How a medical device is developed and tested
A medical device reaches its pivotal study by a path of its own: a clinical need, a prototype, bench work, animal work and often a feasibility study before anything is designed to confirm performance and safety. Because a device does not act pharmacologically, that path asks for fewer subjects and tolerates more design changes than a medicine's. An implant's preclinical phases rest on design control, bench testing, risk management and biocompatibility testing, each documented for the submission, and studies designed for certification can also be designed to answer the questions that decide funding and reimbursement.
Differences that follow from a non-pharmacological mode of action
The inherent differences between medical devices and medicines have implications for clinical research and medical writing. Because a device does not achieve its principal action by pharmacological means, it has fewer opportunities to interact with the body than a medicinal product with its many possible systemic effects, though it can still cause harm by introducing infection, promoting thrombosis, stimulating allergy or causing conduction disturbances. Those complications are generally biophysical and can usually be anticipated, so a smaller cohort suffices to confirm safety and performance and approval is faster than for a medicine, where unexpected side effects can still emerge after extensive testing in large numbers of patients. Knowledge of pharmacokinetics, pharmacodynamics and pharmacogenomics is very relevant to developing a medicine and not to most devices.
Compared with a medicine's, a device's development is more technical and involves engineers, runs on a faster cycle, needs fewer patients in its clinical studies and brings more frequent product updates.
A device is also relatively simple to alter, and changes rarely have detrimental effects; it is not unusual, for example, for several iterations of a product to be tested during a study to fine-tune its design. In pharmaceutical development, by contrast, a small change to a molecule can have major consequences, as when acetylating salicylic acid to make acetylsalicylic acid was found to reduce its side effects significantly, giving aspirin.
From clinical need to pivotal study
Devices are developed specifically to meet a clinical need: the first step is to find a possible solution and the second is to build prototypes, work commonly done by engineers, often in close cooperation with physicians. The first heart valve, for instance, was developed by a retired engineer with a background in hydraulics and fuel pump technology working with a surgeon.
The device is usually bench-tested first, by studying a physical property such as the elastic recoil of a stent, and research in animals may then be required. Animal studies work well for certain parameters, such as toxicity or degenerative behaviour, but are often insufficient to predict ultimate behaviour in humans: positioning of the device, frequency of rapid pacing, acceptance of paravalvular leakage and degree of oversizing were a few of the many issues the first transcatheter heart valve studies had to address. Devices requiring complex implantation techniques are therefore often subject to feasibility studies, to see whether the whole procedure works as intended, before a pivotal study is started.
Preclinical phases of an implant
Implantable devices are introduced into the body either surgically under direct visualisation or through minimally invasive interventions under external visual control. Their research and development is complex and time-consuming. Because they are invasive, implantable devices are considered high-risk devices requiring extensive preclinical research and testing. Many are described as revolutionary or breakthrough inventions, or as novel applications of existing technologies. Some are considered disruptive to accepted treatments or standards of care and may require new medical subspecialties to be qualified. Marketed implants that change substantially through new materials, processes, techniques or designs can require new regulatory approvals. Transcatheter heart valve implantation is an example of a disruptive therapy: redesigning existing surgical biological valves and catheter delivery systems allowed an artificial valve to be implanted into the beating heart without opening the chest, a heart-lung machine or suture fixation.
Developing new and innovative implants is exciting but challenging and often resource-intensive. Keeping new implants in the pipeline takes a culture in which innovative ideas are nurtured and quickly initiated, and an infrastructure committed to the development and preclinical phases even though their risk of failure may be high. Despite the recent increase in regulatory hurdles, a complete and successful submission depends on thorough planning, attention to detail, rigorous testing protocols and accurate, complete documentation in the early preclinical phases.
Optimising a device's evaluation, its test results and their presentation in a submission requires an understanding of the development phases and processes, the international standards to follow and the regional requirements. Medical product development can be divided into five phases — ideation or discovery; preclinical research, meaning design specification, prototyping, bench performance testing and in vitro and in vivo testing; human clinical trials; regulatory preparation, review and submission; and post-market surveillance — with timelines that depend on the device's risk class and on the extent of its preclinical testing and clinical results. Implants in direct contact with tissue, bone or blood are class III devices requiring extensive preclinical testing and clinical trials in both the EU and the US.
