Patient‑Centric Drug Development Comes of Age

In light of the fact that patients are generally becoming more informed, with immediate access to information for many, it is unsurprising that bio/pharma companies’ approaches to drug development are shifting. Factoring in the trend toward targeting niche disease areas and increasing focus of regulatory bodies on patient experiences, patient-centric drug development becomes an apparent inevitability.

“Whilst the need for patient centricity has always existed, the focus on it has never been greater,” explains Ronak Savla, scientific affairs manager, Catalent Pharma Solutions. “Every dose design decision during development has the potential to influence patient outcomes. Besides safety and efficacy, patient-centricity should be the foundation of creating a target product profile.”

Agreeing with Savla, Stewart Griffiths, product commercialization manager, 3M Drug Delivery Systems Division, adds, “Nowadays, patients expect to be more involved in managing their own health. We live in a world of empowered patients, who are better informed thanks to digital media and the Internet.”

The incentive for companies to focus on and involve the patient during drug development is that the end product is more easily accepted and used by the patient, Griffiths further explains. If issues surrounding the use of different treatments and therapies can be overcome then the likelihood of market success should be increased, he states. 

“Patients, along with providers and payers, are demanding more holistic health solutions,” says Michael Dennis, director, operations science and technology, AbbVie. “Thinking through product design, development, and lifecycle can translate into better patient experiences, compliance, and adherence. This includes defining, at the earliest stage possible, the quality target product profiles (QTPPs) and critical quality attributes (CQAs) to ensure the safety and effectiveness of the new drug product,” adds Bill Huang Sr., principal research scientist, formulation sciences, AbbVie.

Therapeutic value and the importance of adherence

“It’s important to understand as early as possible which approaches will offer the most therapeutic value to patients, and that includes the proposed compound’s path to treatment and dosing regimens,” notes Kim Zubris, formulation director, Particle Sciences. “Obtaining desired or required bioavailability in pursuit of therapeutic targets begins in formulation and often involves addressing issues related to dose concentration, form, and administration routes including oral solids and liquids, inhalants, intravenous, long-acting injectables, and topically administered medications.”

An analysis performed by the Catalent Applied Drug Delivery Institute, which looked at new drug approvals since 2009, revealed that approximately two-thirds of the drugs were not ‘outcomes-optimized’, in terms of API-wasting formulations, addressable side effects, low bioavailability, and regimen complexity, among other factors that should have been considered, reveals Savla. “Combining the biopharmaceutical and physicochemical knowledge of a drug molecule with how it impacts the patient’s experience should be undertaken early,” he says.

There is tremendous onus on the patient to take the medication correctly-the right amount, at the right time, in the right way-to ensure it is effective, confirms Torkel Gren, senior director, science and technology officer at Recipharm. “It is fairly common for patients to forget to take medicine, a study from 2012 (1) suggests that more than 60% of the patients forget to take their medication,” he continues. “There are a lot of opportunities to improve adherence by offering better drug products, which pose less development expense than that of new chemical entities. As such, patient-centric formulation is an area where bio/pharma companies can get the best cost-efficiency during development.”

Essentially, however, patients do not want to be reminded they are patients, asserts Savla. “The persistence level for most chronic therapies continues to decrease after three months (2), and can be as low as 30% just two years after starting a medication,” he says. “Adherence rates are inversely correlated with dosing frequency (3). Whereas once or twice daily doses are acceptable, there is a drastic drop in adherence for three-times-daily dosing (4). The use of modified-release technologies can reduce dosing frequency and may improve side effect profiles. Poorly soluble drugs, especially those indicated for cancers, can have high doses in the hundreds of milligrams range that require the patient to take multiple or large dosage units, which can be difficult to swallow.”

Zubris concurs that medication inconvenience being linked to poor adherence is well documented. “The therapeutic value and health benefits of a drug compound can only be realized if patients follow the course of treatment properly. Ease-of-administration and fewer negative side effects are just a few of the more critical aspects of formulation that drug developers need consider for good patient compliance,” she notes. “Minimizing or eliminating the pain involved in administering the effective dose, as well as minimizing the number of dosing events in the first place, ensure that a drug is easier for a patient to deal with.”

A robust formulation design can minimize pill burden as well as mask unpleasant taste, improve swallowability, and minimize side effects, adds Huang. “The optimal dosage form can make all the difference in whether patients will consistently comply with administration instructions,” he says.

Delivering the goods

During formulation and development, some of the delivery issues facing bio/pharma companies include solubility, stability, and poor gastro-intestinal absorption of the drug molecules, states Dennis. “Additionally, we face problems with highly potent and/or toxic drugs requiring higher quality, in terms of purity and uniformity, and greater patient monitoring and compliance. Or novel molecular combinations requiring complex manufacturing controls,” he adds.

