Patient-Centricity: A Drug Development Imperative
By Michael Dennis, Director of Technical Operations, Science and Technology, AbbVie and Bill Huang, Sr. Principal Research Scientist, Formulation Sciences, AbbVie.
Success in the pharmaceutical industry is about more than the efficacy of compounds. It’s about facilitating positive patient outcomes. We know positive outcomes are in no small part dependent on the patient’s acceptance and administration of—and ultimately their experience with—the therapies we create. The connection between drug manufacturing and patient outcomes is not in question; but how much is patient-centricity influencing the process of therapy development today, and how much room does the industry have for further patient-centric improvement?
The answer is increasingly clear. Progressive pharma companies and, subsequently, contract manufacturing organizations, are reimagining drug development from the patient’s perspective from the outset. Patient-centricity, as we’ve come to call it, is a movement that’s one part altruistic—it aligns with our industry’s mission of life-improving, outcomes-based pharma—and one part impressed upon us, the result of growing interest from regulatory bodies and advocacy groups to put patients at the nucleus of therapy development at even the earliest points of drug research and discovery.
The altruistic part is driven not just by a desire to meet patients’ growing expectations of information and transparency, but also by the acknowledgement that a sharper focus on aligning the attributes of therapy with patient preferences and behavior has a very real and measurable impact on the outcome of treatment. Those preference- and behavior-impacting attributes include, but aren’t limited to, the ease with which a therapy is administered, how it feels, how it tastes, the risk factors involved, the way it’s packaged, and the patient’s physiological reaction to it. In many cases, the manipulation of those attributes begins at the earliest stages of R&D and doesn’t end until patients experience positive responses.
Setting Patient-Centered Drug Development Goals
The end-to-end nature of patient-centricity in pharmaceutical manufacturing demands an enterprise-wide culture shift. Patients, along with providers and payers, are expecting more holistic health solutions. Incorporating the patient’s voice into drug discovery and development is becoming more common and important. That’s causing biopharmaceutical companies to reimagine drug design and manufacturing to tackle the challenges and embrace the opportunities presented by patient-centricity. Thinking through product design, development, and life cycle can translate into better patient experiences, compliance, and adherence. This includes defining, at the earliest stage possible, quality target product profiles (QTPPs) and critical quality attributes (CQAs) that take the patient experience into account to ensure not only the safety and efficacy of the new drug product in traditional terms, but also the patient experience to improve outcomes.
QTPPs include attributes such as dosage forms, delivery systems, routes of administration, dosage strengths, release profiles, and packaging. In determining these attributes, the consideration of patient needs and preferences is as important as the science behind the molecular entity. These attributes demand patient needs are understood early on to ensure patient acceptance when the therapy hits the market.
With patient preferences and behavior established and reflected, we can turn to aligning the CQAs of specific therapies with the attributes defined in the QTPPs.
In parenteral dosage development, for instance, one particular CQA of note is the compound’s rheological behavior which impacts the patient on several levels. Most obviously, this characteristic is directly related to the deliverability of the therapy; particularly for prefilled syringes and/or on-body delivery systems (OBDS). That’s why, during formulation and development, biopharma companies must address delivery issues including solubility and stability of the drug molecules. Additionally, highly potent and/or toxic drugs require more greater patient monitoring and compliance, while novel molecular combinations can also require complex manufacturing controls.
Similarly, the colloidal suspension characteristics, such as agglomeration, flocculation, injectability, particulate characteristics, re-suspendability, and viscoelastic properties, are key considerations in the manufacturability, pharmacokinetics, and stability of liquid oral drug products.
With the science understood, we must now acknowledge that these physicochemical attributes and variables can no longer be analyzed with a singular, myopic focus on efficacy. They also have a direct effect on ease of administration, impacting the patient experience long before the compound has the chance to prove its therapeutic value in patients. The product’s packaging, consistency, texture, and taste—and the physiological reactions and side effects they elicit—work collectively or individually to influence the likelihood of patient compliance with dosing instructions.
Patient-Centric Manufacturing Processes
As we seek to influence the manufacturing process with patient-centric outcomes in mind, there are tenets, some obvious and some more novel, to which we can subscribe. In solid oral dosage products, for instance, robust formulation design can minimize pill burden as well as mask unpleasant taste, improve swallowability, and minimize side effects. The optimal dosage form can make all the difference in whether patients will consistently comply with administration instructions.
Drug targeting to the diseased area and absorption window—which are often built into the formulation design—can also be employed to maximize drug efficacy and minimize adverse effects. Various enabling technologies help drugmakers address delivery challenges, depending on the physicochemical properties of the drug substance.
While effective dosing methods for more complex molecules are less straightforward, recently developed techniques are proving helpful. For example, amorphous solid dispersions are now commonly being used for poorly soluble compounds to improve bioavailability without compromising drug product stability. Hot melt extrusion (HME) and spray drying have proven to be promising techniques for the preparation of amorphous solid dispersions. Unlike other formulation options, HME technology is solvent-free. By drawing on continuous processing, HME is not only more efficient using a smaller manufacturing footprint; it is a well-controlled process, ensuring robust adherence to CQA requirements, which ultimately align with the patient-centric mission of modern drug development and manufacturing.
