Continuing our in-depth coverage of patient-centricity, we look at how companies are listening to the patient voice at each stage of a drug's life cycle

Read part one of our special in-depth feature on patient-centricity 

Research: early insight  

Patient-centricity in drug development can begin right at the planning stage. PatientsLikeMe's Paul Wicks says that listening to what patients are saying before development starts means that companies can end up with a product that is more likely to meet patient need.

"We'd like to see pharma companies asking patients what the unmet need is. In the lab you develop a molecule that is very similar to another and it hits the target, the science is there, but it may not fill an unmet patient need. You might have a new drug that deals with a side effect or a symptom no one else has dealt with but when you look at the many symptoms that patients get, the issue that the drug resolves could be number 25 on their list of 80. It might pour a bucket of water over a development programme or it could easily become a real differentiator that drives how appropriate your products are for the market and how likely you are to get an approval
and then how likely you are to generate sales."

This does not have to be anecdotal, he adds. "We can query large numbers of patients, stratify their demographics, and ensure they are a representative sample. Then we run simulations of all the options for a drug, tweaking them to assess the impact of changing a dosing regimen or other factors. The idea is to build it into the decision-making process. This is not an advocacy role but a research one."

Such insights can give a whole new perspective on a disease, as UCB found when looking at Parkinson's disease, says the company's Lode Dewulf. "If you ask people in the industry what Parkinson's is about they'll say shaking and that's how all drugs were developed; how well do they control shaking? But we've talked so much with patients now that we've realised the hardest part of living with this disease is not the tremor, which is relatively easy to manage, it's other things like sleep disturbances and gastro problems that have a much greater effect on your life. That will drive your clinical studies and the drugs you go for."

As well as influencing the targets a company pursues, patient insights can determine mechanism of action and delivery, explains LEO Pharma's Gitte Aabo. "From interacting with patients we've learnt that if you have psoriasis on your scalp, in your hair, supplying our treatments in a tube or bottle is actually not very convenient if you want to have a precise dosage. One of our main treatments used to be an ointment, but it's like applying Vaseline to the skin and it's very greasy, so patients found it to be very sticky in clinical trials and did not use it in real life. So, we have developed a new formulation that absorbs quickly into the skin."

Andrew Schorr of Patient Power, is keen to emphasise that gathering these insights can be quick and easy for pharma. "It is lightning fast. We did a survey that got over 1200 responses, but we actually had 200-300 responses in the first hour, answering a very detailed 20-question questionnaire. Pharma would spend $100,000 or more to do the same and it would take a long time if they could even do it. We did it on a shoestring in a matter of days," he says.

Tailor-made trials  

Patient insight is increasingly being used to design clinical trials that patients actually want to take part in, helping to drive recruitment and retention, says Wicks. "A patient may not care about having a vial of blood drawn but they might care if they have to drive 200 miles or if the scientists want them to do an extra test procedure like an MRI scan that might be unpleasant. We can help pharma understand the extent to which this might increase or decrease interest and what concerns patients might have."

There are measurable benefits, he says, citing a project with Genentech. "The science team wanted patients to undergo a somewhat invasive and potentially painful procedure before the trial began but the physicians on the ad board thought that patients who had been through the test before would not be willing to go through it again. To test this, we sent a survey to 2,000 patients that met the inclusion criteria; only a third of patients said the procedure would decrease their interest in participating in the trial. In fact, the strongest reaction was from people who had never had the test so the biggest issue was fear of the unknown. By educating patients and by reassuring them that we would make it minimally painful and that it was an important test, this insight allowed the team to figure out the best way to train the study investigators and write the recruitment materials."

For Dewulf, the proof of the pudding is in the eating. "I have never met a team who engaged with patients to help them improve their study design who afterwards thought that it was a waste of their time," he says, adding that his company changed the way it designs phase I studies based on patient feedback. "By bringing patients in we found that they don't like the typical phase I, placebo-control study, because they are pretty sick and they don't want to miss out on a drug that might work. We told them that there is another study design, a delayed onset study, where you start half the patients on placebo and then move them on to the drug at a later stage. The patients liked that idea.

