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© 1997 The Journal of Bone and Joint Surgery, Inc.
Current Concepts Review - The Conduct of Orthopaedic Clinical Trials*   *One or more of the authors has received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this article. In addition, benefits have been or will be directed to a research fund, foundation, educational institution, or other non-profit organization with which one or more of the authors is associated. No funds were received in support of this study.
The work of clinical investigators is commonly said to be a search for the truth. Many years ago, Cannon rephrased this objective in less pretentious rhetoric, saying that the investigator tries to learn whether facts that others will recognize as facts can be established and whether the facts will support some projected theory6. Today, we call a projected theory a hypothesis and we call facts clinical data. Civilized countries have established rules governing the attainment of such data, and these rules, or standards, govern the scientific and ethical conduct for clinical trials. The art of clinical trials has become more refined over the years through the application of recognized scientific principles to the interpretation of results. In addition, today's computer technology, coupled with powerful statistical methods, permits rapid evaluation of complex variables. A clinical trial to determine the safety and efficacy of an orthopaedic device represents a process in experimental therapy in which the surgeon's skill and the implant both play a major role in securing scientific evidence. The evaluation of drugs is substantially different than the evaluation of devices. For example, a dose response generally can be predicted from certain experiments conducted in animal models. Unfortunately, there are few good models for the evaluation of devices, and none, to our knowledge, for the preclinical study of orthopaedic implants. Furthermore, clinical response to pharmaceutical agents is prompt and depends partially on how the drug is administered. While a dose response to a drug is based on simple delivery to the patient, the effect of a device also depends on the skill of the user. An implanted device may immediately affect body function, but its long-term utility and potential side effects may take years to assess. The goal of any new therapy is to improve a patient's health status with use of processes and products that may apply similarly to a larger population of patients who have a common illness. Clinical trials of medical devices fall into four generic stages: clinical feasibility—the first human application of the idea, in which the viability of the concept and its safety are assessed; clinical research—in which the idea evolves and is perfected in well defined groups of patients under the close supervision of the inventor; clinical validation—in which multiple clinical centers evaluate and attempt to reproduce the results of the initial concept or product; and acceptance—the postmarket surveillance of the product. During the life of a device, the sponsor continues to compare the long-term performance and possible adverse effects with those of similar products3. In the United States, therapy, whether in the form of a drug or a device, must be safe and effective. In Europe, the regulatory requirements for devices emphasize safety and allow practitioners to decide on efficacy. Initial performance is easily predictable for most drugs, but long-term evaluation of a large population is required for optimum assessment of safety. The risks associated with medical implants, in contrast, cannot readily be recognized at the inception of use but can merely be inferred from similar applications of like devices. While the short-term function of a device can be assessed by comparing the medical conditions before and after its use, the assessment of long-term viability and potential side effects requires many years of follow-up. The current article focuses only on clinical trials of devices. The public-health implications of trials of devices require that trials be conducted under the control of international treaties and standards as well as national, regional, and, perhaps, local regulatory bodies. The Food and Drug Administration is the most widely known regulatory agency in the United States. The Food and Drug Administration applies innumerable regulatory controls to clinical trials as part of the Premarket Approval process. Furthermore, because health-care reimbursement is carried out on a regional or national level, financial underwriters often apply their own criteria for reimbursement, perhaps precluding funding for clinical evaluation. For example, unless a device or procedure is substantially similar to one already in existence (that is, unless it is non-experimental), most insurance carriers, most managed-care organizations, Medicare, and Medicaid will not reimburse patients or the providers of the care. With this brief background, the current article will cover the history of the ethics of clinical trials, the international standards pertaining to clinical research, and the comparative regulatory requirements in other countries and the United States.
In the nineteenth century, Pierre Louis, a French surgeon, conducted one of the earliest trials of medical devices when he tested the efficacy of bloodletting in the treatment of pneumonia5. In 1803, the English physician Percival wrote that, before proceeding with therapeutic innovation, physicians should consult their peers27. This is generally regarded as the first authoritative statement on medical ethics, and Percival is officially recognized as the first codifier of such ethics27. In actual practice, concern for ethics in human experimentation may have begun more than 100 years ago, with Pasteur. During his work with the rabies vaccine, Pasteur emphasized that he would undertake trials with the vaccine only after extensive and decisive experiments with animals15. Furthermore, he insisted that human experimentation take place exclusively under the supervision of a qualified physician15. True clinical trials did not begin until at least the 1940s, although the early 1930s were witness to a number of methodological contributions, which provided essential statistical tools for the design and analysis of experiments4. However, no rules of conduct for clinical studies were formulated until after World War II. The watershed concern for ethical practices resulted from the unprecedented cruelty and animality exhibited by presumably well trained physicians in Nazi Germany. Experiments performed on prisoners in concentration camps were in fact brutal crimes, committed under the guise of medical research. Atrocities included examining the effects of poisons, intravenous administration of gasoline, and immersion in ice water on unwilling subjects2. Unlike true medical research, which is humane, respectful, and beneficent, these sadistic experiments caused untold suffering to and involved the murder of helpless human beings. Whether to use the data from these experiments has been a controversial issue; most researchers have elected not to legitimatize the results because of moral concerns and respect for the victims32. Nazi medical experiments fell into two categories: those sponsored by the regime for a specific ideological or military purpose, and those performed ad hoc for the Schutzstaffel (SS) doctors' alleged scientific interest. The behavior of the Nazi doctors during the Hitler regime is regarded as the