Article
January 16, 2025

Key Considerations for Development and Commercialization of Drug Device Combination Products in Rare Diseases

Developing drug device combination products for rare diseases presents unique challenges and opportunities for biopharmaceutical companies.

These advanced drug delivery products, which integrate a drug and a device into a single treatment, can be particularly beneficial for patients with rare diseases, offering novel solutions that may improve treatment efficacy, patient adherence, and quality of life. However, the development process for these products is complex, requiring careful consideration of regulatory requirements, technical feasibility, clinical efficacy, and patient-centered design.

Understanding the Unique Needs of Rare Disease Populations

Rare diseases, by definition, affect fewer than 200,000 people in the U.S, or less than one in 2,000 in Europe but globally, they impact some 300 million people.1 It is estimated there are more than 7,000 rare diseases. Yet, with a mere five to seven percent of these conditions having an FDA-approved drug, they remain largely untreated.
People with rare diseases face numerous challenges, including the pursuit of an accurate diagnosis, accessing suitable and sufficient medical care, and working toward better social inclusion and independence. Each condition has its own unique characteristics, progression, and symptoms, which often require tailored treatments. These variations necessitate a personalized approach in designing drug device combination products.

Key considerations:

  • Conduct thorough research on the rare disease to understand its pathology, symptoms, and treatment challenges.
  • Engage with patient advocacy groups to gain insights into patient needs and preferences.
  • Design drug device combination products with flexibility to accommodate variations in disease presentation and severity.

Regulatory Pathways and Requirements

Navigating the regulatory landscape is arguably the most critical aspect of developing and commercializing drug device combination products. Regulatory bodies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have established specific guidelines to ensure the safety and efficacy of these complex products.
First, companies must determine the regulatory pathway applicable to their product. Understanding the regulatory classification of a drug device combination product is essential and depends on its principal mode of action. This will dictate whether the product will be regulated as a medical device, a drug, or a combination product. This determination influences the type of regulatory submission required and the specific requirements for demonstrating safety and efficacy. In addition, rare diseases often qualify for expedited regulatory pathways, such as the EMA Accelerated Approval pathway or in the US Fast Track, Priority Review, Breakthrough Therapy, or Accelerated Approval, which aim to speed up the approval process and provide incentives for developers.

Key considerations:

  • Familiarize regulatory guidelines for combination products, which often differ from traditional drug or device approval.
  • Understand the requirements for both drug and device components, including quality control, safety, and efficacy data.
  • Leverage orphan drug incentives to offset costs and expedite the approval process, such as tax credits, fee waivers, and market exclusivity.

For those orphan drugs that are granted an expedited approval pathway, the challenge for the biopharmaceutical company is to leverage their own or their partnering CDMO’s drug development, manufacturing, drug device design, final assembly, and packaging knowledge. This expertise will help build a drug device strategy that maintains the integrity, quality, and timeliness of the manufacturing process, ensuring a complete regulatory submission package is generated to support filings. Aligning development, analytical, manufacturing, pack design and device packaging functions internally or via a CDMO providing integrated end-to-end advanced drug delivery solutions is vital to aid speed to patient and keep activities on the critical path for regulatory submission.

Formulation and Device Compatibility

The successful integration of a drug and a device requires meticulous design control to address the unique challenges posed by combination products. The compatibility of the drug product and the device, as well as the potential impact on the product’s stability and performance, must be thoroughly assessed during the development phase.
For combination products, it is critical to evaluate the chemical and physical compatibility of the drug with potential device materials and designs. Container closure studies are conducted during the development of drug products to compare the performance, stability, and compatibility of the product packaged in different container types.
Evaluating multiple container closure system configurations early in the development lifecycle provides optimum flexibility and accelerates speed to market. For example, certain drugs may require specific types of delivery mechanisms, such as injectors, inhalers, or depending on viscosity – on-body injectors. If the device component is not properly designed to work with the drug product, it can lead to decreased efficacy, increased side effects, or device malfunctions.

Additional studies to conduct:

  • Stability testing under various storage conditions (e.g., temperature, humidity) to evaluate the degradation kinetics of the drug product and ensure the drug product maintains its efficacy and safety when used in the device.
  • Functional stability testing following ISO 11608-5 guidelines, testing cap removal force, activation force, extended needle length, dose accuracy, injection time, and lockout force to ensure the device can accurately and consistently deliver the required dose.
  • Container Closure Integrity Testing (CCIT) is critical for maintaining the sterility and stability of the drug product. Both vials and prefilled syringes undergo testing to ensure that the closure system combination effectively prevents contamination and leakage. CCIT may be conducted in parallel with auto-injector functional stability testing.

