By Wayne Koberstein, Contributing Editor
Drug-device combinations generally have two alternative purposes: to enable a new use, indication, or effect; or to extend a product’s life cycle. Each alternative brings a particular set of technology choices and influences the timeline in product development. But both demand a level of coordination and planning — starting at the earliest possible point — that companies often cannot or do not achieve. One large pharma company addressing the challenge is Janssen Research & Development, LLC, one of the pharmaceutical companies of Johnson & Johnson, where Douglass Mead, director of regulatory affairs and medical devices and combination products, leads the regulatory strategy for a drug delivery device team dedicated to parallel development of drug-device combination products.
Janssen recruited Mead in 2006 from the device industry to navigate the regulatory pathways for its new auto-injector combined with large molecule drugs such as monoclonal antibodies (mAbs). As combination product regulations evolved, he recognized the full extent of the Janssen portfolio — about 30 drug-device combinations either on the market or in the pipeline. These included everything from prefilled hypodermic syringes and auto-injectors to transdermal patches, as well as kitted devices such as oral syringes and vaginal applicators. In short order, he was working closely with a new drug delivery group that has grown to about 40 people, consisting equally of medical device and drug delivery/packaging experts, as an operating unit within the company’s drug-development program.
“We recognized early on that we needed to devote resources and expand competencies in delivery device technology — its development and regulatory pathways,” says Mead. “Patients are prescribed a drug but they rely on a device to administer some of them. We consider this premise now as we design, test, and manufacture the device component of the drug combination products. We also focus on understanding the applicable regulatory requirements for drug-device combinations and how to structure the dossier for submission in the U.S. and the rest of the world. Combination-product regulations are evolving rapidly, but in many countries, regulations lack specificity, giving local authorities more regulatory discretion, which often requires more negotiation.”
ORGANIZATION & PROCESS: LINEAR TO PARALLEL
By its very mission — to focus on combination-product development — the Janssen device group breaks from the past, when companies typically delayed thinking about how a new drug therapy might benefit from or even require a device component. Another experienced drug-device developer, Sesha Neervannan, VP of pharmaceutical development at Allergan, describes the industry’s shift from the traditional paradigm:
“Most of the time, it has been a pharmaceutical company developing the drug-device combination, with the drug being the primary mode of action, so the company would not think of the device until much later in development; its main concern was whether the drug was safe and effective. But now, in many cases you cannot have a drug without the device and vice versa. So more and more companies are thinking about devices and the delivery approach very early on.”
Neervannan says companies are learning this basic lesson in drug-device development: “Don’t wait until it’s too late, because the drug will have certain properties and those properties can be optimized to a certain device. And if you know them ahead of time, you can develop the drug and device together.”
By creating a separate unit for combinations, Janssen implemented parallel development of their drug and device components. Formally, Janssen established two development processes, one for drugs and one for devices, that work in tandem. The ideal approach is to consider the physical characteristics of the drug and the planned device component initially and then bring them into alignment at the right moment for studying the product performance and the pharmacokinetic (PK) comparability questions that may arise — anytime between the first PK study to some part of the Phase 3 program, he says. “You need to plan the timing very carefully for each product.”
Formerly at Janssen, when research discovered a molecule, developers began preclinical testing to establish its safety profile and look for efficacy signals to the degree possible, at least with a monoclonal antibody. Then they produced a useable formulation to study the molecule in humans — say, a lyophilized or liquidin-vial compound. Only later, typically before Phase 3, would they move from the liquid-in-vial to a prefilled-syringe formulation and begin to look at certain issues of usability, such as the influence of silicone on the compound, viscosity, and needle-gauge selection.
Now, says Mead, the team develops two or three formulations for a compound with representative viscosities and physical stability and tests them with delivery devices to assess, very early, any challenges that occur from the combination of the products. “For example, an auto-injector has a fixed spring force, and we want to make sure that the viscosity of the drug is appropriate when used together and working as a delivery system. We can make adjustments to the formulation or change the needle gauge, for example, to optimize combination-product performance before we lock down a formulation for Phase 2 or 3.”
Besides earlier testing of formulation and device in combinationproduct development, companies have also focused more attention on predicting how drug-device combinations will work in practice, not just therapeutically but ergonomically. Low-cost, efficient human factor studies with health workers and the intended patient population, using candidate products, now guide much of the innovation in drug-device development.
Janssen has adopted the concept of “design controls” from the device industry — a formal FDA regulation for planning, design, and development of medical devices. “Design controls look at all activities within the development sphere, including design inputs such as user needs and technical requirements, and follow them through design validation — ensuring that the device’s intended uses are met,” Mead says. “We consider the drug formulation to be a design input to the delivery device, and then we carry that through specification, bench testing, and ultimately design validation in trials or human factor studies.” The ultimate criterion for a successful drug-device combination is often “ease of use” coupled with a minimum of use errors.
