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Nabil Dib, MD, MSc
Nabil Dib, MD, MSc
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 procurement of funding. Engineers trained in the sciences of design, prototyping and manufacturing create products according to rigorous quality standards to ensure safety, functionality and reliability. Pre-clinical (bench and animal) testing establishes basic aspects of safety, functionality and efficacy. Clinical testing is performed to determine clinical utility (i.e., how does the product benefit 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 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 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, certificating 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 inefficiency of time and money. Consequently, on the one hand, many brilliant ideas never make it to the clinic, and on the other hand, significant resources are spent on ideas with little chance of success.
There is a recognized need for development of formalized curricula for teaching the foundations of Translational Research within academic institutions. These are currently in their infancy. The goal of this textbook is to bring together elements of each step of the process (Fig. 1) and to provide specific examples where this has been successfully applied.
Figure 1. Steps in the Translational Research Pathway.
Our focus is on cardiovascular applications. 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. Finally, specific attention is given the device-based, biologic-based and drug-based approaches.
In order to set the stage for the topics of this book, 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 is original, 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 a patent. Such protection provides value and interest from the investment community in providing support. It is critical that the idea be protected before any public disclosure of the idea, either in the form of oral presentations or publications. This topic is reviewed in detail in Chapter l.1.
Products need to be categorized into devices, biologics or drugs. The regulatory pathway for each is distinct. Each product type requires specific manufacturing, a quality control system, pre-clinical 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; clinincians 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. Cell-based therapy is another example where cross-functional collaboration is required. A clinician doing research in the hospital may not be familiar with the daunting task of product manufacturing, regulatory requirements and associated costs, both long and short-term. A cell based therapy could be optimized for growth and expansion in vitro, but may lose its regenerative potential in the process. It could be optimized for all aspects of expansion, regenerative capacity, storage and shipping, but not delivered to the therapeutic site in the patient because of poor targeting. Incompatible manufacturing materials toxic to the cells or inadequate skills of the clinician working with the device can lead to failure of a product that could have been otherwise successful. Unless there is a broad and extensive understanding of the essential elements leading to success, attempts to develop innovative ideas are destined to fail. Not for lack of effort, but for lack of a full understanding of the interplay amongst the governing elements. Consider one final example involving cells and biomatrices. Many differentiated cells require specific extracellular interactions to maintain a differentiated phenotype. Much work has been undertaken to develop matrix materials synthesized in the laboratory under controlled manufacturing conditions that promote differentiated cell growth and function. These same biomatrix materials that are optimal for growth in vitro and function can attract cataclysmic foreign body and/or immune reactions when introduced into living tissue. Superiority in vitro does not automatically translate to utility in vivo.
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 priority number one. The animal testing enables the most detailed access to tissue, physiologic measurements and pathologic 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 measure the therapeutic intent of the product. For example, 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. If the goal is to develop a cellular therapeutic, the measures are far different and must show successful delivery, targeting, minimal effective dose, and unequivocal improvements to relevant physiologic measures. As few of these parameters are well established we need translational research teams to be standardized from toxicology study design and endpoints to phase I, II, 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, 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 toxicology studies required for a Biologics Licensing Application (BLA), Investigational New Drug application (IND) 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 not ideal for myocardial infarction (MI) studies because of the extensive collateral circulation in the that makes it difficult to induce MI (9). Meanwhile, pigs and sheep have less collateral circulation, making it a far better choice for myocardial infarction 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 Phases I, II, and III. The objective of each phase is different. Phase I concentrates on the feasibility and safety of the product. Phase II emphasizes safety and defining a dose to establish efficacy if biologic or drug were used. Phase III is designed to confirm the efficacy at the dose(s) established in the Phase II, and further define safety. 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. Further information can be found at www.fda.gov.
Critical details of design endpoints and interpretation will be provided in the chapters 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 BLA, IND, and IDE applications is provided in the chapters within this textbook.
Funding for translational research is the final integral part of success. At the current time, the investment community is risk averse, which penalizes the 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: too long for traditional investment funding. It is expensive, and requires experts in business/market development, fund raising, intellectual property (IP) 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. This may be best done in the hospital/university environment. 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 vs. the traditional grant based funding is the most advantageous for achieving lasting success. The traditional grant writing and proceeding with a proof of concept is a slow and arduous process, which after peer review, often gets watered down into flawed design by committee. This usually involves a scientist, 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 mentioned in the preceding steps in translational research.
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, we need to provide subject matter with supplimental curriculum that includes discovery and the topics mentioned above.
I hope you find the chapters of this textbook helpful in guiding development of concepts and their successful translation to patients.