"They also said 'why does placebo have to be so long, at this stage does that really matter, don't you just want to know if the drug works for us?' They then pointed out that they can tell us in half of the time of the regulators. We agreed, so we've been simplifying studies and making them more interesting for patients and it's been wonderful."

Another important tool for determining what works for patients is study simulation, says Guy Yeoman of AstraZeneca. "We simulated a study in lupus, taking a group of patients and the investigator at the site and running through the proposed patient visit. From their input we had 24 recommendations, 16 of which were adopted, saving significant time and costs. The patients also felt more comfortable taking part in that study."

GlaxoSmithKline has found that helping patients understand the entire trial process in this way is beneficial for everybody, says Murray Stewart. "Educating patients is important. We ran a session with our health advisory board – which includes patient advocacy groups – where we took them through discovery and development, and explained what we mean by lead optimisation and what a phase I clinical trial involves. Before we did that I would have said there wasn't much value in involving patients in phase I, but the advisory panel said that was exactly when they wanted to be involved because the earlier they are involved the better influence they have."

Patients point out simple things that scientists don't think about, he says. "Scientists would love to do tests every week or they might want a fasting sample, but if you're trying to recruit elderly people there might be no point asking them to come in at 7am if their bus pass doesn't start until 8am. Patients might also ask if they could do a phone call instead of a face-to-face visit. We've since run cardiovascular outcomes studies using phone calls in-between actual visits and we've found that patients do come back after six months. Bringing patients into the scientific realm creates a sense of reality and adds a dose of pragmatism," he says.

"Another thing we're starting to do are end-of-trial questionnaires to ask what they liked about the study and whether they found the visits cumbersome or not. These are quite revealing and have helped alter our approach," adds Stewart.

Like many companies seeking to make their trials ever more patient-centric, GSK is increasingly looking at patient-related outcomes (PROs) or endpoints that are relevant to patients' everyday experience. "If you try to get a drug approved for respiratory, for example, the regulatory authorities want a change in FEV1 but you can't ask a patient whether their FEV1 has improved," says Stewart. "Patients say they feel less breathless, that they can walk further and they go into hospital less often because they've had less infection."

As a consequence, GSK has started designing respiratory studies that focus on factors such as a reduction in exacerbations, hospital visits and less costly admissions. "The endpoint of the clinical trial was a fall in patient impact, which is a much more relevant clinical endpoint for patients. It took a while to persuade the regulatory authorities but we did and our drug is approved. We are finding that uptake of the drug is very successful because patients, payers and physicians get the value of the endpoint."

The company is also using technology to demonstrate endpoints in clinical trials, particularly in rheumatoid arthritis. "What good is looking at an x-ray change on a joint when patients want to know if they can move better?" says Stewart. "We've partnered with McLaren, using the technology they use in Formula One where their drivers have practically everything monitored; reaction times, the turn of the steering wheel, range of movement. We're using these monitoring devices in some of our movement trials to measure hand movement, whether patients can clench their fist, seeing what range of movements they have at the beginning of the trial and again after therapy to see if there is an improvement."

Even after the study is completed, the patient still needs to be taken into account, says PatientsLikeMe's Wicks. "I've seen data that showed that nine out of ten people weren't told the results of the trial they participated in, which just sounds crazy. Also, most clinical trials are not published open-access so you could be in a clinical trial for two years about your cancer and if you want to read the results in detail you have to pay to download the journal article some years later. That is unacceptable."

Stewart, whose company has started to address some of these points, says that the problem goes beyond simple access to the article. "We've agreed to publish our results but even then they're not transparent to someone who might not be a scientist. If I said to you the study showed a certain P value and it reduced your risk of having ischaemic cardiac disease, it's gobbledygook to someone without a scientific background. So we're starting to produce plain language summaries, where we try to translate each study into very basic language – for example 'the study showed there were less heart attacks'. You think, why didn't we do it before? But, actually, it is quite challenging to summarise something because you don't want to oversimplify it and make it misleading."

