Opportunities and Challenges in Biologic Drug Delivery

Biologic drugs have been called the driving force in pharma for good reason. They comprise more than half of drugs in development, and they have the potential to address many chronic diseases and various unmet medical needs. Some of the first biologics to come to market, among them Abbvie’s Humira and Roche’s Rituxan, quickly became multibillion dollar blockbusters. It’s no wonder pharmaceutical companies are racing to bring biologics and biosimilars to market.

Indeed, the number of biologic drugs in development continues to increase exponentially, with more than 2,700 remedies in development as of mid-20171 , triple the 900 in development in 20132 .

The largest growth is occurring in the therapeutic areas of cancer and cancer related conditions, rare diseases and neurologic disorders (Figure 1). In addition, increasing emphasis has been placed on developing biologics to treat autoimmune disorders. All signs indicate that the trend for increased development, approval, and use of biologics will continue into the foreseeable future.

Figure 1. Parenteral drugs in clinical development administered subcutaneously and intravenously.

The biologics pipeline is comprised of a range of products, with monoclonal antibodies (mAbs) representing the most broadly developed4 . Currently, mAb-based biotherapies account for 50% of the top 100 drugs and are projected to maintain a dominant position in the pharmaceutical market over the coming years.

The success of these biologic drugs reflects their ability to treat certain cancers and the other diseases they target better than existing drugs and with fewer side effects. This, combined with an aging population that will be more susceptible to such diseases, is driving the growth of the global biological drugs market according to Transparency Market Research (TMR)5 .

But there are problems with biologics that could limit their reach and potential. Anyone who keeps up with the news knows that pharmaceutical companies developing biologics are constantly dodging bullets hurled at them by constituencies concerned about the high prescription costs, no matter how defensible those costs are.

And prescription cost is not the only drawback that could limit the commercial success of biologic drugs. These drugs have two other problems. They are difficult to make and they are hard for patients to take. As such, they require a de-risking strategy that employs a new, patient-focused drug delivery system coming to market.

How Drug Administration Costs Can Limit Successful Commercialization of Biologic Drugs

Cost-effectiveness analyses (CEA) are routinely used to determine which medical technologies offer value-for-the-money. Applied to biologic drugs, the economic value may be determined by how much is spent on administering these drugs6 , i.e. how much of healthcare resources are spent on drug administration and whether trade-offs exist between drug acquisition and administration costs. In order to provide pharmaceutical companies better tools for making go-no go R&D decisions that are similar to the cost-effectiveness analyses conducted by payers after the drugs become available, British researchers developed a new administration-cost algorithm.

The researchers found that across a range of biologic drugs, the variables ‘subcutaneous’ and ‘intramuscular’ (IM) were associated with lower administration costs, regardless of dosing frequency. The key decision, they concluded, is to formulate a biologic product for subcutaneous or IM administration rather than intravenous delivery despite the difficulties such formulations present.

However, biologics are big, complex drugs. Whereas the molecular weight of synthesized drugs ranges in the few hundred to perhaps a few thousand Daltons (Da), the molecular weight of biologics can reach upward of 150,000 Da. This large size leads to higher mg/ ml concentrations and consequently higher viscosity drugs7 that would necessitate too great an injection force for IM administration. Consequently, the most prevalent mode of administration is intravenous administration requiring the services of a health professional in a costly healthcare setting, precisely the factors that drive up the cost of administration that could result in an unfavorable cost-effectiveness analysis by payers.

The Critical Role of Human Factors

In addition to adding significant drug delivery costs to the equation, intravenous administration is unpopular with patients. It is inconvenient. It can be painful. It is not patient-centric. And it is forcing the pharmaceutical industry to look for ways to improve the patient experience significantly so they are more likely to comply with prescribed therapy. The question becomes how to improve the patient experience significantly for increased compliance with prescribed therapy while at the same time reducing costs.

Since LVWI devices are built to simplify the self-administration of a subcutaneous injection over relatively longer periods of time, numerous human factors considerations have been incorporated into their designs. Foremost among these include ease of use, patient comfort, and discretion.

To simplify patient device operation, LVWIs utilize clean ergonomic designs and can typically be operated using an intuitive three-step process consisting of placement, activation, and injection initiation. Since patient comfort is a top concern, the devices use small bore needles that are never visible to the patients. They incorporate pause and flow-rate control features to allow for patient control and comfort. Another important safety feature includes automatic needle retraction to prevent accidental needle sticks to patients and caregivers. As patients prefer discretion during self-administration, most of the advanced LVWIs are designed with a low profile and smooth edges that allow them to be easily and safely concealed beneath clothing over extended periods of time and while moving around freely.

