AN OVERVIEW OF CLINICAL TRIALS FOR MEDICAL DEVICES

 

-Dr. S. Vijay Kumar, Professor (Associate) & HOD (Retd.)

            

       Medical devices play a critical role in the lives and health of millions of people worldwide. They play an important role in the practice of medicine, with the creativity and diversity of this sector contributing to enhancement in the quality and efficacy of healthcare. MDs cover a wide range of products, from simple bandages to life-supporting devices such as stents, and play a crucial role in the diagnosis, prevention, treatment, and care of diseases. From everyday household items such as oral thermometers to complex implantable such as deep-brain stimulators, patients and the general public rely on regulators to ensure that legally marketed medical devices have been shown to be safe and effective. The Medical Device sector has become increasingly important for the healthcare of citizens, with an immense influence on expenditure. Medical devices play an important role in the diagnosis, prevention, treatment, and care of diseases. However, compared to pharmaceuticals, there is no rigorous formal regulation for demonstration of benefits and exclusion of harms to patients. In many countries, the medical technology industry is dominated by large numbers of SMEs.

Medical Device – WHO Full Definition:

‘Medical device’ means any instrument, apparatus, implement, machine, appliance, implant, reagent for in vitro use, software, material or other similar or related article, intended by the manufacturer to be used, alone or in combination, for human beings, for one or more of the specific medical purpose(s) of:

·        Diagnosis, prevention, monitoring, treatment, or alleviation of disease,

·        Diagnosis, monitoring, treatment, alleviation of or compensation for an injury,

·        Investigation, replacement, modification, or support of the anatomy or of a physiological process,

·        Supporting or sustaining life,

·        Control of conception,

·        Disinfection of medical devices

·        Providing information by means of in vitro examination of specimens derived from the human body.

 

Clinical Research – Clinical  Trials:

Clinical research is a branch of healthcare science that determines the safety and effectiveness (efficacy) of medications, devices, diagnostic products, and treatment regimens intended for human use. These may be used for prevention, treatment, diagnosis or for relieving symptoms of a disease. Clinical trials are a type of research that studies new tests and treatments and evaluates their effects on human health outcomes. The medical device industry argues that the classical evidence hierarchy cannot be applied for medical devices, as randomized clinical trials are impossible to perform. Three major barriers identified for randomized clinical trials on medical devices, namely: (1) Randomization, including timing of assessment, acceptability, blinding, choice of the comparator group and considerations on the learning curve; (2) Difficulties in determining appropriate outcomes; and (3) The lack of scientific advice, regulations, and transparency. Regulators expect data that are provided by device manufacturers to reflect the risk profile of the device and need more crucial clinical evaluation before market approval. Higher-risk and innovative moderate-risk devices (approximately 4%of all medical devices), which generally require the clinical evidence to show that the benefits of technology outweigh its risks are the primary focus. Clinical evidence of medical devices is often critical not only for showing the safety and effectiveness of the device but also for informing clinicians and patients about the preferred use of the device in the marketed clinical setting. Regulators are demanding more clinical evidence because they want to see more of it before granting market approval. Not only regulators but payers are also requiring more of it to substantiate product value claims and approve reimbursement. Even healthcare systems and physicians are asking for more of it when making purchasing decisions. This demand for clinical evidence from various stakeholders is forcing medical device companies to amass more clinical data on their products than ever before. Companies are responding to this pressure by running more clinical trials, focus group studies, and responding in real-time by making changes to the beta version (a version of a piece of software that is made available for testing, typically by a limited number of users outside the company that is developing it, before its general release) of their medical devices. The latest trend is medical device companies increasingly are turning to clinical trials to differentiate their products from competitors and improve their odds of adoption in the marketplace.

Clinical Trials for Medical Devices:

1. Blinding: Blinding is an important element in all clinical trials; it reduces measurement bias related to the observer’s, doctor’s, or patient’s subjectivity. For ethical or practical reasons, blinding is often more difficult to perform in randomized clinical trials on medical devices compared to pharmacological randomized clinical trials. Medical device companies need to remember that when it is not possible to blind healthcare professionals, a blind assessment of the outcome should be planned with experienced and trained staff as outcome assessors. The data managers, the adjudication committee, the independent data monitoring, and safety committee, the statisticians, and the conclusion drawers should also be blinded. In case blinding is not used, medical device companies and their clinical trial correspondent need to give the reasons for not blinding and discuss the limitations when reporting the results. As blinding of patients and trial personnel may be less often achievable in some medical device trials, objective outcomes must be chosen. Recently, regulatory agencies have emphasized for medical device companies to search for creative methods to blind individuals in their trials, if they choose to incorporate a novel technique, they must ensure that the blinding process itself does not introduce bias by impairing the ability to accurately assess the outcome. Any novel blinding technique should have three qualities: (1). Successful concealing of the group allocation, (2). No impairment in the ability to accurately assess outcomes; and (3). Acceptance by the individuals that will be assessing outcomes. Despite careful consideration of methods to blind individuals in medical device clinical trials, situations will invariably arise when some or all groups of individuals simply cannot ethically be blinded. Medical device companies must accept this reality and incorporate other strategies to minimize bias when blinding is not possible.