Clinical Trial Design and Execution

The generation of robust clinical evidence is paramount for the successful commercialization of drug device combination products. Companies must design and conduct clinical trials that not only demonstrate the product’s safety and efficacy but also provide meaningful real-world data on the interaction between the drug and the device.
The design of clinical studies should align with regulatory requirements and consider the unique challenges posed by drug device combination products. Well-designed clinical trials should consider patient populations and clinical endpoints. Collecting data on both the drug and device components individually, as well as their combined effects, is essential for building a comprehensive body of evidence to support regulatory submissions.
Clinical trials for rare diseases, however, present unique challenges, such as small patient populations, heterogeneous disease presentations, and limited geographical distribution. For drug device combination products, these challenges are compounded by the need to evaluate both the drug and the device in a single study.

Key clinical trial considerations:

  • Design flexible and innovative trial protocols that accommodate small and diverse patient populations. 
  • Consider adaptive trial designs, which allow modifications based on interim results to optimize limited patient numbers. 
  • Engage with rare disease networks and patient advocacy organizations to facilitate patient recruitment and retention. 
  • Real-World Evidence (RWE) can supplement clinical data, particularly post-market, to support ongoing effectiveness and safety. This is crucial for rare diseases where patient numbers are limited. 

Patient Centric Design and Usability 

Human factors engineering (HFE) forms a critical aspect of drug device combination product development, especially for patients with rare diseases who often have specific needs and limitations and may lack experience using medical devices. Therefore, creating a drug device combination product that is easy to use and suited to their unique requirements is essential.
With a patient-centric focus, the interaction between users and the product as received is paramount. Understanding how patients and healthcare professionals interact with the packaging, IFU, and device itself is vital for optimizing usability, minimizing user errors, and enhancing overall safety, efficacy, and adherence to gain improved health outcomes.
Conducting usability studies and incorporating human factors considerations early in the design process can help identify potential issues and inform design modifications. Human factors and usability engineering are integral components of regulatory submissions and are essential for demonstrating the product’s usability and user comprehension.

Key design considerations:

  • Involve patients and caregivers in the design process to ensure the device is user-friendly and addresses their needs. 
  • Implement human factors engineering (HFE) to enhance usability and adoption of self-administration devices. 
  • Design devices with intuitive controls, clear instructions, and support for various stages of disease progression. 

Device Strategy – Intellectual Property (IP) Protection

One of the benefits of developing therapies for rare diseases is market exclusivity – seven years in the U.S or ten years in the EU. A key decision to be made regarding device strategy is whether there is a unique need for device innovation for specific patient populations or if traditional, readily available platforms would be suitable. Selecting established platforms that have received regulatory approval as part of a drug device combination product previously may be deemed lower risk for rare disease therapy and may provide greater speed to market. For innovative platforms, as part of a company’s device strategy, securing intellectual property (IP) rights is crucial in the competitive landscape of drug device combination products. Companies must carefully navigate the patent landscape to protect their device innovations and establish a strong IP position.

AdvantagesDisadvantages
Established platform • Lower upfront costs 
• Leverage of existing capital infrastructure
• Smoother regulatory path
• Robustness of device uses currently in the market 
• Limited product differentiation • Higher unit costs
• Coemption of supply for popular devices 
Proprietary platform • Product differentiation – competitive advantage
• Custom design for specific applications
• Extend Intellectual Property (IP) life of the product
• Lower unit costs if scale competitive advantage
• Custom design for specific applications
• Extend Intellectual Property (IP) life of the product
• Lower unit costs if scale is achieved
• Higher upfront time 
and costs, for example, design, IP, capital technology
• Complex regulatory path 

Key considerations: 

  • IP strategy should consider both the drug and device components individually and in combination. To ensure competitive exclusivity, this may require separate patents and coordinated patent lifespans. 
  • Determine if the high investment costs of device innovation are warranted for small patient populations and if the added cost can be recovered. 
  • Orphan drug exclusivity can be a major factor in recouping development costs and attracting investors. 