While many companies are investing time and money in seeking patient insight, this is a new field with new challenges, says Wicks. "Many of the factors you need to consider are unique to a specific trial, to a specific disease area, to patient demographics. If a trial involves a once-daily pill or a spinal infusion, these are apples and oranges. What's more, people in pharma want to know the return on investment before they've done the study, and, of course, it's very difficult to say ahead of time. Right now, when you hold a physician ad board, are you able to put an ROI number on every comment a doctor makes? I doubt it, but we have reached a point where these kinds of activities are reflexive. With patient-centric approaches, at first, we may have to take a risk but with a view to collecting data as we go along."

He adds: "I believe patient input will become the norm in the next five years and it will become as unusual not to listen to patients in the design of studies and the way you run your business as it is today not to listen to statisticians or physicians."

healthy hoops 

HTA: Patient decision-making  

Many of these patient-centricity efforts will amount to nothing if health technology assessment bodies (HTAs) do not take into account what patients value when reviewing drugs – but thankfully many bodies have already adopted such an approach.

England's NICE both has patient representatives as part of its committee assessing drugs, and hears from patients with the disease in question – including those who have used the drug in a clinical trial – when reviewing an application.

"We get the opportunity to get real patient explanation of what's important to them and how that particular technology has affected their experience," NICE committee member Paul Robinson, who is also executive director, scientific medical and patient perspective at MSD in the UK, explained at eyeforpharma. "Value is in the eye of the beholder. There's no single definition. We did some work recently where we had a choice between a once-daily HIV medicine or a twice-daily medicine that was probably more effective. We actually had to go the patients and ask which they valued most, and a little to our surprise they preferred a twice-daily regime that was better, whereas the pharma industry mantra has always been that one a day is what you need. You need to actually go and ask people."

He added that on a number of occasions he has seen patient testimonies turn a potential 'no' into a 'yes' by conveying what's important to them and how the technology improves it. "There was one case where… the cost-effectiveness was not attractive, but we had a drug that cured people of this cancer. I remember the patient was a police constable, she'd just got engaged, and on a difficult call both her testimony about how the tumour had affected her life and how she was now looking forward to her marriage and to serving society played heavily in which way I voted."

Ultimately, Robinson thinks that companies demonstrating empathy and consistency with the patient experience will be most successful in HTA. "If a company is saying something, the patient organisation is saying something very similar, and the clinicians are saying the same it makes the committee's decision an awful lot easier."

Meanwhile, the Scottish Medicines Consortium has made significant efforts to make itself more patient-centric in recent years. It has set up a Public Involvement Network (PIN), which ensures the views of patients are used to inform SMC decision-making, as well as introducing a Patient and Clinician Engagement (PACE) process for end-of-life medicines and very rare conditions.

"The PACE discussion explores the quality of life benefits of a medicine which aren't always fully captured in the conventional clinical and economic analysis," explains Professor Jonathan Fox, chairman of the SMC. "Participants agree a final statement which gives SMC a better picture of both the impact of a disease on patients and carers and the potential quality of life benefits a new medicine could bring."

One recent recommendation from the PIN advisory group that was implemented was the embargoed early release of SMC decisions to submitting patient groups. "Under the embargoed early release scheme, submitting patient groups sign a confidentiality agreement to find out decision details five days ahead of publication," says Fox. "This gives them extra time to prepare all the support mechanisms they need to put in place for patients once the decision is published."

Continuous patient engagement  

Although the push towards patient-centricity has been pioneered in R&D, the benefits of seeking patient insights are clear well beyond drug approval and launch. After all, a product that has been developed with the patient in mind is simply more likely to be used.

Patient support programmes – sitting firmly within the marketing sphere – are increasingly being shaped around insight into the patient journey, says Peter Rutherford, vice-president of integrated market access at Quintiles. "Learning from R&D should be coming straight through to the post-launch phase planning. While there is still a key knowledge gap between the insights gained in the development programme and their use in practice, there is a role for both healthcare providers and pharma companies around supporting patients in decision-making and the taking of therapies."

