Ethics is the branch of philosophy that addresses questions of morality. Biomedical ethics, therefore, narrows this focus onto the morality judgments that must be made in the field of medicine, and its allied subjects including biomaterial science. Biomaterial science has evolved at a tremendous pace, with innovations that have empowered clinicians and scientists beyond the imagination of their predecessors. This empowerment has resulted in new sets of ethical questions that were not posed previously. Questions of morality have direct relevance to the practical work of scientists and clinicians in the field as the influence of Institutional Review Boards and ethics committees continues to grow. Furthermore, there is also increasing public scrutiny of biomedical science in general. Therefore, it is important that engineers, scientists, and physicians become familiar with the relevant ethical issues, and actively participate in the debate that guides professional standards in the field of biomaterial science.
Medical device innovation often originates with an observation by a creative individual who encounters a problem in clinical practice and postulates a possible solution. To reach this solution, a linear pathway from the original idea through bench research, preclinical testing in an appropriate animal model, followed by clinical trials and eventual human use is intuitive. However, this linear pathway does not reflect the complexity of innovation. In reality, biomaterial development is recursive, with multiple iterations that may return to in vitro and in vivo testing multiple times, due to the highly regulated environment that is necessary to ensure safety for human patients. Each phase of this recursive process, including ideation, bench-work, animal research, and clinical research, has its own unique ethical requirements, which manifest in regulatory guidelines. This chapter will focus on the ethical principles that have been established and applied to the field of biomedical research and development. At the conclusion of this chapter, we will describe a pathway for the development of a new prosthetic heart valve which will be used to illustrate the application of biomedical ethics as it applies today.
The paramount ethical principle in biomaterial research is the protection of patients. With this goal in mind, the US Food and Drug Administration (FDA) has established a set of regulatory guidelines to standardize studies related to medical devices. As a result, scientific investigation into the development of medical devices must be performed in accordance with defined best practice standards, which carry the weight of law. Preclinical studies must use Good Laboratory Practice (GLP), the manufacture of devices must follow Good Manufacturing Practice (GMP), and clinical trials must be in compliance with Good Clinical Practice (GCP). These Good Practice guidelines are quality systems concerned with organizational processes that are founded upon ethical principles and ensure accountability at every level from the designers, the manufacturers, and the investigators.
Preclinical studies must be conducted according to good laboratory practice (GLP). GLP is outlined by the Organization for Economic Cooperation and Development (OECD), an international organization which countries may apply to become members. Therefore, data collected under GLP standards is accepted much more readily, as it is considered to be of exceptional quality as opposed to data obtained without adherence to GLP. Within the Code of Federal Regulations, the FDA has outlined rules for GLP. All preclinical studies in the United States that use animals must be performed using GLP prior to clinical studies in human patients. Results, either from preclinical studies in the United States that are not conducted in compliance with the FDA rules, or from studies performed in countries outside the United States that do not conform to GLP guidelines, may be inadmissible in support of an Investigational Device Exemption for use in human subjects. In a preclinical study conducted using GLP each involved entity has defined responsibilities.
