Patient-Centric Drug Delivery: Do Possible And Preferable Always Align?

By Tom von Gunden, Chief Editor, Drug Delivery Leader

If you watch enough television, particularly via streaming services in the U.S. market, you will likely recognize what I’m about to describe — that is, the narrowing of commercials into essentially two categories of offerings: pharmaceutical products and online gambling. For the science-trusting among us, embracing the former is likely to seem much less of a “roll of the dice’ than the latter. Nonetheless, the promotions for both use the thematic pull of pretty much all advertising — the desire for a better life.

In the case of pharmaceutical products, in addition to the hope of therapeutic relief, if not outright cure, an increasingly core selling point is convenience, particularly for chronic conditions. According to the ads, even an advanced biologic can be something you can self-inject or something you can swallow.

Along with ease of administration, embedded in that promise are two hallmarks of convenience: speed and proximity. No more (or very few) trips to a clinical setting to receive treatment. The  stated or implied takeaway about treatment regimen goes something like this: “You won’t have to change your life in order to change your life.” That’s an alluring proposition and one that, for many grateful patients, will be eagerly embraced.

Simple as that? Well, yes and no. There is nuance, and I hinted at that nuance in the question posed in this article’s title: “Do Possible And Preferable Always Align?” What I was pointing to there and will explore below is the intersection between, on one hand, delivery capability (i.e., the science and technology of “can do”) and, on the other hand, patient preference (i.e., the human factor of “will do” and, perhaps ideally, “want to”).

As we will see, pondering scientific and technical possibility can sometimes, in the end, prove to have been little more than a rhetorical question, with the answer to “Is it possible (to formulate/deliver in this way)?” being a disappointing, “um, sorry, but no.” However, as we will also see, perhaps surprisingly, that  other consideration — “Does the patient prefer to receive the medication in this way?” — might also result in a “no” or “not yet” even in scenarios in which enhanced convenience might seem to make “yes” a foregone conclusion.

So, join me in considering patient centricity from two perspectives: those of therapy developers and those of therapy recipients.

Patient Centricity In Product Development: When And In What Ways?

On the product development side, explorations of possible delivery formats do (or should) include patient preference along with patient capability, patient adherence, and patient accessibility. Frankly, the investigative scope should include just about any patient-centric aspect of formulation design and delivery that answers the regimen-determining questions, “Who is going to administer this? Where, how, and how often?”

In a recent online Live event I hosted here at Drug Delivery Leader, “Injected, Infused, or Implanted: A Penetrating Look At Patient Centricity,” I was keen on hearing from the panel about when during product development — especially for a complex, large molecule biologic — those various patient considerations begin to come into play and/or move fully to the fore. For starters, I wanted to know the start, as in, “How early?”

As related by panelist Beate Bittner, Head of Product Optimization at Roche, very early — at the outset of moving a lead candidate into formulation. “The prerequisite, of course, is that the molecule itself is already safe and well tolerated,” Bittner explained. “And for these high-dose biologics, to achieve this decentralized care setting, you need to start early. This means you aim to have the optimal product profile available with the initial launch of the molecule.”

Early ExploratIon Of Delivery Method Feasibility

Of course, early is well ahead of later clinical stage and even post-market testing of usability, use error, user preference, and the like. For that reason, it may be wise for developers to accommodate the unknowns and the “too early to tell’s”  by keeping delivery options open, even if a desired ultimate format (e.g., a prefilled syringe or an autoinjector) and ideal user profile (e.g., clinician, non-clinical caregiver, or patient) has already been proposed.

At the Live event, Bittner provided the following rationale for optionality in early stage development, illustrating her points with the example of a mAb. “For our high dose monoclonal antibody formulations, you will typically see that we do not just initially do a sub-Q [subcutaneous] formulation. We also have an IV formulation,” she explained. “And the reason for this is that currently we do not know whether a high concentration formulation with a lower volume is sufficiently stable.”

As Bittner went on to confirm, key decisions about injection volumes and device selection are dependent upon additional inputs about tolerability and other factors. “From a development perspective, there’s more and more information on the feasibility of the formulation,” she said in reference to those careful early assessments. “And then we can, for example, drop the intravenous administration route and just pursue subcutaneous administration.”