An Alternative to Extreme Measures

New biologics delivery technology makes that possible - and relatively simple - while potentially reshaping the drug administration landscape8 without taking more extreme measures adopted by pharmaceutical companies aiming to be perceived as both patient centric and cost-conscious.

For example, Novartis AG recently agreed to forego payment altogether by the U.S. Centers for Medicare and Medicaid if its new $475,000-per-patient childhood leukemia drug, Kymriah, does not lead to the desired outcome by the end of the first month.

Bristol-Myers Squibb, in their bid to improve patient-centricity, paid Halozyme $105 million upfront to access its Enhanze technology - to enable subcutaneous delivery that eliminates the one-hour timeframe for an IV infusion. But Enhanze does not eliminate the time it takes patients to travel to and from a health facility, check in, wait for their appointment, and travel back home. And there may be other issues with patient acceptance of a painful injection. Nor does Enhanze eliminate health system costs by removing the healthcare provider from therapy administration.

There is a new and different mechanical drug delivery capability that more simply and more cost-effectively replaces IV administration, giving patients and pharmaceutical companies a highly desirable patient-centric subcutaneous delivery option.

LVWIs: Disruptive Technology to Replace IV Delivery With A PatientFocused, Cost Saving Approach

With so many biologics in development and no patient-centric way to deliver them, it was inevitable that innovative delivery solutions would emerge that enable a new pharmaceutical product to meet two top criteria: satisfy patient demands for easy drug administration without disruption to their everyday lives, and address health system demands for lower costs and more value.

The solution lies in adoption of large volume wearable injectors that, in combination with biologic drugs, enable patients to self-inject even the most viscous formulations and volumes of up to 50 mL with ease and comfort in their homes or workplaces. Small in size – as small as an Oreo cookie – these devices take quite advanced therapies out of the costly clinical setting.

The Key to Success for Pharmaceutical Companies Embarking on New Development Projects Today is to Integrate Delivery Device Early in Development

Nearly 60% of pharmaceutical combination product experts say that the time to add the delivery device constituent is in early stages of drug development9. Introducing a device platform at the early clinical stage provides an opportunity to engage patient populations early in product development. It improves the product’s ability to meet patient needs and thus to improve chances that the outcomes align with the expectations of governments and payers. It also enables the pharmaceutical company to answer contextual questions regarding the patient sooner, and thus decrease cycle time for new product development.

There is also the potential for better uptake and greater product differentiation at launch. Conversely, pharma companies who postpone inclusion of the delivery device until after the clinical trial stage miss a huge opportunity and are likely to find themselves at a substantial competitive disadvantage.

From the patient perspective, the delivery device is the element that often defines the treatment experience more than any other. In today’s clinical trials, the patient’s role is pivotal. It’s become much more important to have a representative person experience the treatment. Physiological data is of course gathered, but patients are now reporting back on how the treatment experience feels, how it could be made easier, what they liked and disliked about it.

Figure 2. Today’s most advanced LVWIs can reduce combination products time to market by months or even years.

The drug itself represents a diminishing share of what comes together to deliver an overall outcome. In fact, regulatory agencies are evaluating new biologics in combination with their delivery mechanisms. Thus, from process chemists to manufacturers, drug developers should be thinking about LVWI delivery early, while the biologic molecules are still in development and ahead of any scale-up.

An early start will also reward formulation teams. Today’s more advanced LVWI devices, such as Enable Injections’ enFuse™ (Figure 2) can reduce time to market by months or even years. These devices provide the means to more easily:

  • Deliver more volume of product
  • Deliver much higher viscosities
  • Resolve biologics’ greater propensity to precipitate out of solution

LVWI Benefits and Features

Large volume wearable injectors provide other advantages in addition to speeding drug development and improving the patient experience significantly. As a result, they are quickly being adopted by the pharma industry. Analyst reports10,11 indicate “explosive growth” in these socalled bolus injectors, with 42 million devices expected to be sold by 2027 and a CAGR of 23% until 2024.

A number of companies are developing LVWIs. To date only one has been approved by the FDA, with more approvals pending. Table 1 lists features of the most advanced biologics delivery devices. Those that are platform technologies de-risk drug development and can deliver drug volumes of greater than 20 mL and up to 50 mL.

