Winning design: Designing drugs for better patient adherence

Chris Halling, director, global communications & marketing at Catalent writes about how drug design affects patient adherence.

For many years, the conventional thought behind drug design and formulation is that a once-a-day, orally taken tablet is the most suitable option for patients. However, the industry faces many challenges to ensure that products that are brought to market are not only efficacious, but are also convenient for the patient. Drug innovators are now considering the ‘appeal’ of new products to patients much earlier in the development process, and employing intelligent drug-design to drug substances, drug products and packaging, to assess how outcomes and drug adherence can be affected, and where more patient-centric designs can be of benefit.

Patient drug adherence is a major problem and there are multiple factors that can lead to non-adherence such as the route of administration, pattern and frequency of dosing, ease of administration, length of treatment, and drug side-effects. Studies have shown that as the number of medications taken by patients per day increases, adherence begins to decrease.

This in itself leads to issues with some patient groups, such as those at either end of the age spectrum who may have difficulty swallowing; or cancer patients whose drug regimen may be very complex; so for those companies looking at how drug design and patients’ needs can be harmonised fully, there are multiple factors to consider. For drug formulation scientists and dose form developers, the challenge is to bring new innovative technologies to market in order to overcome these and to understand the critical needs of the patients.

Changes in drug design get more costly as products progress through clinical development and so to maximise the benefits that can be achieved, modifications that are currently often carried out as late as Phase I, need to be considered much earlier. For patient-centric design to be truly beneficial, the process needs to be intentional, rather than implicit, and should start with a clear understanding of patient outcome-driving factors during the medicinal chemistry phase of development. This includes determining some of physical properties of the drug, such as the correct salt form and polymorph, so that the optimal form of the molecule progresses forward.

It is at this pre-formulation stage that the best formulation approach can be identified and confirmed in animal models to bridge the gap into clinical evaluation. Early dose form selection can take place with a view to ensuring it enhances the patient outcome. That initial optimised formulation should be taken into Phase I, and then, with the best dose form, into Phase II studies. It may be appropriate however to structure a comparative Phase II study if there are multiple patient-focused dose form options.

Finally, following further optimisation of formulation and dose form within Phase III studies, structured appropriately to also build evidence of advantaged patient-focus design for the product versus comparator marketed products, comes patient-focused packaging and labelling design.

The industry is reacting to these developments, albeit at differing rates, and there is a great deal of research focusing on drivers of patient treatment, discontinuation, and adherence published each year. Companies that tend to be at the forefront of adoption include niche innovators, who focus on a few therapeutic areas such as diabetes, or speciality companies focused very precisely on treating one disease or patient population. These companies typically nurture very close relationships with patients, caregivers, and advocacy groups in their area of disease focus, and look to understand the patient’s whole treatment regimen, including concomitant diseases, and put NMEs in development in the context of current competitive treatments and other drugs that typical populations, or subpopulations, of patients currently take.

Opportunities in patient-centric solid-dose formulations

While the ultimate goal of any drug development needs to be in the patient’s benefit, for pharmaceutical companies, a return on their R&D investment is crucial in order to be able to continuously develop and provide novel treatments. By incorporating patient-centric approaches in drug development, pharma companies and innovators have the opportunity to directly demonstrate benefits to patients with a view to these being valued not only by patients, but also by regulators and healthcare providers. Consequently, return on investment should be higher for pharmaceutical companies investing in patient-centric approaches.

In order to maximise the application of patient-centric drug design, many pharma companies are seeking collaborations with experienced external service and technology providers to combine expertise in the core areas. To make these collaborations as valuable as possible, it is important to stay focused on patient needs and use individual technologies as a means to an end. From that perspective, working with an external partner who provides multiple technologies to select from when addressing a specific patient need can be more attractive than working with a provider of a single-technology, since any potential technology bias can be easily minimised.

Patient centric oral dosing technologies

To meet the patients’ needs and overcome the challenges the small molecules currently in development, many of which have either poor solubility, or poor bioavailability – or even both – formulation scientists have turned to a number of technologies to assist in dose form development. It is important to note that many of the developments in dosage development that have been made recently are as a consequence of implementation of intelligent drug design, where the focus is on the enhancement of patients’ experiences. For innovators and developers looking to focus on patient-centric benefits, a mentality must be adopted whereby it is not acceptable to settle for drug substance or product characteristics that are widely known to impact patient outcomes; be that by limiting patient compliance, increasing safety risk, or side effects, or underserving a specific sub-population of patients.

As a Contract Development and Manufacturing Organisation (CDMO) in this field, Catalent offers a number of advantages to innovator companies, not only in a wide number of dosage forms, but also in its expertise in assisting and launching hundreds of new products each year. The technologies it offers in oral dose forms include:

Controlled release technology

Across a number of dose forms: tablets, capsules and other formulations, there are a number of technologies that can be employed for sustained/modified drug substance release to increase a drug’s efficacy, and reduce the patient’s pill burden.

Patient preferred softgel solutions

Developments in the proven softgel technology to accommodate patient-centric design include coated softgels, which provide optimal drug release profiles, helping enhance both therapeutic performance and patients’ experiences. Different types of coatings can be applied to help enable targeted delivery, modified release, reduced side effects, better API stability, and even fixed dose combination.

Orally Disintegrating Tablets (ODTs) such as Zydis technology

Catalent’s proprietary fast-dissolve tablet, is a unique, freeze-dried oral solid dosage form that disperses within in the mouth, typically in under three seconds and with no water required. With more than 20 products launched in 50 countries, Zydis fast dissolve continues to be the world’s best-in-class ODT technology used to enhance pharmacokinetics, improve patient compliance, or seeking a marketing advantage for a valued brand.

Soft Capsule Technologies

Using a unique, patented shell derived from plant polysaccharides, bioavailability and solubility issues can be overcome, going beyond conventional softgel technology. Allowing higher temperature fill formulations, and a wider pH range for semi-solid and highly viscous fill formulations, as well as accommodating a wider range of compatible fill excipients for enhancing drug bioavailability and stability, the technology also gives the potential to modify or extend the release of compounds from softgels.

Although the consideration of a patient’s needs would appear an elementary priority for anyone engaged in a development programme, it is sometimes difficult not to compromise on the ideal dose form and dosing regimen when dealing with the realities of a challenging molecule, or a development programme that is required to meet multi-site clinical trials and for a global launch. Even scaling up from clinical to commercial volumes can compromise the success of a programme and yet, these later stages of commercialisation are difficult to fully visualise, especially when a new drug delivery technology is selected. The choice of a development partner that is experienced in a variety of drug delivery technologies is key, but choosing one that is also familiar with the realities of successfully launching products to a global market, that can help with network supply strategies, and that crucially, can help overcome unforeseen problems that may arise later, is hugely beneficial to developers, and ultimately to the patients for whom the products are designed