Drug targeting to the diseased area and absorption window can be employed to maximize drug efficacy and minimize adverse effects, Huang continues, which is often built into the formulation design. “Various enabling technologies help drug makers address delivery challenges, depending on the physicochemical properties of the drug substance,” he says. 

Poor aqueous solubility can severely limit the usefulness of an API and the ability to dose these molecules in traditional forms, explains Zubris. “Without exploring alternative formulation techniques, these actives may not progress through the development pipeline,” she confirms.

Effective dosing methods for more complex molecules are certainly less straightforward to determine, however, there are several techniques available that can help in these cases. “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 and spray drying have proven to be promising techniques for the preparation of amorphous solid dispersions,” Huang reveals. “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. Parenteral injectable delivery systems are often considered for large molecule biologics and some small molecules with poor oral absorption-for which more patient-centric long-acting intramuscular or subcutaneous injectable are considered to reduce the dosing frequency.” 

Drug delivery devices can also help with effective disease treatment and management. “Drug-eluting devices, long-acting depots, and transdermal patches can combine anatomical specificity with API uptake considerations and are proving highly effective at treating disease effectively,” adds Zubris. “Divorcing the patient from actively administering dose after dose at precise intervals is inherently patient centric.”

For Griffiths, ease-of-use of the delivery device is particularly important for patient engagement. “If you design with the end in mind, by developing a device that is easier to use, patients are more likely to adopt and take on that new therapy,” he says.

Using inhalation therapy as an example, Griffiths reveals that there is a trend being witnessed by the industry towards connected devices. “Technology has a major part to play,” he notes. “A connected device can send reminders to a patient to help with adherence, for example, and also has the potential to help improve technique by providing feedback to a patient about errors in use.”

Packaging also has its part to play in improving adherence rates, according to Gren. “Development of new packages that are easy to open or transport can help,” he says. “Injectable dosage forms may not be considered to be patient centric as they are often seen as an impractical and expensive way of administering drugs. However, in some cases parenteral depot formulations are an excellent way to ensure that the right dosage is always delivered to the patient. Making injectable formulations more patient-friendly will be a focus going forward.”

Bye-bye blockbuster?

New drug development was buoyant in 2018 with an increased level of new drug applications, many of which were in the orphan drug category, states Zubris. “At the same time, regulators are providing better drug development economies for therapies in certain preferred categories, assigning special regulatory considerations to speed up their approval process,” she says.

Gren highlights that even though the prospect of developing new drugs for huge markets is still attractive, it has become quite challenging to achieve. “For many of the big disease areas, there are already reasonably good pharmaceutical products on the market, and it is often difficult to come up with something that is significantly better and of course the competition is fierce in these areas,” he adds. “Going for smaller markets and focusing on the needs of smaller patient groups, requires reduced R&D expenses and the chances of success are significantly higher.”

Additionally, the focus on smaller patient groups is prompting drug innovators to integrate patient-centric principles and introduce them at the earliest stages of drug development, asserts Zubris. “This strategy will ensure pharma companies can develop new, more effective drugs faster while improving their therapeutic value with formulations and forms that treat disease more efficiently,” she explains.

Furthermore, Savla points out that many of the smaller patient populations with orphan diseases are more likely to include members of patient advocacy groups and generally have a better understanding of their condition, which means that patient-centric approaches are beneficial in the development process. “Involvement of these patients is more frequently an integral part of the drug the development process,” he confirms. “Also, for more niche disease areas, developers may need to tackle unique administration challenges, such as a reliance on caregivers to administer drugs. Therefore, pharma companies need to more strongly focus their efforts on improving outcomes not only by maximizing the efficacy and safety, but also the patient’s experience.”

The decline of the ‘blockbuster’ could be seen as a promising shift as it may lead to companies developing existing drugs into more patient-friendly options, according to Griffiths. “We’ve got some well-established molecules that have been around for decades that are still big sellers, and now we’re looking at how we can improve those products,” he states.

Considering patient populations

“Patient-centricity is a universal concept that benefits all patients. Geriatric and pediatric patients, in general, have the potential to be the biggest populations to benefit from more patient-friendly dosage forms,” emphasizes Savla. “However, a drug designed to be patient-centric for one group of patients does not necessarily extrapolate across different patient populations.”

In Gren’s opinion, geriatrics represent the most important patient population to consider for patient-centric dosage forms, as it is the group of patients where non-compliance is most common. “For geriatric patients, it is common to need multiple medications each day, which can make dosing more complicated and in fact, more difficult to remember,” he says. “By introducing extended‑release medicines, the number of dosing occasions could be reduced, and fixed‑dose combinations could reduce the number of tablets required on these occasions. Dosage forms that are easier to swallow and packets that are easier to open would also be appreciated by elderly patient populations.”

