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Laura Child is CRO Sector Lead at ramarketing
Oral solid dose formulations (OSD) continue to lead the market as a preferred dosage form. To gain better insight into drug dose delivery technology trends, Laura Child spoke to leaders from five top contract development and manufacturing organizations to find out what is on the horizon for patient-centric drug delivery.
Contract manufacturing leaders offer insights into drug delivery innovation and development.
As more of the world gains access to healthcare, the demand for safe effective therapeutics of all kinds will continue to grow. This broad global acceptance of pharmaceutical-based medicine has accelerated the development of more sophisticated medications to treat the unmet needs of an increasing number of patients.
Not surprisingly, the market for all pharmaceuticals has been dominated by North America, followed closely by Europe. However, with an increasingly ageing population and growing spending on healthcare per capita, demand for pharmaceuticals in the entire Asia-Pacific region is expected to see significant growth for the foreseeable future.1
Because of their inherent patient centricity and ease of administration, oral solid dose formulations (OSD) continue to lead the market as a preferred dosage form. According to the US FDA Center for Drug Evaluation and Research (CDER), of the 38 small molecule drugs approved by the agency in 2019, 26 (68%) were OSDs (19 tablets and 7 capsules).2
Pharmaceutical development and innovation is coming from both drug developers and their contract manufacturing partners. Pharma is relying more and more on external partners to provide the capabilities and technical solutions they need to deliver their formulations to explore the new modalities, personalized genetic therapeutics and chemistries being introduced.
To gain better insight into drug dose delivery technology trends, Laura Child, CRO Sector Lead at ramarketing, invited leadership from five top contract development and manufacturing organizations (CDMOs) for their input and perspectives on what is on the horizon for patient-centric drug delivery.
Putting the patient in the spotlight
Regulators are providing more drug development opportunities for therapies in certain preferred categories, assigning special regulatory considerations to speed up their approval process. R&D investment is following these opportunities and more focus is clearly being directed toward genetic-driven disease targets, orphan drug development and creating therapeutics serving the needs of smaller patient groups.
What is driving patient-centric approaches?
This focus on treating patients with more effective treatments is prompting drug innovators to integrate patient-centric principles at the earliest stages of drug development. This increased targeting can help achieve better clinical outcomes and ensure pharma companies can develop more effective drugs while improving their therapeutic value with formulations that treat disease more efficiently.
What considerations are important for patient centricity?
As early as possible in the drug development process, it’s important to understand which approaches will offer the most therapeutic value to patients. Obtaining the required bioavailability in pursuit of therapeutic targets begins at the formulation stage and involves addressing issues related to dose concentration, form, and administration routes.
Ease-of-administration and fewer negative side effects are just a few of the more critical aspects of formulation that drug developers need to consider for good patient compliance. Minimizing or eliminating the pain involved in administering the effective dose, as well as decreasing the number of dosing events in the first place, ensure that a drug is easier for a patient to deal with.
Most pharmaceuticals prescribed by modern healthcare are self-administered — and this is especially true for oral solid dose medicines. The therapeutic value and health benefits of a drug compound can only be realized if patients follow the course of treatment properly.
Study after study has demonstrated that dose compliance is essential in treating chronic disease and other conditions cost effectively. These studies also confirm that the more inconvenient a medication is for a patient to take, especially those required to take doses routinely over long periods of time, the less likely they are to take it correctly. That has a tremendous impact on health outcomes and the costs associated with treating the disease effectively.
What’s on the horizon?
Emerging generics and biosimilar competitors (among others) are pushing pharma companies to adopt more aggressive development and product life cycle strategies.These advances and pressures have also made the industry more willing to invest time and capital going after more sophisticated and complex formulations and dosage forms.
To compete, drug developers need to either grow these capabilities in-house or acquire them through more strategic partnerships with third-party contract services providers.
It’s likely we’ll see a continued rise in pursuing the development of insoluble drug compounds and a more sustained effort exploring orphan indications. In order to deal with these future needs, flexibility of mindsets and manufacturing facilities will be a continued requirement and will address the ongoing drive to put the patient at the center of drug development and administration.
Contract manufacturing partners will play a critical role in patient centricity
Patient centricity has always been a vital concern that now only grows in importance as new diseases, some requiring urgent solutions, emerge across the globe. No patient should be left waiting for an urgently needed treatment, cure or vaccine. The pharmaceutical industry, including contract manufacturers, play a critical role to ensure that medicines reach the patients in need reliably and quickly.