(You can glean more of Bittner’s insights about formulation and device alignment by viewing “Determining Dosing For IV Or Subcutaneous Delivery,” a video segment from the aforementioned online panel event.)

Understanding The Landscape Of Delivery Device Options

Later in the panel discussion, Fran DeGrazio,  who is President and Principal Consultant for Strategic Parenteral Solutions LLC and also serves as Senior Industry and Technical Advisor here at Drug Delivery Leader, continued the thread about the increasingly and necessarily synergistic relationship between the delivery method and the patients who may become both recipients and administrators of their treatments. “When you're looking at these biologics and this move towards self-administration, one of the biggest challenges has been around high volume because you are moving from an IV to, for instance, a sub-Q,” she offered.

For DeGrazio, the dual challenge of delivering complex formulations even while expanding administration options makes it imperative that biopharmaceutical development organizations thoroughly familiarize themselves with the diverse range of capabilities across several types of device technologies. “Understanding what's out there, not only in respect to autoinjectors and on-body injectors, but also prefilled syringe systems — [about] all of these things, you should understand the landscape,” she urged.

(Hear more from DeGrazio on delivery options by viewing panel event segment “Selecting Injection Devices And Platforms.”)  

The Patient Perspective On Patient Centricity: What Matters And Why?

The theme of delivery optionality has been similarly prominent in other kinds of conversations I’ve been a part of lately: those with patients. Spoiler alert: In at least one instance, the patient’s take on preference may surprise you. (More on that in a moment.)

At the most recent PODD (Partnership Opportunities in Drug Delivery) conference, I attended a session featuring panelists Cathleen Bergin and Todd Kennedy, two lived-experience experts from the patient community. Each narrated their treatment trajectories, concluding those stories with details about the life- and health-transforming benefits they enjoyed once core components of their therapies moved from IV administration to subcutaneous injection.

Not surprisingly, convenience — in terms of treatment regimen time and/or location — underscored their gratitude. Both Bergin and Kennedy described dramatic gains, or regains, in life experience because their time was no longer so onerously consumed by treatment management. (I reported my initial response to hearing those stories in “What Do Patients Appreciate? Therapeutic Innovation And Accessibility,” an article which includes the video and transcript from a quick convo I had with Todd Kennedy right after the conference session.)

New Delivery Options: Differences In The Pace Of Adoption

I recently followed up on my interest in those patient stories in a videocast episode, “From IV To Subcutaneous: Easing Administration, Advancing Efficacy,” featuring Todd and Cathleen. Joining us was Chief Medical Officer Charles Theuer from delivery systems developer Halozyme, which contributed to the therapeutic advances Cathleen and Todd descibed. Again the “time saved / life regained” theme was central to our discussion of the benefits of innovations in drug formulation and delivery.

For Kennedy, the formerly IV, now sub-Q, component of his treatment regimen (for the blood cancer multiple myeloma) continued to be administered in a clinical setting. Nevertheless, the replacement of long hours spent in an infusion center with, instead, a comparably quick injection had Kennedy concluding that the choice of sub-Q over IV delivery, from a patient perspective, would seem to be an obvious one. “It’s much more than convenience; it is a transformative experience,” Kennedy explained. “And that's why, when they do the research and they say, hey, what do you like, patients? Do you like IV or sub-Q? You know, 90-plus percent say, yes, give me the sub-Q. Why wouldn't you? I mean, seriously, why wouldn't you want that?”

Now, here’s the “twist” I telegraphed with my “spoiler alert” above: Acknowledging the 90% for whom a switch from IV to sub-Q might be a “no brainer,” Bergin placed herself in a smaller patient population: the contentedly cautious. Her treatment journey did ultimately lead to a transition from clinical IV administration  to subcutaneous injection of her core immunotherapy, Vyvgart  — even to self-administration after the injectable Vyvgart Hytrulo formulation  became available. But Bergin chose not to make that move right away.