The development team
A project-specific new product development team should be created to reduce communication barriers between departments and improve the submission process, with representatives from engineering, research and product development, animal testing, medical and clinical affairs, medical writing, quality, safety, regulatory, manufacturing, packaging, labelling, product management and marketing. A diverse interdisciplinary team brings a wide range of knowledge and experience that can expedite discussions within and between departments, offer suggestions and generate questions on new findings. Team leaders traditionally come from engineering and product development and are responsible for managing information within the team and to company leadership. Rotating the lead, or naming co-leaders with expertise in the current development phase, should however be considered, because it can improve focus on that phase's goals and timelines and better address its issues. When it is time to develop clinical trial protocols and prepare for human trials, for example, a medical or clinical affairs member is better placed to interface with and direct the team than someone from engineering. Rotation also supports growth in members' expertise, encourages creativity, develops new leadership skills and motivates members' involvement.
Ideation and discovery
Ideas for new devices usually arise from the need to treat or alleviate unmet clinical challenges of diseases in a larger patient population. Clinicians with considerable knowledge and experience of a specific disease often develop ideas to improve patient outcomes, and their patient observations and early research are key to collaborating with industry on early evaluations and on defining the engineers' initial concepts, designs and materials. The discovery phase has to weigh anatomical structures, biological reactions, clinical complications, engineering issues, material availability and mechanical limits. Device engineers may need knowledge of fields that may include biocompatibility, structural design, electromechanical systems, delivery systems, power management and wireless communication. A complete review of the scientific and medical literature, covering in vitro and in vivo animal research and human trial experience, helps in understanding the underlying disease process, current standards of care, device inputs and designs, compatible materials and the clinical results of similar marketed devices, and it should be available for the submission. Surgically implanted devices may need new instruments or implant accessories, whereas minimally invasive techniques will require additional instruments or delivery devices to bring the implant to its target. Changes in visualisation techniques can also be necessary: in transcatheter therapies for structural heart disease, for example, multimodality imaging now enables more reliable pre-procedure planning, accurate placement and post-procedure follow-up. Such adjunct devices also need development or modification documentation, testing and regulatory approvals, and their documents must be included in the implant's submission and may require separate approvals.
Design control
Design control is an integral part of product development that ensures the device being developed is safe. It is meant to avoid undocumented changes, improve predictability and reduce unanticipated surprises during development and production. The FDA first included design control requirements in its approval processes, now in 21 CFR 820.30; the MDR places design control in the manufacturer's quality management system addressed in Annex I chapters 1 and 2; and ISO 13485:2016 covers it in section 7.3, with which the FDA rule is fully aligned. Its phases are design planning with the user and patient needs, design input, design output, design verification and design validation, and a design history file is required to hold their records and show that the design was developed according to the approved plan and requirements. In the planning phase the user identifies the product's intended use, its indications for use and its patient population. The intended use is the purpose of the device, and the indications are the disease state or disorders it diagnoses, prevents, alleviates or cures. Design inputs are measurable design features covering all the device's physical, functional, safety and performance requirements; they can be driven by guidance documents, predicate devices, competitive products, industry standards or risk analysis, and their descriptions must be clear and concise and are tested against pass or fail criteria. Design outputs show that the inputs have been implemented and can guide production and assembly, as specifications, manufacturing procedures and assembly instructions, engineering drawings and engineering or research logbooks do. Design verification demonstrates that the product was made correctly and consistently meets the design inputs, and its test reports must be documented with objective evidence in the design history file. Design validation ensures that the correct product was consistently manufactured and meets all the identified user needs and intended uses.
