In vivo reversible electroporation (or EP) is an enabling technology that allows for electropermeabilisation of the cell membrane to facilitate the delivery of large-molecule therapies. An electromechanical device is used to send a known waveform of electric pulses to the cell wall, thereby improving the permeability of the cell to complex molecules, including DNA-based treatments and vaccines. The process is considered essential for delivering large molecules and therefore enabling the success of these treatments.
The successful development and commercialization of an in vivo, reversible electroporation system present an array of challenges, from the specifics of generator and instrument development to the regulatory hurdles to market entry.
Medical Device Development Process
The process of successfully developing a complex medical device for the clinic follows a standard process that ensures quality, efficacy, and successful treatment:
- Defining user needs, taking into account all end users, from clinicians to patients
- Defining system requirements, translating stated needs to technical specifications
- Planning the development work, and determining which of the various paths forward has the highest likelihood of success
- Performing the development work, reducing the ideas and various concepts to repeatable practice
- Verifying that the design output meets the design inputs to ensure that the device was made correctly
- Validating that the finished device meets the user needs to ensure that the correct device was made
Unlike the process of developing drugs, bringing an electromechanical medical device to market relies on several variables that often remain in flux during the development process and need to be managed after clinical release.
During the process, parts may become obsolete, functional requirements can change, field failures occur, or several other issues can delay or postpone production. This means that device development is not just an initial activity, but something that needs ongoing support and evaluation for the life of the product.
Defining Device Requirements
In the device design process, the first challenge to developing an electroporation device is to define requirements. Translation of electroporation research from bench to animal to human is not trivial. The volumes in a typical laboratory electroporation cuvette are, of course, radically smaller than in a human patient.
Field strengths, pulse durations, and other parameters do not scale linearly and require additional design features to ensure that what is required is consistently what is delivered. Some manufacturers of electroporation equipment intentionally obscure their pulse parameters, while other equipment does not behave as expected.
Ultimately, there are a few keys to a successful electromechanical medical device design process. The right measurement equipment and algorithms must be deployed to ensure consistent and repeatable treatment parameters. This will vary, based on the therapy to be delivered as well as the tissue to be targeted, which requires rigorous characterization and requirements development at the early stages, along with quality checks along the development process. Finally, the teams developing the drug and electroporation device need to work collaboratively through the development phase as the final system will rely on a combination of therapeutic agents.
Technical Problems Defined
Once the requirements are defined, the next challenge is to realize them. With electroporation’s basic premise that we need to apply high-strength voltage fields to relatively electrically conductive humans, the process generates high currents. With this comes a concern for electrical safety, but also the need to avoid thermal injury, muscle contraction, and other usability problems. This means considering the safety of both the operator and the patient.
Many requirements call for a square-wave output waveform, which is tricky if it needs to flow down a cable into an applicator at tens of amps into tissue that has variable impedance. Characterization of loads and understanding of measurement limitations are critically important to success.
Ensuring Regulatory Compliance
The process of in vivo electroporation also presents significant regulatory concerns. In the US, the FDA has determined that any therapy that uses both a drug and a device is a Combination Product and is subject to certain additional regulations, including the successful completion of a multi-center clinical trial with patient follow-up using the final, commercial-ready manufactured device.
Combination Products lead to much more onerous requirements for the design, testing, and documentation of that electroporation system. This is true even if that injection is via a separate standard hypodermic needle not in any way connected to the electroporation device because, in the eyes of regulators, the electroporation device is part of the therapy itself, not simply a delivery vehicle, a la a syringe.
Being a relatively new technology, there is sparse published data or predicate devices to draw upon, which will require some creativity to overcome. As a dedicated team with deep knowledge in electroporation delivery equipment, Minnetronix Medical works to extend capabilities across a product’s lifecycle, identifying critical goals to get products to market and accelerate breakthroughs. Contact us to learn more.