2. Outsourcing Work to Experts: It is an industry-wide trend that most device makers lack the internal resources and expertise to run a complete clinical trial operation in-house. It might be possible for a large medical device company to have an in-house clinical development team which can help in facilitating the clinical trials, however, for small medical device companies, which have little bandwidth, experience, and margin for error, the success of clinical trial or failure can be very crucial and sometimes clinical trial means life or death for the small company. As a result, we are witnessing a corresponding rise in the outsourcing of clinical services to contract research organizations (CROs). Medical device companies are turning to CROs for assistance with clinical operations management, investigator recruitment, clinical monitoring, data management, biostatistical analysis, health economic and outcomes strategy, quality assurance, regulatory approval, and other needs. The single most important factor to consider when choosing clinical service providers or a CRO is experience in the medical device clinical trials or expertise in the field. A new way of working is outsourcing work to on-demand experts. This is particularly beneficial to small companies who cannot afford the heavy costs and management spends on working with CROs  or traditional consulting firms. Hiring individual medical device consultants can help to save time and costs, while working with experts directly to customize deliverables. Specialists in the medical device industry are offering their services on a freelance basis.

3. Outcome Assessment for Clinical Trials on Medical Devices: Defining relevant outcomes for clinical trials on the medical device is complex. This is partly due to the great variation in complexity and application for the different types of medical devices such as pacemakers, insulin pumps, operating room monitors, defibrillators, and surgical instruments, and partly due to a large variety of potentially relevant outcomes. A barrier specifically related to the medical device industry is that a common understanding of the concept of outcomes is missing. In clinical trials with medical devices, traditional outcomes such as survival, complication rates, or surrogates (biomarkers, imaging techniques, and omics) are used instead of the more appropriate hermeneutic outcome measures such as quality of life, autonomy, discomfort, disability, and life satisfaction. This does not mean to exclude specific outcomes for the functionality of medical devices such as device failure, device breaking, device slipping, migrating of the device or screw loosening, etc. Trials on medical devices funded by industry are prone to report positive outcomes and to conclude in favour of experimental interventions when obtaining non-significant test results. While industry involvement is necessary to improve technology and to drive innovation of medical devices, it must be based on scientific grounds and fully transparent. The outcome measures selected for MDs should reflect the whole procedure, and all different kinds of settings that the MD can be used in. According to the expert panel, the choice for the most appropriate outcome measure depends on the (1). Primary objective (increase of benefit, reduction of harm); (2). State of development of the technology (feasibility, effectiveness, efficiency); (3). Quality criteria (validity, reliability); (4). Acceptance (by patients, physicians, and scientific community); and (5). Acknowledgement of the value of better tolerability or convenience.

4. Early Scientific Advice and Expert Panels: The medical technology industry is dominated by large numbers of Subject Matter Experts (SMEs). They are not trained in running trials or in trial methodology but have a high output of diverse and innovative products. Access to early scientific advice, especially for smaller companies and academia, needs to be as easy and affordable as possible. Early scientific advice about the clinical development strategy and clinical trials for their devices is wished for. Engaging in the relationship in a meaningful way early helps align on SOP (standard operating procedure) and technology.

5. Regulatory Requirements for Medical Device Clinical Trials: The above tips represent only a fraction of the best practices of clinical trials for medical device manufacturers. Apart from these key tips, compliance with regulatory and ethical requirements is also very important. The new Regulations on Medical Devices imposes increased responsibilities and well-defined interactions between all economic stakeholders involved, like medical device manufacturers, authorized representatives, importers, and distributors. Last, but not the least, trust, and transparency in clinical trials of medical devices is vital. Reviewing clinical trial data. Regulatory review and peer-review of clinical trial results have different objectives, but final published results for either process should conform to the approved clinical trial protocol and specify major deviations and amendments. There should be strict “Regulatory Mechanism”  to check the performance  and authenticity of the medical devices manufactured in a country.