Using proprietary HME equipment that runs from 18 to 70 mm, we’ve successfully developed, scaled-up, and commercialized many challenging chemical entities. The process involves distributing active pharmaceutical ingredients through a polymer matrix to form a solid solution with known potency and bioavailability. Through this process, pharmaceutical HME can improve both drug efficacy and drug delivery efficiency. Sometimes, more complex oral formulation approaches are selected, such as multilayer tablets and multiparticulates, to modulate drug release profiles, improve drug stability, reduce food effects, and so on.
In a pioneering move in the mid-2000s, HME technology was leveraged to great patient benefit with the development of amorphous solid dispersion formulations of poorly soluble drugs. These melt-extruded products exhibit significant enhancement in the bioavailability of active substances over alternatives like soft-gel capsules, resulting in improved stability and a variety of other enhancements such as improved palatability and side effects. These improvements are patient-centric to the core. They led to an economical alternative for global distribution of treatments that previously required stringent refrigeration controls in transport, greatly reducing supply chain complexity and improving accessibility in developing markets. This illustrates the strategic role that drug developers and manufacturers play in the patient-centric development and marketability of biopharmeceuticals.
Demographic Considerations In Patient-Centricity
It’s accepted that issues with administration frequency, pill burden, side effects, and compliance are more prevalent among certain types of patients. Geriatric and pediatric patients, for instance, face specific user experience obstacles that can adversely affect their outcomes. Understanding what these populations face can lead to better decisions in formulating therapies that meet their needs.
Geriatric patients, for example, commonly require multiple medications each day and even every few hours. This adds complexity to dosing schedules, which places a burden on patients to map out or remember which medicines to take, when, and in what combination.
Conventional approaches to drug delivery have proven less than optimal in pediatrics, where developmental status and dosing requirements are considerably different from other subsets of the general population.
In both cases, different formulation designs are required to aid the development of age-appropriate medicines to maximize patient acceptability while maintaining safety, efficacy, and accessibility. Long-acting intramuscular or subcutaneous injectables are one relatively recent patient-centric development that can improve absorption window targeting and dosing frequency in affected populations. Parenteral injectable delivery systems are now frequently considered for large molecule biologics and some small molecules with poor oral absorption, improving the patient experience by reducing the dosing frequency. Easier-to-swallow oral formulations also benefit both example demographics highlighted here.
Patient-Centric Packaging Design Challenges
One particularly vexing challenge to the patient experience, especially in the context of age-specific therapies, is packaging design. Many biopharmaceutical companies have focused on innovation in packaging design and manufacturing in the past decade, turning what historically was simply a repository for medicine to an important enabler of specific treatments. Packaging design has evolved from being less about what’s good for distribution and more about what’s best for the patient.
Human factors testing is now a valuable source of feedback, where the patient voice is directly influencing package designs. Making the packaging easy to open for people with dexterity issues, providing directions that are simple to follow and being visually appealing are examples of simple innovations in packaging design. Making complex treatment plans easy to understand is also key to ensuring patient compliance and effective outcomes.
Drug manufacturers are even leaning into applying patient experiences to injectable dosage forms, which, historically, have been both expensive and impractical from an in-home user experience perspective. Parenteral formulations in conjunction with devices, from prefilled syringes to more complex delivery systems, are one example, whereby prefilled single-use packaging ensures the right dosage is always delivered to the patient.
Regulatory Bodies Advocate For Patient-Centricity
Among the chorus of calls for patient-centricity in drug development are regulatory bodies, which are embracing standards that drive not just efficacy and safety, but also the patient experience. Ease of use and error mitigation are important human factors that regulators are considering, and they’re calling on drug manufacturers to draw on real patient experiences to shape their patient-centric initiatives. Draft guidance issued by the FDA under the 21st Century Cures Act states that sampling methods during development should be used “for collecting information on the patient experience that is representative of the intended population to inform the development” of medical products. Both the FDA and the European Medicines Agency are focused on how best to assess the patient experience, and therefore are expecting more patient-reported outcomes in clinical trials, as these assess outcomes that are important to patients, not just doctors and regulators.
What’s Next For Patient-Centric Pharma?
As we continue to measure the benefits of patient-centricity in drug formulation and manufacturing, we anticipate that the innovation driving drug deliverability will only accelerate. Digital technologies, still nascent in the bio/pharma space, will prove transformative as they help uncover previously unseen insights. Individualized medicine will continue to be a market driver, and pharma will be more effective in targeting disease and delivery for specific, localized disease. There’s promise that the expenses historically associated with individualized medicine will be mitigated to some degree by technologies like artificial intelligence, which will bring large-scale efficiencies to small-scale projects. Increased patient dialog, hastened in part by mHealth initiatives that leverage the ubiquity of mobile communications devices, will inform the industry’s approach to patient-centricity at an unprecedented level. While our challenges are great and growing, so are the tools and technologies enabling the innovation required of patient-centric therapy development.
To learn more about how AbbVie can help with your drug development efforts, contact us at www.abbviecontractmfg.com.