The research sponsor is responsible for informing the contract laboratory that the preclinical study must be performed using GLP, and for monitoring contracted studies to make sure they are compliant. Management responsibilities include designating study directors, overseeing adequate quality assurance, ensuring that all articles are appropriately tested and that all personnel understand their roles. They also approve standard operating procedures and verify that resources are available. Management should also determine that the facility itself is GLP-compliant, document approval of the study plan, and verify that the study plan is available for inspection and quality assurance. The monitor may serve as the liaison between the sponsor and the study director, assess scientific and technical capabilities of sites to meet the requirements of the study, and be responsible for providing characterized test materials to the laboratory where the GLP study is to be performed. Study directors have overall responsibility for the performance of a study, including the interpretation, analysis, documentation, and reporting of the results. As such, the study director represents the single point of control for a study, and ensures that a defined study plan is followed. Raw data should be fully documented, and it must be accessible for inspection by the monitor. Documentation of studies performed using GLP should be complete enough to allow experiments to be accurately reproduced by another laboratory. Study directors must also be prepared to document any deviation from the study protocol, as well as to note unforeseen circumstances affecting the integrity and quality of the data, and must take corrective action if necessary. Principal investigators may be assigned to oversee parts of a study performed at a test site, and to ensure that all phases of the study are conducted in accordance with GLP and the study plan. They are also obliged to ensure that experimental data are recorded accurately, and that deviations from the study plan or operating procedures are communicated promptly to the study director. Principal investigators should also sign a compliance statement regarding the phase of the study conducted at their test site for the study director’s final report. Study personnel have the responsibility of following all protocols, reporting any deviations to the study director, keep their training updated, and informing the study director of any unusual responses or unforeseen circumstances. Finally, the quality assurance unit reports to management separately from the study director and all other study personnel and is responsible for monitoring each study to make sure that it is compliant with GLP. They are responsible for inspecting the study at intervals that ensure the integrity of the data and maintaining signed records of each periodic inspection with any problems and corrective actions taken. The quality assurance unit should also review the final report to ensure that all reported methods and results accurately reflect the raw data.
In summary, GLP is a quality system that ensures the integrity and quality of data supporting the approval and eventual manufacture of a regulated medical device. It includes compliant organization and management, a defined study plan, defined standard operating procedures, suitable facilities and material, documentation and archiving of results, as well as an independent quality assurance program. Personnel at every level of the study must understand how their role in the research is conducted within GLP regulations.
Good manufacturing practice (GMP), also known as current GMP, constitutes a series of quality system requirements that govern the methods, the facilities, and the controls used by manufacturers, processors, and packagers of medical devices intended for human use. GMP ensures that all finished products are safe and in compliance with the US Federal Food, Drug, and Cosmetic Act as mandated by the FDA. GMP regulations address all facets of manufacture of medical devices, but most GMP requirements allow manufacturers the flexibility to individually determine how they will comply with the required controls. Design controls ensure that specified design requirements are met. These controls include design validation, as well as an archived design history of all changes to the design. Document controls require manufacturers to designate an individual or individuals to review and approve all documents and subsequent changes. Identification and traceability controls mandate that each unit, lot or batch of finished devices must be identified with a control number. Production and process controls ensure that devices conform to their specifications by establishment of check-points where deviations from device specifications could occur as the result of the manufacturing process. Acceptance controls include inspections, tests, and other verifications to ensure that only accepted products are used, installed or distributed. Procedures for controlling nonconforming product must be established, including the documentation of corrective and preventative actions. Labeling and packaging controls ensure appropriate handling, storage, and distribution in order to prevent mix-ups, damage, contamination or other adverse effects on the products. All records need to be maintained in a location accessible to manufacturing officials and FDA inspectors. These include the device design, the design history records, the quality system records, and all complaint files. By mandating these controls, the GMP regulations aim to protect patients from defective medical devices, and ensure that high-quality products are manufactured.
Once pre-clinical assessment has indicated that an investigational biomaterial or medical device is suitable for use in human patients, clinical trials must be designed according to good clinical practice (GCP) guidelines. GCP protects the rights of human subjects participating in clinical trials consistent with ethical principles, and ensures the integrity of clinical research data. Therefore, GCP defines a standard for clinical practices which encompasses the design, conduct, monitoring, termination, audit, analysis, documentation, and reporting of the studies and which ensures that the studies are scientifically and ethically sound, and that the clinical properties of the product or device under investigation are properly established (World Health Organization, 1995). All clinical trials should be conducted in accordance with the following ethical principles, based upon the Declaration of Helsinki. A clinical trial should not be initiated unless the anticipated benefits outweigh the risks. Furthermore, the rights, safety, and well-being of trial subjects take precedence over the interests of science and society. Clinical trials should be scientifically sound and described in a detailed protocol that is subject to review by an institutional review board or independent ethics committee. Informed consent must be obtained without coercion from each subject prior to participation. Each individual providing medical care to the trial subjects should be qualified to do so. Confidentiality of records that could identify subjects should be protected in accordance with applicable regulatory requirements. Investigational products should be manufactured, handled, and stored according to GMP, and used in accordance with the approved protocol. Quality assurance systems for every aspect of the clinical trial should be implemented. By conducting clinical research in accordance with these ethical principles, GCP provides a basis for ensuring that participants in clinical trials are not exposed to undue risk, while guaranteeing that data generated from the research are valid, accurate, and fully documented.