This is especially true as therapies become increasingly complex, he says. "Patient-centric services can support adherence, scheduling, organisation, general wellness and keeping patients informed about the therapy they are receiving. For companies that are developing complex chemotherapy regimes, for example, which could require frequent infusions, the nature of the therapy is not a mystery on the day of launch. They know the regime from the very earliest stage of development and you need to plan for services to allow patient access."

So, what kinds of patient insights do companies need? "There is no one-size-fits-all model; it must be decided for each individual therapy, developing services that also need to change over time. You need to ask: what is the disease and what is the therapy? What are the real practicalities of the new product, whether a tablet, infusion, self-injection? What are the likely co-morbidities? What is the likely polypharmacy? You then need to look at the service or patient pathway to design a programme that is most likely to be effective and deliverable," says Rutherford.

One advantage of this approach is where a therapy involves disruption to an established care pathway. "Cardiology or lipid clinics are not used to the new biologics for lowering cholesterol, for example. So, when planning and designing support services, it is essential to consider how it will impact the current delivery setting. Then it needs to be executed in a compliant way, in a way which is compatible with all regulations and requirements of healthcare delivery, and where the outcomes are examined in terms of its effectiveness," he says.

Guy Yeoman offers examples of programmes that AstraZeneca has piloted. "One that stands out is Me and My COPD, an individual, personalised goal-based treatment programme. It was determined with insights from both the patient and the physician so the goals are individualised and meaningful for the patient. Through the use of smart technology linked to devices, the physician will know when the patient is using their inhaler, when the reliever is used more frequently and the patient is starting to deteriorate, and can respond accordingly for that individual patient. The outcome we are looking at – the effect of the programme on exacerbations and hospitalisation – is meaningful for the patient, the physician and
the payer."

He gives another example, in oncology. "LVNG With is a programme that enables patients with lung cancer to support other patients. They can feel very isolated and alone and don't know how to respond to their diagnosis and subsequent treatment and management. Through the programme we are connecting patients both digitally and face-to-face to share experiences and learn from each other, helping them to engage with their disease and feel more in control," says Yeoman.

In its patient support programmes, Teva strives to retain patient insight from its clinical trials, says Jason DeGoes, senior vice-president of global patient solutions. "When a drug is in the late stage of development, we start preparing the design of the patient support programme. We do a lot of work with our R&D teams to examine the clinical trial and determine what elements of importance to the patients might be lost in that post-approval setting. Even after five years under a clinical trial condition a patient is about 90 percent persistent, but in the first year after launch persistency drops by about half and efficacy drops with it. These elements that are more prescribed in the clinical protocol are things that we can build into the patient support programme to try and help them achieve that good therapeutic outcome."

Improving adherence is a key goal of its patient support programmes, says DeGoes, adding that to be successful in this area pharma must understand why patients are non-adherent. "Patients often become non-adherent to therapy because they don't understand why they're taking it to begin with or their expectations about the benefits or potential side effects are not accurate. If they think they're going to start feeling better straight-away and after a couple of weeks they don't feel anything, or if they have a side effect that they weren't made aware of in advance, they might discontinue. The other side of the coin is that sometimes the medicine will work and the patient will feel better, so then they stop taking it. We can talk to them about what they can expect; understanding what those expectations are, what the knowledge of their condition and their therapy is, is very important to designing a programme that works with them."

For a disease like multiple sclerosis, the prospect of injecting a medication three to four times a week for long periods of time, even the rest of their lives, can be quite daunting. "It's great for physicians to be able to say: Here's a service to help give you advice and education and training on how to go about that, what experience you can expect both positively and negatively."

Support programmes need to be tailored to each condition, says DeGoes, although there are some common elements to work with. "The expectations of a migraine patient are going to be different from the expectations of a Huntington's patient, or a caregiver for a Huntington's patient, but what they have in common, whether it's somebody with asthma or somebody with multiple sclerosis, is they're looking for the ability to control their condition rather than have the condition control them. If you've got a chronic condition, so much of your life is centred around how you manage or don't manage it, the amount of time spent going to physicians, taking therapies, seeking out different resources. Whatever we can do to alleviate that, to give them a feeling of more control over their condition, is a very positive thing."

