Basic Concepts in Device Development
Overview of Cardiovascular Translational Research
Nabil Dib, MD, MSc
Nabil Dib, MD, MSc
Robert Califf, MD
Advances in medical therapies and diagnostics result from integrated efforts of multidisciplinary teams that take an idea from concept to market. Ideas are generated by health care workers from a wide spectrum of professional and educational backgrounds. Assessment of the potential applicability (market analysis) and patentability of ideas leads to assignment of value for the purpose of procuring funding. Engineers trained in the sciences of design, prototyping, and manufacturing create products according to rigorous quality standards to ensure safety, functionality and reliability. Preclinical (bench and animal) testing establishes basic aspects of safety, functionality, and efficacy, while clinical testing is performed to determine clinical utility (i.e., how the product benefits the patient). Such testing relies on partnerships between sponsors (industry), physicians, hospitals, and volunteers (patients) involving a host of real and implied legal, ethical and moral responsibilities. Final approvals from regulatory bodies take into account results from the entire history of the product’s development and evaluation. In the current social, economic, and political environments, development costs and the costs to deliver new therapies and diagnostics are of paramount interest and importance. Ideally, oversight of the entire process by an experienced management team ensures seamless integration of the appropriate teams to achieve the end result of an approved, marketable product.
The entire process of taking an idea from concept to market is called translational research. In the past, translational research has been defined simply as application of findings from basic sciences to enhance human health and well-being. However, with recognition of the complexity of the process, translational research can itself be considered a discipline that is subject to advancement through scientific methods based on the cycle of hypothesis generation and testing. Accordingly, we can propose to define translational research more broadly as “a field of science that aims to develop concepts for medical therapies or diagnostic tests from knowledge gained through basic or clinical research and establishes their safety and efficacy through cost-effective processes.” From a practical perspective, declaring translational research as a field of science in this manner establishes the concept that the process of generating new therapies and diagnostics can be improved so that available funding will more likely lead to successful launch of products at lower costs to patients.
Traditional educational curricula are well established in teaching the individual components of translational research, particularly when it comes to medical sciences and engineering. However, exposure to topics such as market analysis, intellectual property, venture capital funding, quality systems, and regulatory requirements, which are the “glue” of the translational process, are traditionally obtained through specialty education, certification courses, seminars, or on-the-job training. It is not suggested that every individual interested in translational research need become expert in all these fields. However, lack of high-level understanding of what it really takes to create a medical therapy or diagnostic test leads to inefficient use of time and money. Consequently, many brilliant ideas never make it to the clinic or, conversely, significant resources are spent on ideas with little chance of success.
While there is a recognized need to develop formalized curricula for teaching the foundations of translational research within academic institutions, such programs are currently in their infancy. The goal of this document is to bring together elements of each step of the process (Figure 1) and to provide specific examples where this process has been successfully applied.
Figure 1. Steps in the Translational Research Pathway
Our focus in this document is on cardiovascular applications, and most of the concepts apply across fields. However, the details and standards of many aspects of the translational pathway are organ system-specific and even disease-specific. This is reflected in the fact that regulatory bodies have separate divisions to oversee products for different organ systems.
Viable Translational Concept
In order to set the stage for the topics of this document, it is important to establish a working definition of a “translational concept,” which is an idea for a therapy or diagnostic test that is based on available basic or clinical data. We consider a translational concept to be “viable” if it meets all or most of these criteria: is original, is patentable, provides a solution for an unmet clinical need, is feasible for clinical application, has the potential to provide benefit(s) to patients, is cost effective, and can stand the test of comparative effectiveness. Some of these criteria are mandatory and we also believe that the greater the number of these criteria that are fulfilled, the more likely a project is to succeed in attracting the necessary scientific and economic support required for execution.
It is essential that any concept being considered for translation to a therapy or diagnostic test be “protected” in the form of a patent. Such protection provides value and interest from the investment community in providing support. It is critical that the idea be protected before there is any public disclosure of the idea, either in the form of oral presentations or publications.
Products need to be categorized into devices, biologics, or drugs, because the regulatory pathway for each is distinct. Each product type requires specific manufacturing, a quality control system, preclinical animal testing in appropriate disease models, and well-designed clinical trials with appropriate therapeutic endpoints. All members of the translational research team — including basic scientists, clinical scientists, toxicologists, regulatory personnel, manufacturing experts, business experts, and medical reimbursement specialists — need to be aware of the focus for each product type and collaboratively design and execute the development plan to avoid introducing errors into the linear development pathway. For example, a medical device engineer might be extremely knowledgeable in device development, but he is not familiar with the complexity of the anatomy and applicability of such a device when used in a patient. The clinician might not understand basic engineering, testing and documentation requirements such as design control, product specifications, prototype development, manufacturing requirements, quality control, sterilization and biocompatibility; clinicians are notorious for requesting device modifications several times during a development cycle without understanding the time and cost implications of even what seem to be minor changes.