In addition to their moral obligation towards patients, scientists and clinicians involved in biomaterial research have an obligation to protect their research subjects. This includes animals as well as human subjects.
Although biomaterials undergo rigorous procedures during in vitro testing, this process is limited in that the assessment cannot provide definitive evidence of human safety and efficacy. Animal models are designed for anatomical, physiological, and pathological similarity to humans. In vivo models can provide information about the performance of a biomaterial within the context of complex interrelated living systems which can be extrapolated to human patients. Therefore, the results of animal studies have direct implications for patient safety, as well as unforeseen catastrophic events. However, animals have a moral standing even with respect to human beings, as discussed specifically in Chapter II.3.6 of this volume). Consequently, research scientists have a moral obligation not only to human patients, but also to their animal subjects. When using animals for biomaterial research, humane care and ethical treatment of the animals is essential. Guidelines with standards for treatment of animals as research subjects were first published in 1963 by the Institute of Laboratory Animal Resources. Two basic ethical principles relate to the use of animals in biomaterial research. Firstly, experimentation on living animals should be reduced to the minimum necessary to obtain the necessary scientific information. Secondly, pain, distress, and other harm to the animals used should be reduced to the minimum necessary to obtain valid scientific data. Only biomaterials and medical devices exhibiting the most promise with regard to biocompatibility, function, and efficacy through rigorous in vitro laboratory testing should proceed to a preclinical in vivo assessment using an animal model. Preclinical assessment is required for FDA approval for a device to proceed into a clinical trial. The primary purpose of in vivo testing is to provide a critical assessment of safety in humans, with a secondary purpose of determining efficacy in the context of comparable technology. Given the growing public sensitivity to the use of animals in research, extra care must be taken to recognize and comply with the current definitions of humane animal use and care.
Activities involving live animals should be overseen and guided by the Animal Care and Use Committee of the sponsoring institution. Investigators also need to design studies in compliance with local laws and regulations. In the United States, FDA guidelines assume compliance with the Animal Welfare Act, which governs the use of animals in research (see discussion in Chapter II.3.6 of this volume), and also related guidelines of AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care), and the National Institutes of Health (NIH) (Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals, 2002). These guidelines are enforced by the Animal and Plant Health Inspection Service (APHIS) of the US Department of Agriculture. Specific species are covered by this Act (including non-human primates, dogs, cats, rabbits, and guinea pigs), while other species are specifically exempt (mice, rats, and birds specifically bred for research use, as well as horses and other livestock species used in agricultural research). The Act also provides specifications for the procurement of animals from licensed suppliers, as well as husbandry and veterinary care. Institutions that use species covered by these regulations must be registered by APHIS and submit annual reports that contain a categorization of all animals used by the institution in the previous year with respect to the level of discomfort the animals were subject to during the course of research procedures. Regulations also require all research protocols involving animals to be reviewed and approved by an Institutional Animal Care and Use Committee prior to the initiation of the proposed study. In addition to a detailed plan of the investigation, submitted research protocols must include a discussion of alternative approaches that are less harmful to the animals, as well as a justification for the number of animals required to address the purpose of the study without being unnecessarily duplicative. In addition to the federal guidelines, some state governments have mandated additional regulations. For example, at some state-supported institutions Institutional Animal Care and Use Committee reports and deliberations must be conducted in public (e.g., Florida, Massachusetts, North Carolina, and Washington). Different regulations may apply in other countries and jurisdictions.