Understanding patient behaviour and motivation is also crucial, he says. "It comes down to insights around their individual perspective and needs, and how they view not only their condition but their goals of therapy. They want to make it to some milestone, whether it's a graduation or a wedding. For patients with less life-threatening conditions it's often things like being able to go back to work or to play with their children. You can help build a plan that helps them have the best opportunity to achieve those goals."

The benefits of these programmes extends to the pharma company itself, says DeGoes. "If you look at the recent PatientView surveys, Teva is in the middle, which is not particularly good from my perspective. But, if you look in areas where we focus our patient support efforts, like multiple sclerosis, patient organisations focused on neuroscience have a very high perspective of our reputation.

"Patient support programmes in pharma were invented by marketing groups," he adds. "We've tried to step away from that paradigm. My people do not have commercial sales metrics; we have patient-relevant metrics. We track quality of life, we track patient satisfaction, we track very disease-specific things about what it means to an individual patient to be successful. We're not worried about meeting this quarter's numbers, and we're also not worried that if a change comes in the importance of a drug that something will change in the programme."

road arrows directions 

The right product  

New technologies are even enabling continuous patient engagement through the product itself, particularly the collection of data on how patients use drugs and devices.

Novartis has been experimenting with this approach in respiratory care, says David Epstein. "We signed a deal recently with Qualcomm where we're integrating chips into our Breathaler device for COPD. This means that patients can stay connected through their iPhones or iPads, with data collected that will be useful for them and their physicians to further adjust their disease treatment."

For UCB's Dewulf, patient-centricity can even extend to the packaging of a product. "With one of our products, the second biggest reason people were calling and asking for a replacement in the US was that they had put it in the freezer and not the fridge, because the instructions on the packaging were not very clear. We thought that was interesting, so we brought in a few patients and we learned from them what was misleading and simply adapted the instructions to make it more clear. Since then we've seen a dramatic drop in calls.

"Another example is where we brought patients in and gave them different packages to work with. Here we discovered that rheumatoid arthritis patients found it very difficult to lift the corner of some packages, so we experimented and added little round cutouts on the corner that are easier to slip your finger into," says Dewulf. "We've also just launched a new product in the US that is often given to people with mental disability, so if doctors ask them what dose they are on they may not be able to say. So, for each dose, we developed a different coloured package and matching pill so they'll know whether it's a blue pill or a red pill, which automatically tells the doctor what it is."

Abbott Diabetes Care has combined patient insight with technology at every stage to influence the development of FreeStyle Libre, a flash glucose monitor designed to alleviate the pain and hassle of routine finger pricking for insulin diabetes patients.

"You get a water-resistant sensor the size of a £2 coin which sits on the back of the upper arm and stays there for 14 days," explains general manager Mike Clayton. "With the simple swipe of a reader over the sensor, which works up to 4cm away and through clothing, the patient can collect data, which helps them make better decisions around their day-to-day monitoring."

Abbott developed a number of patient-focused initiatives to see what patients would want from such a device. "One of the biggest barriers to optimal glucose monitoring was the pain of finger pricking, which puts patients off doing it regularly. There's also the hassle of having to get all the equipment out, especially in public, and we had feedback that some people were viewed with suspicion when they got equipment out in a restaurant or when other people see blood. The second insight was that while the data generated by current finger prick systems offer an accurate result, it is at a single point in time. The challenge we were given by patients was to give them data over time in a simple way to help them make decisions. For example, if your sugar is five you don't know whether it has fallen from eight in the last hour or whether it's been stable."

Consequently, the company developed FreeStyle Libre to give patients not just a point-in-time glucose reading but also a directional arrow to better understand if their levels were stable or moving up or down. "It helps patients understand their glucose levels with a much greater depth and in a very simple way," says Clayton, who adds that feedback has been overwhelmingly positive. "We've had many patients come back and tell us that they can now get a proper night's sleep because, for the first time in many years, they're not scared about going to sleep because they know where their glucose levels are and where they are likely to go.

"The big learning we have taken from it is that designing products that people really want and value is hugely fulfilling. The challenge is to work out how you continue to listen to the real-life needs and challenges of the people who are going to use your products."