Research suggests that by 2040,3 patients, rather than health providers, will be the decision makers determining when, where, and with whom patients engage for their care. This will change healthcare fundamentally and industry leaders must get ahead of this curve, working continuously to truly understand and address patients’ key needs.
Consequently, pharmaceutical manufacturing organizations must strive to grasp how science and innovation can render manufacturing to be more resourceful, more effective and faster. Agility will be key.
At Pfizer CentreOne, we regard our customers’ patients as our own and approach the drug development and manufacturing journey together. A current case in point is the Pfizer “Five-Point Plan”4 to battle Covid-19, within which we make our manufacturing capacities available to enable other companies to bring lifesaving breakthroughs to patients.
Knowing that so many patients count on us for their health, which is a truly personal matter, is my key motivator and makes me bring my best self to work every day.
Creating better patient partnerships and clinical research outcomes
Patient safety has been the primary focus of clinical trial design since 1947 when the Nuremberg Code outlined the ethical guidelines for clinical research. Trials must be designed to avoid injury or suffering, and patients must give consent and are free to leave the trial at any point.The current world of drug development governed by ICH-GCP makes it mandatory to have all necessary steps taken by sponsors, CROs and investigators to keep patient safety as utmost priority.
The role of patients in pharmaceutical drug development is fundamental. However, the change now is around how we involve patients in the drug development process as partners and not just as participants. This is largely referred to as patient centricity.
Engaging people, not patients
Becoming more patient-centric in clinical trials starts by engaging patients more as individuals — people not patients. If research partners can design studies focusing on outcome measures that are meaningful to an individual patient, this is a move towards becoming more patient-centric.
To gain patient centricity trial designers are increasingly:
Selecting endpoints that are meaningful to the patients and easily understood. These might be characterized by levels of tiredness or pain and can be used alongside the traditional measures of symptoms or disease progression.
Designing the study with the patient experience in mind. The number of clinical visits and the time of day and clinic location all impact the patient experience. Complicated treatment regimens can diminish willing participation and jeopardies data quality.
Providing a report written with the patient, not the clinician in mind. These are known as Plain Language Summaries and are in addition to clinical study reports. When patients can understand the results of the study, the better they will feel about the whole experience. This is currently not mandatory, but industry expects it to become a regulatory requirement.
Taking advantage of the cloud to communicate and monitor patients remotely. With the advent of smart phones and applications, it is possible to collect actionable data in real time.
Mining rich trial data for patient truth
To understand and move closer to patients, trial designers need data. Biometric experts have much greater latitude in collecting trial data.5 Electronic patient-reported outcomes in real-time offer researchers new ways to assure patient safety and the clinical assessment of the candidate. Advances in artificial intelligence and machine learning are helping trial designers reach out to patients and connect them to the right clinical trials.
The integration of mobile health (mHealth) tools can generate large streams of data that researchers can explore, analyze and draw conclusions from. By creating a rich data-centric environment, researchers have a more accurate picture of the patients’ reality, avoiding having to rely on patient recall, and possible bias to the data caused by inaccurate recall, or influences of patient perception.
Currently, 50% of sites are unable to enroll more than a single patient and 85% fail to retain enough patients to continue. When trials are designed to improve the overall patient experience from the outset, they may attract more participants and improve protocol compliance.
The 21st Century Cures Act in the US is a classic example where governments and regulators are placing serious emphasis on patient-focused drug development.The Adaptive Pathways approach from European Medicines Agency (EMA) is another strong example, which aims to enable timely access for patients to new medicines.
In the space of just 70 years the industry has moved well beyond patient consent and is beginning to embrace patient centricity. The benefits of integrating patient centricity into clinical trial design are far reaching, helping create better trials, better medicines and better patient treatment outcomes.
Connecting the API to the patient
A patient-centric approach has always been core to MedPharm’s development philosophy. Patient centricity is getting increased focus now that a greater understanding of molecular biology and genetics is available to help define the unique needs of individual patient groups.
Development starts with the discovery of an active pharmaceutical ingredient (API) for potential use against an unmet or underserved medical need. Even at the very beginning it's important to emphasize to clients, many of whom are small speciality biotech start-ups with limited funding, that even at the very beginning of the development cycle it is crucial to consider how the patient will apply the product or administer the dose.