Prototyping and bench testing
Prototyping identifies the optimal design, compatible materials and manufacturing processes; early prototypes are mostly made by hand, may go through several iterations and are not always in final production materials. Non-clinical bench performance tests then simulate anatomical and physiological conditions to validate the plausibility of the device concept. They can cover mechanical and engineering evaluations such as fatigue, material wear, tensile strength, compression and burst pressure, and they are performed on ex vivo, in vitro or in situ animal or human tissue, animal carcasses or human cadavers. All testing is to be governed by documented protocols. A submission requires complete test reports giving every test performed with its objective and method, predefined pass or fail criteria, a results summary, discussion and conclusions, and regulators often also request a table of test summaries. The overall objective is to demonstrate substantial equivalence to a predicate device, or reasonable assurance of safety and effectiveness, and that the implant is durable and can be consistently produced, before it is implanted in a human. In the early design phase bench testing can pinpoint potential design and mechanical flaws and check performance and safety; once the initial design is finalised it documents that the device meets its specifications; and preproduction prototypes or production units are also tested when available. Technical testing of materials and electronic components is part of the proof-of-concept testing. The development team should carefully review the testing strategy so that all required and appropriate tests are transparent and complete, including tests for pre- and post-marketing requirements such as comparative testing with earlier models or other similar marketed models, or for marketing brochures and labelling.
Risk management
The early design phase also includes creating a risk management plan and assigning a team knowledgeable about the device's construction, function, production and use and about risk management. The MDR mandates risk management in Article 10(2) and describes it in Annex I section 3, the FDA's quality system regulation addresses it too, and both use ISO 14971:2019 as their guidance. Its purpose is a device free from unacceptable risk, and the process runs from design and development to final market withdrawal. Most manufacturers have managed risk through a failure modes and effects analysis (IEC 60812:2006) traditionally owned by engineering, but a design analysis of that kind looks specifically at component failures, their consequences and their mitigation, which is only part of the process. Risk management under ISO 14971 identifies and analyses known and foreseeable hazards and the resulting harms, estimates the acceptability of each risk, and then identifies and verifies risk controls and residual risk. This analysis is best documented in a dynamic hazards matrix that is reviewed and updated regularly, especially when production data, complaints, post-market surveillance, literature or clinical evaluation report updates bring new information. A risk management file must also be established to hold the records for a submission or an auditor.
Biological evaluation and biocompatibility
Following bench and technical testing, the materials or the implant must undergo biological evaluation and biocompatibility testing to demonstrate that it performs its intended function without short- or long-term adverse effects, across endpoints such as cytotoxicity, mutagenicity and genotoxicity, haemocompatibility, irritation, sensitisation, acute systemic and subacute or chronic toxicity, carcinogenicity and material-mediated pyrogenicity. In vitro and in vivo animal tests are often performed to evaluate the interaction with body fluids, cells and tissue, and the animal model depends on the materials and the implantation site. FDA guidance released shortly before 2022 focuses on more efficient testing and on well-designed large-animal studies that leverage safety tests such as systemic toxicity, chronic implantation and in vivo thrombogenicity, replacing the traditional small-animal model. ISO 10993 on biological evaluation runs to 20 parts that can help the manufacturer select the most appropriate tests to screen for biocompatibility and manage biological risk. Part 1 sets out the applicability of the other 19 and the need to evaluate results within the risk management process, and its attachments A to F give recommendations, examples and summaries of the reports to be written for the biocompatibility section of the submission.
Stages and designs of clinical investigations
Annex I of ISO 14155:2020 helps define the stages of a device's clinical investigations and the types of study design. A pre-market investigation may be at a pilot stage or at a pivotal stage. The pilot stage is exploratory and captures preliminary information early in the device's design, development and validation. It might not require pre-specified statistical hypotheses, though its design and outcomes can be more straightforward if statistical considerations are provided, and it helps plan the further steps of design development, such as the need for design modifications and the parameters for the pivotal investigation. The pivotal stage is confirmatory: it collects data on the device's clinical performance, effectiveness or safety in a statistically justified number of subjects, and it may or may not be preceded by an early or a traditional feasibility study.
Pilot investigations take three forms. A first-in-human investigation evaluates the device in humans for the first time, and a burden to subjects is expected. An early feasibility investigation is a limited investigation of a device early in its development, before its design is finalised, done in a small number of subjects when the information cannot be provided by non-clinical assessment or the non-clinical tests are unavailable; it evaluates the design concept with regard to clinical safety, performance and effectiveness, and what it finds can guide modification of the device. It does not necessarily involve the device's first clinical use, so compassionate-use studies, for example, may precede it. A traditional feasibility investigation, or proof-of-concept investigation, is done on a near-final or final design, commonly to capture preliminary performance, effectiveness or safety information and to plan an appropriate pivotal investigation. Because it takes place later in development, more non-clinical or prior clinical data are expected for it, and it need not be preceded by an early feasibility investigation.
