topic for anybody in clinical research and every specialist; even if you work in oncology or HIV or any of the life-threatening diseases. The truth is that compliance is a given barrier in these topics.

 Any final takeaways that you would like to give to the listener?

Lina: Yes, I guess we didn’t speak so much about adherence from the patient’s perspective and how we should achieve 100% of their adherence which can maximize outcomes for an individual. It’s more about fitting it in with their everyday life and that might not mean a hundred percent adherence even if that has an impact on outcomes. And I think, at the end of the day, it’s an individual’s choice to appreciate, implement and persist with the treatment that they have been prescribed.

There would be some exceptions of course within mental health, and also, now with COVID, where people might have been forced to do certain things, that most of the time people have a choice. I think our role as healthcare providers, medication manufacturers is to ensure that individuals have accurate and understandable information to help them in their choices; just to help them achieve treatment success and what that treatment success means to them. And that we really listen and act when treatments need to change. It is important that we hear the patients’ voices.

 Alexander: Awesome! That was a fantastic statement. Thanks so much, Lina for all these discussions. We have lots of references of course; a link to Lena’s profile, to her company, everything is in the show notes.

So just head over to theeffectivestatistician.com and search for Lena from Sprout, and then you’ll find that easily.

Thanks a lot.

 Lina: Thank you, Alexander.

I hope you really loved the show. If you want to learn more about this, then follow Lena. Follow me on LinkedIn and I’m sure you’ll learn much more and check out her company Sprout HS, which is really, really cool.

This show was created in association with PSI. Thanks to Reine and her team at VVS who helped with the show in the background and thank you for listening.

Reach your potential lead, create science and serve patients, Just Be an Effective Statistician. 

 

 

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