When the Janssen team needed an auto-injector technology, it found no 510(k)-cleared device or platform available that it could marry with its own prefill syringe without extensive customization, so it developed its own auto-injector. In other cases, it has adopted offthe-shelf devices, such as the needle guard installed on every prefill syringe for user protection. “We were able to find a state-of-the-art needle guard from a third-party provider that worked successfully and required no customization, which is the perfect solution.”
Neervannan observes that, with sufficient planning and protocol design, delivery concepts can be tested early in clinical development. “We can design a Phase 1 or Phase 2 study, applying innovative but preliminary device or delivery concepts that simulate how a final product might work (such as remote-controlled capsules for site-specific oral delivery). It doesn’t require pathology up front but just answers to questions, such as, ‘Do we need to deliver the drug in certain parts of the target tissue for best absorption?’ Or ‘Is the drug efficacious and safe at a level that can be delivered at a maximum dose or delivery rate for intended route of administration?’ We can answer those questions quickly without investing in a full-fledged formulation and manufacturing effort.”
Janssen evaluates combinations with small, cost-effective nonclinical studies. Bench testing examines the reliability of delivery and performance attributes such as how hard one must press a button to actuate a device or length of delivery time with a particular drug. Focus groups and other ergonomic experiments test how the product actually works in use with patients — down to how the devices feel in hand and where controls should be placed. Beginning with the prototype, Mead says the team conducts “formative human factor studies” with representative users to make these assessments.
“They might be nurses or patients who’ve never experienced a particular technology before or who are hand-impaired if we’re dealing with a rheumatoid arthritis indication. We will study the performance of the device with patients, along with the proposed instructions for use, to evaluate deficiencies that we would then want to mitigate with design changes to improve the product or choose among alternatives,” Mead says.
“Certainly, if you are in a therapeutic area where a device is a must, especially if you’re coming in second or third in the market, you better have a device that’s at least as good as other marketed devices and generally better, to have some competitive advantage — and for that you must establish the design early, based on patient feedback.”
Keith Horspool, VP of pharmaceutical development at Boehringer Ingelheim, echoes Mead’s advice. “If you overlook those aspects, it can be very expensive and time-consuming — in some cases, costing you the product. That is another reason for early development: to get patient feedback on how they’re using the product, what they like or don’t like about it. Otherwise, something that looks technologically exciting to an engineer or a scientist may not necessarily be appealing to a patient, and market adoption may suffer.”
Also emphasizing the “critical issue” of packaging, Horspool says, “With many combination products/devices, how the formulation is packaged and presented in the product is very important to the ease of use and acceptance by patients. Another critical factor is understanding and control of materials that come into contact with the formulation during storage and use. Some device technologies can contain materials that are unprecedented and may not be approved for pharmaceutical use, which requires additional investment and effort for regulatory acceptance. Often, the formulation, packaging, and device engineers work separately. But all three need to be developed in concert, and that’s an area where I’ve seen gaps.”
WHERE IS THE CUTTING EDGE?
Future drugs may create even more demand for new delivery technologies. Mead, Horspool, and Neervannan expect most future innovation to come from the small labs and companies that have pioneered most device development in the past.
“Academia is very good at creating new drug-delivery technologies at the molecular or formulaton level,” says Mead. “But with devices, most innovation comes from small medical device companies, and that’s really been true with some of the injector systems, for example. They can make and design unique products. Our role is with larger combination-product development, where we utilize technologies developed by other groups or develop our own, working with outside design firms.”
Mead no longer considers the Janssen device group an exception among pharma companies; Pfizer, Roche, Amgen, Merck, and others have similar units dedicated to drugdevice development. Horspool believes even companies that have no dedicated unit now coordinate their drug and device activities.
“Every pharma company has some focused effort to look at drug delivery, typically a group or several groups constantly evaluating the technology, and some have dedicated functions,” Mead says. “But it is a very multidisciplinary type of development, and often pharma just doesn’t have the full capabilities needed. So that immediately is a challenge for drug-device development: You need all sorts of extra capabilities and a lot of engineering input, and it is quite different from going to a third party for a device, which takes a lot of negotiation up front.”
Allergan uses an “open innovation” model to find solutions for some of its drug-device challenges, according to Neervannan. The company starts with a large anonymous search for people who can solve the problem at hand, people it may otherwise not know about. “They may not be in delivery technology, but in some component of a manufacturing process or even in another industry. They are not in our network. When we find the right people with the technology solution, we take them as a partner and develop the technology through partnership in research.”
Mead says pharma companies developing combination products need to adjust to how the world of devices works. “You can expect that devices will constantly evolve, unlike the drug world where you don’t want your drug to change very much over its patent life. In the device world, you want it to change, you want to improve it, and you can look at a delivery-device technology now and ask yourself, what are we going to have five years from now? What are we going to have 10 years from now, to improve our product for patients and be competitive?”
Executives in the pharma industry only rarely have a device background. But Mead believes incorporating combination-product leadership into a biopharma company is the first step toward combining the power of two disparate technologies — one stable but flexible, the other dynamic and ever-evolving. The next step is investing in the early development needed to marry the optimum drug formulation with the most complementary delivery device.