It is recommended to complete a detailed product profile questionnaire prior to the initiation of any formulation work, and this should be continually reviewed at each step in the process once it begins. This forms a fundamental part of the risk assessment at all stages of a project and ensures that the development program is always focusing on the end goal of improving the quality of life of patients.
The needs of the API and the needs of the patient must be married to create a stable and effective product that will be convenient and even desirable to deliver.
In the area of topical products, for example, the incorporation of superior aesthetic properties can be the difference between a successful or unsuccessful commercial product. In the case of orphan drug products, it can be useful to engage with patient support groups to ensure that their specific needs are considered throughout the program and achieved upon conclusion.
Interestingly, our pioneering work on advanced in vitro models based on human tissue, which are used to optimize formulations, has started to untangle differences between donors. These insights could allow these models to be predictors of a drug’s clinical behavior and support patient centric development programs.
Packaging a top patient-centric priority too
Packaging has always been a crucial factor to make dosing convenient for patients and hence for improving administration compliance. In the future, we believe this will be connected more and more with technology for monitoring and compliance purposes.
It is an exciting time in the drug development industry. The COVID-19 pandemic has focused the industry’s attention on the value that technology and innovation can bring directly to patients, as well as the expectations governments and populations place on health and well-being.
Patient centricity during drug development and commercialization
Patient adherence remains a major consideration for pharmaceutical manufacturers. Medication works effectively only when patients take the right amount at the right time in the right way, yet more than 60% of patients forget to take their medication.6 To improve efficacy and health benefits, drug manufacturers must build in patient centricity during the development and formulation stages.
Before any considerations can be made, it is important to know and understand why patient adherence is poor. For many patients, taking medication is unpleasant be it taste, difficulties in swallowing or inconvenience, for example not being able to take certain medications with food.
Furthermore, certain patient populations are particularly prone to non-compliance. The elderly, for example, tend to take many medications each day, which can be complicated to remember. They can also struggle with certain packaging.
Opportunities to improve adherence
There are many opportunities to improve adherence by offering better drug products. Developing these new products is significantly less expensive than developing new chemical entities (NCEs). As such, patient-centric formulation is one area where pharmaceutical companies can obtain the best results per pound spent on development work.
Dosage forms can have a direct impact on patient compliance rates. Extended-release products reduce the number of dosing occasions — a clear benefit for those who forget to take their medication. Making oral dosage forms easier to swallow and better tasting will also aid compliance, as would producing creams that are easy to apply.
Injectable dosage forms are often deemed impractical and expensive, but in some cases, parenteral depot formulations are an excellent method of ensuring the right dosage is delivered to the patient. Making injectable formulations more patient-friendly is another focus for developers, resulting in new formulations and new devices to deliver these drugs, safely and comfortably.
When developing new drug products, companies face a plethora of delivery challenges. There are, however, technologies that can improve the patient-centricity of a drug formulation. Modified release formulations offering flatter drug plasma profiles for example can reduce adverse effects, improve therapeutic effect and reduce the number of daily doses.
More therapeutic power and convenience with each dose
Fixed-dose combination (FDC) products are another emerging drug delivery technique that supports better patient compliance, because the frequency of doses and number of medications to take is simplified. Given the possibilities of personalizing therapeutics, the potential to economically offer individualized FDC products to suit different patient groups is emerging right now.
Innovation will continue to drive patient centricity
Innovation and creativity continue to thrive and impress in the sector. The trend in non-oral formulations to allow for local treatment looks set to continue, as it could significantly reduce adverse effects. Using advanced technology has cost implications, particularly for products designed for smaller patient groups. Companies that have development scientists with a good understanding of industrial-scale manufacturing have a distinct advantage.
Engage development partners earlier for better patient-centric delivery solutions
Major as well as pharmerging markets around the world are demanding more pharmaceuticals and more from pharmaceutical developers than ever before. All drugs, no matter what the route of administration, have to do more than ever to meet patient and payer needs. They have to be safe and effective and above all designed for the patient.
One thing all five contributors agree on is that the more complex the dose formulation or delivery mode, the more it makes sense to introduce the program as early as possible to development partners. The efficient development of a safe, effective oral or topical medication hinges on so many things, but it is clear that if patient centricity issues aren’t addressed it will likely never reach patients successfully.
Laura Child is CRO Sector Lead at ramarketing.