Selecting an animal model for testing proof of concept is one of the most critical development choices (1-9). Many diseases are chronic in nature and not easily modeled in animals. Focusing the scientific question to be addressed in animal studies is the number one priority. The animal testing enables the most detailed access to tissue, physiological measurements, and pathological analysis of any phase of product development. Animal models are used to mimic, as closely as possible, the situation to be treated in patients. A few additional animal studies can sometimes avoid years of work and millions of dollars of clinical testing costs when done correctly.
No therapy should be launched into clinical setting without the means to measure the therapeutic intent of the product. Too often, the measures applied in animal testing do not actually measure the product’s therapeutic intent. Demonstration in an animal model that a left ventricular assist pump can sustain sufficient blood flow, maintain this function for a meaningful period of time, and show no evidence of damage to other body organs markedly increases the chances for a successful clinical study. As few of these parameters are well established, we need translational research to be standardized from preclinical study design and endpoints to phase I, II, and III clinical trials so comparison of product effectiveness and cost effectiveness become possible. Once there is a critical mass of teams working on these issues, there may be a higher probability of success in the clinical application of new technologies.
There are both small and large animal models for many disease studies. For proof of concept for drugs or biologics, a small animal model is less costly and allows for testing in a greater number of replicates to demonstrate effectiveness with greater statistical significance. However, for the toxicology studies required for a Biologics Licensing Application (BLA), Investigational New Drug (IND) application, or Investigational Device Exemption (IDE), a large animal model is likely to be required for approval to enter into a phase I clinical trial (10).
The recommended large animal model, whether it be non-human primates, pigs, sheep, or dogs will depend on the therapeutic to be tested. Each model has its advantages and disadvantages. For example, for cardiovascular diseases, the dog model is considered closer to human than pigs for septal puncture and is considered less than ideal for myocardial infarction (MI) studies because of the extensive collateral circulation in canines that makes it difficult to induce MI (9). Meanwhile, pigs and sheep have less collateral circulation, making them far better choices for MI studies, although the reported mortality in pigs is high because of a propensity to arrhythmias (9). Having a cardiac catheterization expert in the animal laboratory substantially increases the survival rate in pig infarct studies. Such experts bring a solid understanding of animal anesthesia, careful monitoring of fluids, arrhythmias, and hemodynamics.
Clinical trials are traditionally separated into early feasibility studies, and pivotal trials in device evaluation and into phases I, II, and III in drug or biologics testing. The objective of each phase is different: This document concentrates on device development and will include sections on early feasibility and first-in-man studies, and detailed descriptions of the design and endpoints of the pivotal trials according to the device tested for what disease.
Understanding the purposes of these clinical trial phases is important, since optimal crafting of the design and endpoints for clinical studies in each phase ensures timely navigation through the regulatory pathway. Critical details of design endpoints and interpretation will be provided in sections to follow.
The critical value of regulatory knowledge and compliance cannot be overemphasized. The regulatory requirements assure that the supporting studies have been completed with sufficient justification as well as the assurance that appropriate animal studies were conducted with sufficient power, appropriate endpoints, and data verification. Regulatory authorities acknowledge standardized techniques and methods because time and investigation has confirmed their rigor and reliability. Data must be collected and reported in the most compliant methods as possible. Much time can be saved and repeated experimentation avoided with good communication and understanding of the regulatory standards. The respect and consideration of the need for regulatory expertise is a key element that a translational team must recognize. A detailed regulatory pathway with requirements for IDE applications is provided in the sections within this document.
Funding for translational research is the final integral part of success. At the current time, the investment community is risk averse, which penalizes truly innovative research initiatives. The demand for a high return on investment in a span of 5 years or less severely restricts the novelty of products developed. If we are to develop practice-changing therapeutics, we cannot rely on the traditional business models. A strong commitment at the academic investigational level needs to be made. This stage of the development poses high risks and potentially long development times that are too long for traditional investment funding. It is expensive, and requires experts in business/market development, fundraising, intellectual property management, and a plan for outsourcing or providing manufacturing capabilities.
One option would be to bring together the didactic training of academic instruction and the applied activities of a translational team, including representatives from industry. This may be best done in the hospital/university environment with collaboration from industry. Practical application coupled with classroom theory makes a powerful force for success, albeit with lower costs than creating the equivalent in the private sector. Fixed funding within university environments versus the traditional grant-based funding is the most advantageous for achieving lasting success. The process involving traditional grant writing and then proceeding with a proof of concept is slow and arduous; after peer review, it often gets watered down into flawed design by committee. This usually involves a scientist and a few students and may only serve for validation of concept and expansion of knowledge. Steps taken to apply for grants should not be confused with expediting science, but a step to generate ideas and feasibility evaluation. Evaluation of the safety and efficacy of a technology and the next steps after feasibility are complex and require a team approach as noted previously.
Currently, most education for physicians concentrates on clinical diagnosis and treatment. However, if we believe that translational research will expedite scientific discovery to benefit patients while decreasing cost, we need to provide subject matter with supplemental curriculum that includes discovery and the topics mentioned above.
I hope you find the sections of this document helpful in guiding development of concepts and their successful translation to patients.
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