Origins of human research subjects’ protection are found in the Nuremberg Code, which outlined standards developed for the Nuremberg Military Tribunal against which the human experimentation conducted by Nazi Germany was judged. The Nuremberg Code outlines many of the guiding principles inherent in ethical conduct of research involving human subjects. These include freely given informed consent without coercion, as well as the option for the human subject to withdraw at any time from the study. In 1964, the 18th World Medical Assembly in Helsinki, Finland adopted the Declaration of Helsinki, which made recommendations similar to those found in the Nuremberg Code. In the United States, the NIH issued Policies for the Protection of Human Subjects in 1966 that were based on the Declaration of Helsinki. In 1974, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was established and issued recommendations four years later that were titled the Belmont Report. This report identifies both basic ethical principles of research involving human subjects, as well as guidelines for conducting research in accordance with these principles. The main tenets defined by the Belmont Report are firstly respect for persons (recognition of autonomy and personal dignity of individuals, as well as special protection of those persons with diminished autonomy), secondly beneficence (the obligation to maximize anticipated benefits), thirdly non-maleficience (minimizing possible risks of harm), and finally justice (fair distribution of benefits and burdens of research). These tenets continue to form the basis of all acceptable conduct of research involving human subjects. Based on the Belmont Report, the Department of Health and Human Services (DHHS) codified regulations relating to protection of human subjects, and in 1991 the Federal Policy for the Protection of Human Subjects (or “Common Rule”) was adopted. This policy was designed to unify the protection system for human subjects in all relevant federal agencies that conduct, support or otherwise regulate human subjects’ research. Regulatory compliance is monitored through routine site visits and audits conducted by federal officials, as well as through the establishment of Institutional Review Boards (IRB).
Any biomaterial investigator involved in human subject research will be regulated by an IRB. The overarching purpose of an IRB is to ensure that all research is conducted with appropriate safeguards for human subjects, as mandated by the federal regulations. An IRB is a group made up of at least five individuals with diverse experience and expertise to professionally qualify the group to adequately review and monitor research activities involving human subjects that are commonly conducted by the institution. The IRB has the legal authority to approve, disprove or require modifications in the experimental design of research activities involving human subjects at the institution with which it is affiliated. Although each institution may have additional committees that review proposed research involving human subjects, no research may be initiated that has not been approved by the IRB. While the IRB overall must possess the scientific expertise to review a specific research design, the membership of the IRB must include at least one member with interests that are primarily scientific, and one member with interests that are primarily nonscientific. Members of an IRB should make every effort to avoid gender or race bias, and the member from the community at large should be a suitable representative. The number of members of an IRB can exceed the proscribed number of five, but it should not become so large that it can no longer function effectively. Investigators may be members of an IRB, but they may not participate in the review and approval of any project in which a potential conflict of interest could arise. The basic IRB review of a submitted protocol focuses on the following components: a risk/benefit analysis; adequacy of informed consent; appropriate selection of subjects; ongoing monitoring of subjects; mechanisms to ensure confidentiality; examination of additional safeguards; evaluation of incentives for participation; and plans for continuing review. The risk–benefit analysis aims to determine whether the risks to the subject are reasonable in relation to the benefits to the subject. Risk analysis is a formal procedure that includes hazard identification, evaluation of failure modes, risk estimation, risk evaluation, risk control, and continuous risk review. The risk analysis is based on the evaluated biomaterial or medical device, as well as the manufacturer’s claims attributed to it. It also takes into account whether the device is novel or just an incremental modification of an existing device. The risks associated with the research are also distinguished from the risks of therapies that a subject would face, even if not participating in the research. It is important to determine that the probability and degree of harm associated with the research has been