Regulatory Strategy: In India, at present only notified medical devices are regulated as Drugs under the Drugs and Cosmetics Act 1940 and Rules made thereunder in 1945. Under these, 14 medical devices were notified as ‘Drugs’. These ranged from disposable hypodermic syringe and needle, perfusion sets, cardiac and drug eluting stents, catheters, intraocular lens, intravenous cannulae, bone cement, heart valve, scalp vein, orthopedic implant, internal prosthetic replacement, and in vitro diagnostic kits for human immune deficiency virus (HIV), Hepatitis B surface antigen (HBsAg) and Hepatitis C virus (HCV). The Medical Devices Rules, 2017 of the Drugs and Cosmetics Act, 1940 came into force with effect from January 1, 2018. The rules are applicable for (i) substances used for in vitro diagnosis and sterile surgical dressings, surgical bandages, surgical staples, surgical sutures, ligatures, blood, and blood component collection bag with or without anticoagulant, (ii) substances including mechanical contraceptives (condoms, intrauterine devices, tubal rings), disinfectants and insecticides; and (iii) devices notified from time to time. A regulatory strategy is often a formal plan that aligns regulatory activities to business strategy, so as to bring a new or modified medical device product to market. Formulating this plan would require, consideration of various regulatory issues in the target markets one wish to place the product. When well planned, a regulatory strategy should be balanced, realistic, achievable, and in support the organization’s mission and vision. It identifies important regulatory requirements to be addressed and provides overall definition and clear direction for the product development team, even outlining the reasons for the path to be taken. Planning regulatory strategy should be done at the earliest possible stage of product development, while putting D&D (Design & Development) work structure in place. There are three points to consider with specific regard to regulatory concerns: (1). Target markets for commercialization. (2). Medical Device Classification and (3). Overall project milestones and timeline.

1) Target Markets for Commercialization: “In which countries product to be sold ?”It is important to know in which markets the products to be sold and prioritize the various market entries. Different markets have varying market size, medical practices, pricing, and reimbursement, as well as distribution activities. Furthermore, regulatory regimes differ between markets. One would need to evaluate all these different factors when considering regulatory strategy. It can be helpful for D&D plans as well. An example of regulatory difference is the risk classification of medical devices, where the same product might be classed slightly differently under different regulatory regimes. With this differentiation, the timing and ease of product release could be affected as well.

2) Medical Device Classification: “Which risk classification does one’s medical device belong to? “As mentioned above, medical device classification is important in establishing the pathway to a specific market. When one has clearly established the options and requirements for “route to market”, one can better plan your product development with a “go-to-market” strategy. Identifying medical device classification  correctly can allow to clearly establish the relevant controls for the product development and risk management. It is also useful for understanding the risk profile of the product, as well as the competitors’. Based on regulatory requirements for the medical device risk classification, one can determine the required scope of verification and validation, and thus estimate the cost and timeline to bring the product to the market.

3) Overall Project Milestones And Timeline: “What milestones one  can look to gauge the progress of his project? “Tying in with the above points, one would be able to craft regulatory strategy when one have a clear idea of his target market’s regulations and requirements that need to be met. For example, one might find that certain markets require more extensive pre-clinical and clinical trials to be done, while others might request for relevant comparisons of his product. Knowing this would also give a good gauge of the time needed for each step of the certification and product registration process. One can then align his product development and business plans accordingly, to maximize his team’s efficiency. With proper consideration of the key information mentioned, one can have a good grasp on timeline for market entry and product development, as well as the cost involved. Accordingly, this means one able to craft his regulatory strategy to bring his device to the market. Crucial to meeting regulatory requirements throughout the world is having a proper QMS (Medical Device Quality Management System). The ISO 13485:2016 standard is often the reference for best practice QMS processes. One can read and learn more about the ISO 13485.

           To conclude, the Study protocol and a summary of the results are to be made publicly available in databases for clinical trials of medical devices. Moreover, access to individual patient data should also be secured. Trust and  transparency of MDs is very important. In many countries, the medical technology industry is dominated by large numbers of SMEs. The global medical devices market size was valued at USD 425.5 Billion in 2018 and is expected to reach USD 612.7 Billion by 2025, grow at a Compound Annual Growth Rate (CAGR) of 5.4% 2018 to 2025. According to a Deloitte report, the growth rate of India’s medical-device industry is around 15 per cent which is more than double of the global industry growth rate of 4-6 per cent, and is expected to become a $ 25-30 billion industry in India by 2025.

References:

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8.     https://www.fortunebusinessinsights.com/industry-reports/medical-devices-market-100085

9.     https://www2.deloitte.com/content/dam/Deloitte/in/Documents/life-sciences-health-care/in-lshc-medical-devices-making-in-india-noexp.pdf