(Perhaps making her hesitation even more surprising is that, coincidentally, Bergin was then and remains an employee of argenx, the maker of Vyvgart.)

In relating her hesitancy about adopting self-injection via prefilled syringe, Bergin positioned her explanation as an illustration of patient preference: “Keep in mind that patient preference is important in collaboration with them because some patients like their IV,” she said. “I didn't jump right away. I was on the IV for six to eight months after the launch of Hytrulo because I was doing so well. So why would I change something?”

Eventually, the demands of work and travel precipitated Bergin’s decision to embrace self-administered sub-Q injections. Yet, she remains steadfast in her belief that patients want and should be presented with options, whenever possible. Reflecting on her personal experience as a patient and her professional experiences as a nurse practitioner and, now, as a clinical field education leader for a biopharmaceutical company, Bergin asserted, “What I've learned is that patients want choices as long as multiple options are safe and efficacious, and they're equal.”

Weaving Patient Preference And Feedback Into Development

For biopharmaceutical development organizations committed to practicing due diligence regarding patient preference, those efforts include accumulating data through various feedback loops, including directly and indirectly gathered Voice of the Customer (VoC) reporting. Moreover, the timeline for doing so is a lengthy one — essentially, the entirety of the product lifecycle.

As was confirmed by Bittner in her comments from the online panel event referenced above, these efforts, including capturing the VoC, should be underway no later than during the earliest considerations of the device-ability of a drug-able substance. “From this patient-centricity perspective, it is really important to have this so-called Voice of the Customer [from] the user, which can be the patient or the provider. You need this early on. You do it at the beginning; you do it during development; and you continue this when the product is already on the market,” she explained, then described types of inputs. “You do preference surveys;  you do advisory boards with patients and providers; and do human factor assessments and also look into the literature, look into what's available about quality of life.”

Patient Feedback On Preference Continues Post-Market

Another panelist who echoed the criticality of including the VoC throughout product development was Shannon Hoste, whose work as Principal at Hoste Consulting includes serving as Chief Scientific Officer at Pathway for Patient Health. Drawing on her long-standing focus on Human Factors (HF) throughout experiences that include HF leadership roles at FDA, Hoste speculated about doing even more to leverage data collection activities even after a product has been commercialized.

Prefacing her comments by saying she was putting on her “futurist lens,” Hoste described a logical extension of existing, foundational efforts in the industry. “We think about getting that [patient preference] information upfront. But then, as we move into market, we have all sorts of mechanisms in place to track for post-market surveillance. Can we also leverage those same pathways to track patient preference?” Hoste posited.

Suggesting the use of digital solutions to ease patient feedback submission and collection, Hoste then offered, “We have surrogates; we have adoption rates, and things that we can look at to try to get to that information. But is there a way we can track and trend and inform [from] that user lens we're bringing back to the project team?”

(To further consider Hoste’s thoughts about ways to gather and leverage patient clinical and field data, view “Monitoring Patient Preferences And Post-Market Safety,” a segment from the online panel event.)

 ‘Make Your Voice Heard’: When Patients Advocate For Patients

Having been presented with route of administration options as patients, Bergin and Kennedy concluded their videocast commentary similarly. Each urged patients to give voice to their preferences and for product developers and healthcare providers to listen keenly to those voices.

Referring to the example of argenx, her employer and immunotherapy developer, Bergin described ways in which hearing from patients can not only inform a biopharmaceutical company’s approach to clinical trials but also influence product development in accordance with patient preferences. “They [argenx] actually asked the patients before they set up the trial, ‘What do you want to see in the trial?’”  she explained. “And patients said they wanted to stay on their supportive therapy because, if they went to placebo, they didn't want to get into trouble.”

About argenx targeting another indication with Vyvgart — in this case, CIDP (chronic inflammatory demyelinating polyneuropathy) —  Bergin offered this illustration of patient preference helping to guide the immunotherapy’s delivery method: “Listening to the patient, argenx heard loud and clear they were not interested in IV formulation weekly. So [argenx] went right to the [Vyvgart] Hytrulo [injected by prefilled syringe] for approval, which is what was approved for the weekly treatment of CIDP.”