Table 1. LVWI Features and Benefit

Further De-Risking Biologic Drug Development: First-Mover Advantage

When McKinsey & Company examined 492 drugs launched over a 27-year period, they found that large pharmaceutical companies who were first to market achieved a 6% market-share advantage that extended out 10 years. Later entrants had a negative advantage12. As well, companies with prior experience in a therapeutic area had almost twice the first-to-market advantage. The first mover effect is strongest of all – a 13% market share advantage – when the first mover expands indications faster than later in entrants in the first five years after launch.

LVWIs, by reducing formulation time by as much as a year or more, can play a significant role by providing greater opportunity for the earliest possible market entry. They accomplish this feat in two ways. They circumvent injectable volume and viscosity limitations, and they can increase the concentration of an API in the formulations. Scientists who incorporate drug delivery technology at early clinical development stages can provide formulation teams with a tremendous advantage that speeds development of stable, bioavailable, clinically relevant formulations.

In addition, LVWIs use of standard vials or syringes to fill the injector in a simple, intuitive way, eliminates the need for new container closure stability studies, further shortening development time and speeding entry of products to market.

Pharma-Device Partnerships

Given the projected increase in development of biologics and the accompanying innovations in biologic delivery systems that increase patient autonomy and reduce healthcare costs, a natural partnership is underway between drug and medical device companies. In the US, FDA regulations point toward a path to approval that includes both components – the biologics drug, and the delivery system as a drug/ device combination product.

Since the biologic regulatory pathway requires a rigorous clinical program, LVWI devices can be leveraged to achieve success by providing flexible dose administration and data gathering capability during early phase pharmacokinetic studies. Synergistic drug and device company partnerships that effectively play to each other’s strengths under a comprehensive strategy should lead to regulatory marketing approval, commercialization, and future improvements to lifecycle management of the combination products.

Ultimately, the innovator pharmaceutical companies require an elegant solution for the delivery of their biologic products that medical device companies provide.

Conclusion

Commercial success of large volume biologics hinges on overcoming the major challenges they pose: they are hard for patients to take, hard to make, and they are costly, with drug administration among the major factors driving up costs. New, more advanced drug delivery technology can circumvent many of these problems if incorporated at early stages of drug development to create combination products that can impact outcomes positively. Biologics, when combined with these patient-centric delivery devices, hold promise of improved outcomes, lower cost and greater commercial success.

References

  1. Statista, Number of biologics in development as of June 2017 by therapeutic category.
  2. PhRma, Medicines in Development for Biologics 2013 Report
  3. Walsh, G. Biopharmaceutical benchmarks 2014. Nature Biotechnology, October 2014:32(10): 992-1000.
  4. Van Arnum, P. Moving to the next level in biomanufacturing. Pharmaceutical Technology. April 02, 2010; 34(4).
  5. Transparency Market Research
  6. Tetteh, EK and Morris, S. Evaluating the administration costs of biologic drugs: development of a cost algorithm, Health Econ Rev. 2014; 4: 26-
  7. Phillips-Medisize. Critical Considerations for High Viscosity/High Volume Drug Delivery Devices. White paper. Pharmaceutical Online, 10/17/17.
  8. Brunsman, Barrett. Cincinnati-made device could reshape the healthcare industry. Cincinnati Business Courier, October 6, 2017.
  9. EdgeOne Medical. Report: Highlighting Challenges in the New Combination Product Regulatory Landscape. EdgeOne Medical: Chicago, IL. February 2016.
  10. Global Industry Insight. Bolus Injectors Contribute Largest Revenue to GlobalWearableInjectors Market
  11. Roots Research Report: Large Volume Wearable Injectors (3rd Edition), 2017-2027. 2017
  12. Cha, Myoung and Yu, Flora. Pharma’s First to Market Advantage. McKinsey & Co. 2014

Author Biography

Michael D. Hooven is President and CEO of Enable Injections, Inc. He has over 30 years of experience in the medical device industry in a broad variety of business, technical and clinical areas. He is the founder of three medical device companies and holds more than 100 issues and pending US patents. Mr. Hooven is the Founder of AtriCure (NASDAQ:ATRC), where he previously held positions as Chairman and CEO. He was also Founder and Chairman of Enable Medical, a surgical device manufacturer that was acquired. He previously served as Director of Product Development at Ethicon Endo-Surgery where he had responsibility for all in-house product development and a team of 200 engineers. He held prior engineering positions at Siemens/Pacesetter and Cordis Corporation. He is a Director and past Chair of BioOhio, a life sciences accelerator. He earned a BSc in physics and MSME in Mechanical Engineering from the University of Michigan.

 

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