minimized as much as possible. When reviewing protocols involving medical devices, both the risks of the device and the risks associated with the procedure for using the device (e.g., the surgery to implant a heart valve) must be taken into consideration. Sponsors should make the initial risk assessment along with the study proposal. If the device study presents significant risk, the sponsor must submit an Investigational Device Exemption (IDE) to the FDA for approval. The sponsor must communicate the results of the IDE to the IRB. If the IRB finds that a device study presents non-significant risks only, the study may proceed without submission of an IDE. Adequacy of informed consent is another important consideration for the IRB. Human research subjects also need to be provided with an accurate and fair description of the anticipated risks, benefits, and possible discomforts. Federal regulations also require that the following information be provided to each subject as part of informed consent: a statement that the study involves research; explanations of the purposes; expected duration; descriptions of any planned procedures (including identification of procedures that are experimental); reasonably anticipated risks or discomforts; benefits to the subjects or to others; a disclosure of alternative treatments or procedures if they are advantageous to the subject; a statement describing confidentiality of records; contact information; and a statement that participation is voluntary and that refusal to participate will not result in the loss of benefits to which a subject is entitled. For research involving more than minimal risk there should be explanations of compensation or medical treatments available if injury occurs as a result of the research. The IRB also needs to ensure that the informed consent document presents the information to prospective subjects in language that can be easily understood, even by those with no medical background. Sometimes it is also appropriate that subjects be re-educated and consented periodically. The criteria for selection of subjects should take into consideration the requirements of the scientific design of the study, the susceptibility to risk, the potential benefits, and whether the selection of subjects from a proposed subject population is equitable (i.e., depending on the benefit of the study to the population as a whole, rather than disproportionately favoring one segment of the population). IRBs should also evaluate whether adequate precautions are taken to safeguard the privacy of information linked to individuals that will be recorded as part of the study. Subjects should be informed that federal officials have the right to inspect research records as part of their regulatory oversight. The initial IRB review of a protocol also includes an assessment of how often a research project should be re-evaluated by the IRB. Repeated monitoring is crucial, as preliminary data may indicate that the research design or the information presented to subjects must be changed, or even that the study should be terminated before the scheduled end date. Only after research has begun can the preliminary data be used to estimate the actual risk–benefit ratio.
Although institutions are ultimately responsible for ensuring that all regulatory requirements relating to human subject research are met, IRBs and investigators also bear part of that responsibility, and can be held accountable. At the level of the investigator, the most likely sources of noncompliance include failure to submit protocols or changes in approved protocols in a timely fashion to the IRB, and problems with obtaining informed consent. Often the IRB can resolve these deficiencies without jeopardizing the safety of the research subjects. However, research involving human subjects conducted by an investigator who has avoided or ignored an IRB cannot be allowed to proceed. Once discovered, the IRB and the institution must halt the research and take measures to correct any regulatory infractions. The fitness of the investigator to engage in research involving human subjects should also be evaluated. Noncompliance with regulations can also occur at the level of the IRB. This may arise from inadequate review of research protocols, not conducting a continuous review of research with a frequency that is commensurate with the degree of risk to subjects, failing to maintain adequate records, and consistently holding meetings without the majority of members present. Failure of an IRB to perform their responsibilities in accordance with DHHS regulations can be grounds for suspension or withdrawal of the institutional assurance. Finally, noncompliance at the institutional level is usually the result of a more systemic failure to meet their responsibilities. Institutions must provide appropriate staffing and support of an IRB so that it can function in accordance with the regulations, as well as ensure that investigators meet their obligations to the IRB as an integral part of their research using human subjects.