Dennis and Huang, while also highlighting geriatric patients, make note of cancer patients too, who may have issues with administration frequency, pill burden, side effects, or compliance. “Understanding the nature of what these populations are facing can lead to better decisions in formulating therapies that meet their needs,” Dennis adds.

For pediatrics, there was general agreement that most conventional drug delivery systems are not ideal. “Pediatrics differ in their developmental status and dosing requirements from other subsets of the general population,” stresses Huang. “Different formulation designs are required to aid the development of age-appropriate medicines to maximize patient acceptability, while maintaining safety, efficacy, accessibility, and affordability.” 

Regulatory input

An important aspect of drug development is in the form of regulatory guidance and standards that need to be met in order for a product to be accepted and authorized for commercialization. In terms of more patient-centricity, regulatory bodies and healthcare providers are also shifting their approaches.

“There’s much more emphasis now to include a structured, scientific human factors program as part of any new device that is being developed,” notes Griffiths. “The introduction of regulatory guidance and standards mean that developers of new products need to confirm that their design is easily used by the patient population without significant use errors. It is expected that a human factors program will inform design changes to a product based upon feedback from real patients.” 

Dennis and Huang highlight the example of the draft guidance issued by FDA in the United States, under the 21st Century Cares Act, which states, in part, 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 (5). “Both FDA and the European Medicines Agency are focused on how best to assess the patient experience, and therefore are expecting more patient-reported outcomes (PRO) in clinical trials as this assesses outcomes that are important to patients, not just doctors and regulators,” Dennis says.

Further regulatory change noted by Savla is the Research to Accelerate Cures and Equity (RACE) for Children Act (6). “This act eliminates orphan exemption from pediatric studies for cancer drugs directed at relevant molecular targets,” he confirms. “The law will come into effect on Aug. 18, 2020. As a result, many pediatric oncologists and pharma companies are gearing up for more studies of oncology drugs for children.”

Better dialogue, better treatment

“Pharmaceutical companies are being urged to develop more patient-centric drug products by various stakeholders, including not only the patients, but also the caregivers, payers, and regulatory bodies,” states Dennis. “Seeking to incorporate the voice of the patients into drug discovery and development is becoming more and more common and important.” 

Further improvement in stakeholder engagement and dialogue by bio/pharma companies is expected by Griffiths to not only inform new product design, but also solicit feedback about how to improve existing products. “As a result, I think we will see a continued move toward connected health. Patients want to be more involved in managing their own health, and they want to have user-friendly devices,” he notes. “However, we also need to remember that, while technology moves at a very fast rate in the outside world, the adoption of that technology into pharmaceutical products is very slow by comparison. Both pharmaceutical companies and the agencies that regulate them are on a learning curve, and within a highly regulated industry with patient safety at the forefront, it’s easy to understand why adoption is going to be slower.”

Dennis and Huang agree that digital technologies and artificial intelligence will be transformative in bio/pharma, providing the basis for more patient-centric innovation. “We also believe individualized medicine will continue to be a market driver, and that pharma will be more effective in targeting disease and targeting delivery for specific, localized disease,” Huang says.

Small patient groups will continue to trend for bio/pharma companies in Gren’s opinion, although he also stresses that manufacturing smaller batches may also lead to increases in cost. “The most logical way to achieve affordability is to consider the costs of raw materials, manufacturing, and quality control early on in the development phase. This, of course, requires development scientists with a good understanding of industrial‑scale manufacturing,” he says. “The cost of goods may also be limited by using intermediates that can be used for different products.”

However, Gren remarks on the impressive level of creativity that is being shown in terms of patient-centric development. “To me it seems like many of the best ideas are realized when experience and insight into healthcare and patient needs are combined with in depth knowledge of pharmaceutical technology,” he summarizes.

References

1. A.S. Gadkari and C.A. McHorney, BMC Health Serv. Res., 12 98 (2012) https://doi.org/10.1186/1472-6963-12-98.
2. D.R. Touchette and N.L. Shapiro, Supplement to J. Manag. Care Pharm.Volume 14 (6) (August 2008).
3. C.I. Coleman, et al., J. Manag. Care Pharm.18 (7) 527–539 (2012).
4. K. Srivastava, et al., Patient Prefer. Adherence7 419–434 (2013).
5. FDA, Patient-Focused Drug Development: Collecting Comprehensive and Representative Input, Draft Guidance (June 2018).
6. Accelerate, “The US Pediatric Equity Act and Race for Children Act,” accelerate-platform.eu.

Article Details 

Pharmaceutical Technology
Vol. 43, No. 4
April 2019
Pages: 16–21

Citation 

When referring to this article, please cite it as F. Thomas, “Patient-Centric Drug Development Comes of Age,” Pharmaceutical Technology 43 (4) 2019.