Now spending a considerable amount of his time and energy serving as a patient and research advocate, Kennedy similarly pointed to the power of the VoC and urged patients to become or remain proactively involved in decisions about their treatment. “There's a difference between what is the matter with you and what matters to you,” Kennedy said. “So, trying to encourage patients to speak up and tell their care team about their lives and how they're trying to manage life and treatment at the same time is really important.”

Considering the challenges Kennedy identified in balancing life and treatment, he had this message to developers of drug products and related delivery methods and options: “My request in this regard is, again, don't forget about that patient experience. Because, as we've described, hopefully in a compelling way, it's not just a matter of convenience. As Charles [Theuer from Halozyme] talked about, there's a safety component. There is an impact on quality of life and productivity as well.”

(Quick reminder: You can watch the full In Combination videocast episode featuring Bergin, Kennedy, and Theuer here on Drug Delivery Leader.)

Regulatory Input On Patient Centricity In Drug Delivery

As for patient-centric considerations in drug and delivery product development, there is one other set of voices that obviously must be considered: that of regulatory agencies. Regardless of patient preferences, FDA and other entities are keenly interested in safeguarding patient experiences around safety, efficacy, and usability.

At the Live online event, I packaged some audience questions that were coming in on the topic of regulatory for the panel to consider. These questions asked about scenarios in which Human Factors concerns appear in FDA CRLs (Complete Response Letters) or in which HF waivers might be applied to further product development.

Panelist Jonathan Amaya-Hodges, Consulting Director at combination products and delivery device consultancy Suttons Creek, acknowledged an increasing degree of FDA scrutiny around HF. “[FDA] has really brought in Human Factors experts and focused on that area,” he said. "There are some recent examples, and it's not just one where Human Factors usability came into a complete response decision. And that's a place people don't want to be. I think that shows that, in some of those cases, Human Factors might have been an afterthought, if a thought at all.”

Making Human Factors A Development Foundation

As he highlighted the possibility/likelihood that HF considerations were an “afterthought” in some submissions, Amaya-Hodges reiterated the panel’s advice about weaving in the patient perspective and related Human Factors considerations early and often. He also offered an advisory caution. “It's important to integrate that throughout development,” he said. “On the other hand, FDA won't really mandate anything [about HF] until you get to the point of the marketing application. You can run clinical trials without significant amounts of Human Factors data. So, sometimes that leaves people to interpret things the wrong way.”

Hoste also commented on the connections among clinical data, Human Factors, and FDA submissions. She illuminated her points with the example of decisions around usability, safety, and efficacy administration in the potential transition from testing device administration in a controlled, clinical setting to non-monitored self-administration in a home setting. “It's the Division of Medication Error Prevention and Analysis [DMEPA] and CDER [Center for Drug Evaluation and Research] that's looking at this,” Hoste explained. “So, medication error being a key term there. When you're thinking about that [transition], if the data isn't showing that this is going to be performed [well] or there will be issues with overdose — especially if it could lead to failure of therapy or specific harms then — that's in the grounds of insufficient safety data to support a submission.”

(Learn more about Human Factors regulatory from Hoste and Amaya-Hodges in the panel event video segment, “Relying On Human Factors Clinical Data For Regulatory Approval,” a video segment from the online panel event.)

Unique Voices From Unique Patient Journeys: In Other Words, All Of Them

As Amaya-Hodges and Hoste commented on those Human Factors considerations, I was reminded of Cathleen Bergin’s description (delivered at the PODD conference session and captured in my aforementioned article referencing the session} of dexterity challenges she had to address in order to self-administer her immunotherapy via prefilled syringe. She acknowledged that here was a former nurse practitioner, one with years of experience injecting patients, who still needed to learn how to effectively self-inject. Ultimately, as she described in our videocast conversation, she came to prefer and to embrace self-administration, but it took a few months of warming up to the idea.

Reflecting on all that I heard about patient centricity from experts in the online panel event and on the videocast, I am honored to have had the opportunity to practice the guiding recommendation that emerged in both forums:

I listened.