Patient approach – tailoring therapies to individual needs

Patient non-adherence is a major problem. It has been estimated that up to 60% of patients do not follow the dosage instructions given to them by their doctor, and while there are many conceivable reasons why instructions might be ignored, sometimes it comes down to something as simple as appearance. A study carried out last year by the Brigham & Women's Hospital in Boston, US, for example, found that patients were 34% less likely to refill their medication if the pill changed colour, and 66% less likely if it changed shape.

It's no longer just a question of tablets, either. Driven by the efficacy and immunogenic natures of large biological medicines, and the poor oral bioavailability of the majority of emerging chemical entities, drug-device combination products are playing a major role in the pipelines of pharmaceutical companies. There is a need for the design of such medicines not only to be innovative, but also to maintain market competitiveness through enhanced patient compliance.

Knock-on effects

After all, non-adherence affects the whole business of drug development. If patients don't take their prescriptions, they don't get better; developing long-term cures becomes harder; and determining the efficacy of treatments is made much trickier. But Sven Stegemann, professor at Graz University of Technology, believes there is a clear solution to this problem: involving subjects in the creation of drugs that will be used to treat them, in what is known as 'patient-centric' development. He has chaired an AAPS-led focus group on these methods for a few years now, working with other luminaries from academia and organisations, such as Johnson & Johnson and Merck, to present the concept to the broader pharmaceutical community.

"The solution is to involve patients as much as possible," he says. "But if you look into the way we usually do our clinical trial programmes, it's quite funny. As soon as the patients enter the trial, the product is blinded, and often the final product that goes to market has not even been evaluated in the concerned patient population. Patients' ability to manage and administer drugs as intended is never established.

"Sometimes, a patient will have multiple morbidities: these are things we have to consider when we develop a drug product. For example, there is evidence of a high prevalence of swallowing issues among people with dementia that prevents them taking large, single-unit tablets. Some patients with diabetes are visually impaired, and get confused with 'white tablets', as they normally receive five or more drugs at the same time. Consequently, non-adherence, medication errors and tablet-crushing will most likely occur, and these affect drug safety and effectiveness."

He uses the case of disabled and elderly patients as good examples of where centricity and better understanding of individual needs is crucial: for them, traditional therapies might worsen a condition before making them better.

"Some of these patients have mobility issues, which means they can't go to the grocery shop and so are malnourished; others are dehydrated from incontinence, or because they have swallowing issues," argues Stegemann. "These issues might cause serious therapy outcomes: patients can suddenly collapse or be completely confused. You find them in delirious state, and they get sent to the hospital for several days, get examined and released and then show up again just a few months later for the same reason.

"This type of thing casts a shadow on the effective use of healthcare resources, which, in these cases, are neither benefitting the patients, nor our healthcare systems. The pharmaceutical industry can and must play an important role here in helping patients through patient-centric products."

Group therapy

As available treatments diversify, and pharmaceutical products find new cures for more conditions, drug therapies and patients become increasingly complex, prone to divergence and nuances in a way that, a generation ago, may not have been the case. All this is contributing to an environment in which, more than ever, patients are divided into many diverse groups with differing needs.

One strength of patient-centric drugs is that their development models take demographics into account, as they are developed for defined groups of patients with specific needs. Patients are not a homogenous group, and if you go to the people who will actually be taking the medication and work with them, their treatment becomes more in tune with their needs. It's about developing the right profile for the product for a specific patient population.

Often, difficult side effects play the biggest role in non-adherence. Beta blockers, for example, and other similar types of treatment for cardiovascular issues, are particularly symptomatic of this problem, according to Stegemann, with side effects that range from dizziness to fatigue causing some of the poorest adherence rates for antihypertensive drug classes such as beta-blockers and diuretics.

"People no longer take the drugs, which of course interrupts treatment," he says. "Here, for example you can circumvent these issues with patient-centricity, by developing fixed dose combination products, and then these side effects are not experienced in the same way and people continue to take the medicine."

A big part of the solution lies in improving cooperation between different actors at all stages of the process, and Stegemann argues that a crucial reason for patient-centric treatment's lack of exposure comes down to how the pharmaceutical industry drives interdisciplinary and multidisciplinary resources.

"That's what it comes down to, ultimately, and I think we need to develop some kind of collaborative environment and shared responsibility," he says. "We want to create a situation in which every stakeholder is working in the same direction."

"Product design is definitely one example of the real power of context in non-adherence, and where needs could be taken into account. Drug delivery can be improved, even by just giving the product an, easily identifiable colour, or colour combination. If every drug comes as a small white round pill, people are lost."

Adherence is not just about taking medication, and a wide range of interventions are made where chronic diseases are concerned; treatment can be as much about face-to-face relationships with medical professionals as it is about pills. Patient-centric drug development is all about staying with the potential patient throughout the whole course of the drug development, a process that, as yet, does not have a defined methodology behind it.

"This is what patient-centricity means, you go to real life patients and you want to test a product, so people will be able to use the drugs correctly," argues Stegemann. "You can monitor the future drug usage with complex patients to make sure they get the correct outcome."

"We don't have one yet, but it could be feasible to have a very simple methodology with this. You can test a product just by giving it to patients and seeing how they use and manage it. Simple observation yields data points, such as how much time patients need, how many errors they made and so on. These enable you to put the other drugs the patient receives in a context, and see how the patient is able to manage a typical therapeutic schedule."

Mind the gap

Patient-centric drugs simply work better, Stegemann argues, and their increased use and popularity is partly filling what is known as the 'efficacy and effectiveness gap'. Integrating patients into the product design process early on will prevent later reformulation, or product modifications, and will also help to streamline the development process.

"Efficacy is all-important in clinical trials: you take a section of the population, give them the drug and prove its efficacy," he says. "This is fine until you go into the real market and give it to a real patient, and find that you cannot reproduce that effect.

"Then you see that the effectiveness in real life is not the same as was found in the randomised clinical trials, because patients are not able to manage the drug product properly for various reasons. These forces driving centricity are increasing adherence, reducing medication errors and inappropriate drug modification, and avoiding complexity."

The industry has not always kept up to speed with these developments, put off by the higher costs that centricity can often bring. As with many developments in the pharmaceutical industry, though, the growth of patient-centric products is being driven by a new market demand.

"This is going to become standard practice," Stegemann argues. "Innovators will start to reflect more about the patient, and how they can improve the therapy further. It's all about better outcomes and more effective use of healthcare resources that will justify reimbursement. Not to forget the increasing patient power and information access that will drive the demand in a new way."

Centricity's growth is due to its increasingly central role in developing medicines for the over-65s - prescriptions for whom constitute 70% of all drugs prescribed - and this explains why nearly every major pharmaceutical company has adopted it as a strategic priority.

"There are a lot of things going on," Stegemann says, "but it's not something that is being tried out in public, as we are just building the science and knowledge around this topic. Like in OTC, however, it will soon become a reality."