Scalable Manufacturing and Securing Supply Chains

The small patient populations associated with rare diseases result in not only smaller clinical batch sizes but also commercial batch manufacturing which can pose challenges for relatively small campaigns and cost-efficiencies.

In sterile fill-finish, often the use of disposable filling solutions provides complete manufacturing flexibility, maximizing product yield, while minimizing any potential risk of cross-contamination at the manufacturing site. For the final assembly and packaging of drug device combination products, device-agnostic scalable technologies with comprehensive tool sets can deliver optimized output, reducing the need to validate new processing lines, helping accelerate supply to patients, and reducing costs.

Regardless of scale, ensuring the quality and consistency of drug device combination products is paramount. Manufacturers, whether that be the biopharmaceutical company or their partnering CDMO, must adhere to good manufacturing practices (GMP) to guarantee the reproducibility and reliability of the product. This involves implementing rigorous quality control measures at every stage of production, from raw material sourcing and sterile filling of the drug product into the primary container to final drug device combination product assembly, labeling, and packaging.

Validating robust scalable manufacturing processes and controls is essential to produce combination products with consistent quality and performance throughout the drug device combination product lifecycle, from clinical trials to commercial market supply. For rare diseases, scaling up should focus on flexibility without compromising quality, as increased patient reach may necessitate changes in manufacturing processes.

For the commercial success of rare disease drug device combination products, ensuring a robust and secure supply chain is vital. Companies should establish strong relationships with suppliers and partnering CDMOs, implement risk mitigation strategies, and have contingency plans in place to address potential disruptions. This is particularly important given the interconnected nature of the drug and device components, each with its own set of manufacturing and sourcing considerations.

Key considerations:

  • Establish partnerships with specialized contract development and manufacturing organizations (CDMOs) experienced in SFF and final assembly, testing, and packaging of combination products at various scales. 
  • Optimise manufacturing processes to reduce costs while maintaining high-quality standards. 
  • Plan for scalability to meet demand as more patients are diagnosed and treatment adoption grows. 
  • Considerations such as dual sourcing for critical components and risk management for supply continuity are key. 

Economic Considerations and Market Access 

Rare disease therapies often come at high costs due to the limited patient base and the high cost of research and development. Small-volume manufacturing, investment in device development, and final assembly and packaging in a drug device combination format adds additional expense. Securing reimbursement from payers is essential for market success. However, payers may hesitate to cover high-cost products, especially for rare diseases with limited patient populations.

Due to a geographically dispersed patient population, the best practice would be to consider multiple formats for regional presentations. Driven by cost and reimbursement, companies increasingly bring different injectable formats to different geographical territories. For example, some may commercialize vials with syringes for Eastern European markets but may look to more advanced prefilled syringes with safety devices or autoinjectors for the US or Western Europe.

Key considerations: 

  • Work with health economists to develop evidence of the product’s value and potential cost savings for healthcare systems by investing in a patient-centric self-administered device. 
  • Gather real-world data to support reimbursement negotiations, demonstrating improved patient health outcomes and reduced hospitalizations. 
  • Develop drug device combination product strategies with flexibility to accommodate geographical reimbursement variations. 

Conclusion 

Developing drug device combination products for rare diseases requires a holistic approach that addresses regulatory, technical, patient-centered, and manufacturing aspects. From understanding patient needs to navigating complex regulatory pathways and designing a user-friendly product, each step is crucial to creating a solution that improves patient outcomes and quality of life. 

While the development process is challenging, advances in technology, patient advocacy, and regulatory support provide an encouraging environment for innovation. By addressing these considerations, biopharmaceutical companies can create commercially viable, effective, safe, and accessible drug device combination products that meet the needs of patients with rare diseases, ultimately improving lives.

REFERENCES 

1. https://www.rarediseaseday.org/what-is-a-rare-disease/ 

About the Author

Bill Welch is Executive Director of Market Development for PCI’s advanced drug delivery business segment, with a focus on injectable drug device combination products. Bill has over 30 years contract development and manufacturing experience, with over 20 years in drug delivery devices and combination products. Prior to joining PCI, Bill served as Chief Technology Officer at Phillips-Medisize, leading a 900-person global innovation, development, and new product introduction service segment. Bill holds a B.S in Industrial Engineering from the University of Minnesota, Duluth.

 Innovation for the Few: Key Development to Commercialization Considerations for Drug Device Combination Products in Rare Diseases  | As seen in International Biopharmaceutical Industry Magazine | December 2024


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