A post-market investigation is done after market approval to answer specific questions about the device's performance, effectiveness and safety, and it can be part of post-market clinical follow-up. When a marketed device is investigated for new indications other than those described in its labelling, the requirements for a pre-market investigation apply.
The annex separates three types of study design. An exploratory investigation, such as a first-in-human or early feasibility investigation, might not have pre-specified statistical hypotheses and can be conducted to generate a hypothesis that a later investigation confirms. A confirmatory investigation is adequately controlled, states the hypothesis of its primary endpoint in the plan before it starts, and applies sound confirmatory statistical testing. An observational investigation draws inferences about the possible effect of an intervention on subjects, but no subjects are assigned to intervention groups and only data from the normal course of clinical practice are collected.
The annex also separates interventional from non-interventional investigations. An interventional investigation, pre- or post-market, decides the assignment of subjects to the device in advance in the investigation plan and pre-specifies diagnostic or monitoring procedures in addition to those of normal clinical practice; an innovative device for a new or established technology and a marketed device for a novel clinical application are examples. A non-interventional investigation is post-market: the device is used according to its labelling, the assignment of subjects is not decided in advance but falls under current clinical practice, no diagnostic or monitoring procedures are defined, and epidemiological methods are used to collect the data.
The development of a bioresorbable magnesium scaffold
Developing a novel device starts with defining its key design requirements, as the life cycle of Biotronik's bioresorbable magnesium scaffold shows. The permanent stent and then the drug-eluting stent had greatly improved the treatment of coronary artery disease, but complications such as restenosis and stent thrombosis arose, and the solution defined was a stent that removes the blockage and then completely disappears. The prototype went through preclinical bench testing of properties such as backbone flexibility and then animal safety studies of restenosis rate and thrombogenicity. Because preclinical data cannot be translated directly to humans, a trial in humans followed: the first-in-human trial PROGRESS and later the BIOSOLVE studies investigated safety and efficacy. The application for CE marking after BIOSOLVE-I was rejected for small sample size and for lack of statistical analysis, which the old regulations had not required. BIOSOLVE-II addressed both and showed that the scaffold dissolved too quickly after implantation, causing restenosis, so changes were made to lengthen its half-life in the body. The results of the following trial were greatly improved, the marking was obtained in 2016, and pivotal and post-market studies, BIOSOLVE-III and IV, were ongoing in 2018. In the manufacturer's account, ideally a device moves through each developmental phase only once; in reality several iterations and improvements are required at every stage before the final product. Publishing validated data before and after the product is released to market is essential to monitor the device's performance and for future developments.
Certification and market-access studies designed together
Pre- and post-market have traditionally been handled by different bodies working in separate timeframes on different aspects of the market, and that division between their regulatory requirements drives disjointed perceptions and processes that waste resources, opportunities and time. Pre-market randomised trials tend to be designed with only the regulatory requirements for a product submission in mind. Questions such as post-market clinical follow-up, health technology assessment and the quality-adjusted life year, which ultimately decide which products receive funding and reimbursement, are often overlooked because certification does not require them. They are deferred instead, which makes it more likely that more data will be needed later, with more work and cost for the manufacturer and a slower path to funding and reimbursement. The MDR now regulates clinical investigations and integrates pre- and post-market requirements, requiring manufacturers to support their product claims before and after marketing through post-market surveillance including post-market clinical follow-up, so in one view it makes sense for clinical studies and market-access studies to work together, to better predict a product's economic viability as well as its safety and performance on the market. On that view, manufacturers can reassess how their trials could be designed to include additional endpoints that can be used downstream. Putting health technology assessment or follow-up questions alongside the pre-market trial questions can produce data that help to focus post-market research or marketing initiatives, free up resources, potentially smooth and speed the path to funding and reimbursement, and benchmark the product in its market. On that view, integrating the design of pre- and post-market trials will both help manufacturers meet the EU's regulatory requirements and optimise the resources they are required to invest.