In the process of developing a biomaterial, investigators may become involved with the business aspects of the technology. Examples include patents, company stock, royalties, a contract or other financial compensation from the medical device company, the academic institution or both. It is desirable to achieve a balance such that these rewards do not unduly influence data collection and analysis. Since research data are vulnerable to alteration by unethical participants, it is vital that principal investigators, companies, and academic institutions manage both perceived and real conflicts of interest to ensure accountability at all levels. Such potential conflicts of interest are common, and should ideally be identified and managed by the academic institution. A simple disclosure of financial interests may be enough to manage a conflict. However, in other circumstances the perceived conflict of interest may be so great that it is prudent to remove the conflicted individual from the research setting.
The emphasis of the above sections has been that compliance to ethical standards is crucial in facilitating good biomaterials and medical device research. Ethical investigators must conduct good science in the setting of GLP, GCP, and GMP standards. The rights of patients, as well as research subjects, need to be protected. Conflicts of interest should be disclosed and managed appropriately. These fundamental elements can then come together to form medical advances, which ultimately improve patient safety and healthcare outcomes. It is the full responsibility of all those contributing to the biomedical and device industry, and those advancing clinical healthcare, to abide by these widely accepted ethical standards.
In this section, we will frame our discussion of the ethical principles in biomaterial research using the example of the process of designing a new heart valve. The development and ultimate production of a new heart valve begins with the incorporation of novel technology. This may either be a significant change in design or the inclusion of a new biomaterial that may improve the performance of the valve. There are many stages of assessment through which a device must be characterized before it is approved for use in human patients. In each stage there may be test results which prompt a return to further in vitro or in vivo testing, disrupting the linear progression of development. These recursive iterations are vital to ensuring maximum patient safety and efficacy of the valve. Following the development of a prototype valve, the first in vitro assessments are performed. This subjects the valve to conditions that exceed physiologic limits to determine durability, wear, and hemodynamic properties. All in vitro experiments must follow GLP. Such experiments should be thoroughly documented, such that an independent laboratory could reproduce the experiments and obtain results suitable for a direct comparison.
Although a device undergoes rigorous procedures during its in vitro testing this process is limited, in that the assessment cannot provide definitive evidence of safety and efficacy in a complex interrelated living system. The primary purpose of in vivo animal testing is to protect patients by providing a critical assessment of predicted safety in humans. A secondary purpose of in vivo animal testing is determining efficacy with regard to the claims of the developer in the context of comparable technology. In this way, in vivo animal testing serves to protect human patients from inferior medical devices. However, only devices exhibiting the most promise with regards to biocompatibility, function, and efficacy through rigorous in vitro laboratory testing should proceed to preclinical animal model testing. In this way, experimentation on living animals is reduced to the minimum necessary to obtain the necessary scientific information. Animal experimentation cannot be avoided, because preclinical assessment is required for FDA approval necessary for a device to proceed into a clinical trial. The preclinical assessment of a valve incorporates multivariable analysis with respect to hemodynamic performance, in vivo pathological effects, ease of handling, and results in the best approximation of use of the new heart valve within a clinical setting prior to proceeding into a Phase I clinical trial. There are two organizations in the United States that dictate regulatory requirements for preclinical assessments of cardiac devices: the United States Food and Drug Administration (FDA), and the International Standards Organization (ISO), in conjunction with the American National Standards Institute, Inc. (ANSI), and the Association for the Advancement of Medical Instrumentation (AAMI). ISO 5840 has defined regulatory standards governing preclinical studies, which are specific to cardiovascular valve prostheses (ANSI/AAMI/ISO 5840:2005). Although the current FDA guidelines are in draft form, they describe nonbinding recommendations for the manufacturing, preclinical in vitro and in vivo studies, clinical investigations, and labeling for heart valves that differ, augment, and complement the regulations defined by ISO 5840:2005. The previous FDA guidance was issued in 1994, before the FDA Good Guidance Practices were implemented in 2000, and before ISO 5840:2005 was published. The 1994 draft was withdrawn in 2005 (70 FR 824, January 5, 2005), and the FDA is in the process of drafting a new guidance. The FDA has recognized only the 2005 version of ISO 5840 (71 FR 16313, March 31, 2006). ISO standards are reviewed every five years and, if necessary, revised to reflect changes in the industry for which the standards define regulatory compliance. One major difference in the current ISO 5840:2005 guidelines from its previous version is the emphasis that is now placed on the use of risk analysis, a formal procedure by which preclinical studies are designed to mitigate to the extent possible the probability and degree of harm caused by the use of a device. Specific steps are outlined in ISO 5840:2005 to perform a risk analysis and include: hazard identification; associated failure modes; risk estimation; risk evaluation; risk control; and risk review. Risk analyses must be updated throughout the characterization of a heart valve through all phases of development. This encourages the manufacturer to strive for continued improvements in design, as well as to ensure safety and efficacy with less reliance on years of clinical assessment for verification of effectiveness. Within the regulatory framework mandated by the FDA and the ISO 5840, there are criteria that must be incorporated into the design and assessment of a new heart valve as follows:
(1) All studies must be completed using Good Laboratory Practice guidelines.
(2) Valves to be assessed must be of clinical quality.
(3) Studies must be conducted using a control valve that is of similar design and has been approved for clinical use. The only exception to this is a proof-of-concept study in which a new heart valve is so different from existing valves that have been approved for clinical use that a suitable control valve cannot be identified.
(4) In vivo studies must be designed to incorporate site-specific implantation of the new heart valve in both mitral and aortic positions. Of note, it is important to standardize as many of the variables as possible, including the surgeon, the device size, and the animal demographics.
(5) Ideally, the limitation of the number of implants should not be determined by the minimum regulatory requirements, but should be reflected by the study length.
(6) There should be a complete pathological examination of all animals within a particular protocol, with two independent assessments, including one performed by a veterinary pathologist, to distinguish complications caused by the model from those caused by the new heart valve.
One regulation not mandated by ISO 5840 is the choice of a definitive in vivo model used for preclinical assessment of heart valves, as there are a variety of in vivo models that are relevant. These include, but are not limited to, sheep, pigs, calves, dogs, and non-human primates. Currently, there is no ideal model for preclinical assessment of heart valves, but existing models can be improved upon by incorporating additional outcomes, for example, including site-specific testing. Other potential improvements include the increased use of focused screening models, such as isolated hearts, the use of risk analysis for determining not only the end points, but also the choice of controls and power of the study, and increased communication with regards to negative findings. Compliant preclinical assessment provides not only an accurate correlation of in vitro and in vivo performance of a device, but also provides a basis for clinical trials.
Once preclinical assessment has indicated that the new valve is suitable for use in human patients, clinical trials may be designed to evaluate the safety and efficacy with regard to toxicity, efficacy, and field conditions. Complete documentation must cover therapeutic indications, contraindications, safety precautions, and safety information. Given the broad public health significance, it is critical for the clinical trial process and resultant data to conform to rigorous ethical standards. Therefore, investigators need to submit a study protocol for IRB review. This protocol will include a risk–benefit analysis, adequacy of informed consent, appropriate selection of subjects, ongoing monitoring of subjects, mechanisms to ensure confidentiality, examination of additional safeguards, evaluation of incentives for participation, and plans for continuing review. The sponsor must also submit an Investigational Device Exemption (IDE) to the FDA for approval. Subsequently, the clinical trial may be conducted according to the general principles described above. Often, during the development process, preclinical assessment, and clinical research, most cardiac valves will have undergone only short-term safety and efficacy assessment in a limited number of carefully selected human subjects before being approved for marketing.
In contrast, post-marketing safety surveillance is utilized in an effort to detect rare or long-term adverse effects not easily recognized during preclinical testing by examining a much larger patient population over a prolonged period of time. Although such events may be rare, their potentially catastrophic consequences cannot be ignored. With better documentation of such problems, future device iterations can be redesigned to attempt to eliminate failures.
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