most shameful and disturbing of all atrocities21. Twenty-four physicians were tried at Nuremberg for performing medical experiments on inmates of concentration camps without their consent15. The trial was termed the Medical Case, or United States v. Karl Brandt et al.30. The Nuremberg Code24, which resulted from the trial, was adopted in 1948 and embodied moral, legal, and ethical standards for judging human experimentation. In the same year, the United Nations defined the term human rights in its Universal Declaration of Human Rights12, which has since come to be regarded as the basis for international law. The international community thus took notice that violations of individual human rights were a threat to peace and that protection of these rights was a collective responsibility. The Declaration reads as follows. "Whereas recognition of the inherent dignity and of the equal and inalienable rights of all members of the human family is the foundation of freedom, justice and peace in the world. Whereas disregard and contempt for human rights have resulted in barbarous acts which have outraged the conscience of mankind, and the advent of a world in which human beings shall enjoy freedom of speech and belief and freedom from fear and want has been proclaimed as the highest aspiration of the common people, . . . Now, therefore, the General Assembly Proclaims THIS UNIVERSAL DECLARATION OF HUMAN RIGHTS as a common standard of achievement for all peoples and all nations . . . All human beings are born free and equal in dignity and rights . . . Everyone has the right to life, liberty and the security of person. No one shall be held in slavery or servitude . . . No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment. Everyone has the right to recognition everywhere as a person before the law . . . No one shall be subjected to arbitrary arrest, detention or exile."12
In 1953, the World Medical Association began drafting an ethical standard for the conduct of clinical trials, based on the original Nuremberg Code. In June 1964, after several years of discussion and research, the Eighteenth World Medical Assembly finally adopted the new code in Helsinki, Finland18. This code (Appendix) has since been amended by the Twenty-ninth, Thirty-fifth, and Forty-first World Medical Assemblies. The Declaration of Helsinki forms the basis for most clinical trial protocols and, by international agreement, should be a part of the documentation of any experimental therapy in humans19. It exposes a fundamental distinction between medical research for a particular patient and a purely scientific endeavor that offers no specific benefit to the individual patient or subject. The Declaration comprises four basic principles. The first principle covers the personal and private rights of the individual being subjected to the clinical trial. Confidentiality is a key objective; researchers must make every effort to secure anonymity. The physical and mental integrity of the individual is extremely important, and assuring patients with regard to their safety and humane treatment is imperative. The study should project a favorable risk-to-benefit ratio, and researchers must exercise care to make sure that the patient does not become dependent on the clinical investigator. In addition, any societal or scientific benefits from the investigation must be secondary to the well being of the individual patient. The second principle is the integrity of the research process. Researchers must base all clinical studies on adequate preclinical data and must ensure that the study design is scientifically sound. The results and conclusions must be valid, all data must be reported, and an independent review board must confirm that the plan conforms to the laws and regulations of the jurisdiction and reviews and approves the protocol. These boards also are termed ethics committees or institutional review boards. Informed consent is the third principle. All patients must confirm in writing that they comprehend the study's purpose as well as its potential risks and benefits. In securing consent, physicians should be cautious to avoid coercion of patients. Subjects also must understand that they have the right not to participate in the study and to drop out of the program at any time without prejudice. The final principle is that only clinical researchers qualified by training and experience should conduct clinical trials. The preferred physician-investigator is one who can ensure the primary health and safety of each patient in the study. The physician always must offer the best proved therapy, and he or she must have the authority to halt the investigation immediately if a major hazard to the patient is discovered. The Declaration of Helsinki as amended is the accepted basis for the ethics of clinical investigations, and it should be understood, observed, and applied at every step of the study, from the first recognition of need and justification to the publication of the results. Although the code has served as a voluntary guideline for the protection of human rights, it is not without controversy. One principle under particular assault is that, in any medical study, each patient (including any in a control group) must be assured that they are receiving the best-proved diagnostic and therapeutic methods. This statement contraindicates the use of placebos or sham treatments when a proved therapeutic method is available26.
Although none were as heinous as the Nazi episode, a number of serious ethical violations also occurred in the United States, and these were documented by Beecher in 19661. His presentation of twenty-two examples of investigators who endangered the health or lives of their subjects, without informing them of the risks or obtaining their permission, was another critical element in the reshaping of the ideas and practices governing human experimentation. Beecher thus contributed to the United States federal policy during its most formative and receptive period, the 1960s. This culminated on July 12, 1974, when the National Research Act (Public Law 93-348) was signed into law. This law created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Among the responsibilities with which the Commission was charged were identifying the basic ethical principles underlying the conduct of clinical research and ensuring that such research is conducted in accordance with those principles. The final regulations concerning operation of institutional review boards, informed consent, and related issues were published by the Food and Drug Administration, first on January 26, 1981, in the new and final Part A—Final Regulations Amending Basic HHS Policy for the Protection of Human Research Subjects10, and then on January 27, 1981, when the agency announced its new and final Part 56 for institutional review boards11. These regulations became effective on July 27, 1981. The Food and Drug Administration recognizes the Declaration of Helsinki, and any foreign clinical study submitted as part of the Premarket Approval process must comply with its ethical principles.
The Declaration of Helsinki is the basis of international standards for clinical trials. These specifications define how testing of a product on humans must be carried out if an item is to receive ultimate regulatory approval for marketing in a particular country. For years, scientists have used voluntary technical standards as a common basis for understanding the relationship between similar items. These requirements are established by common assent as a basis of comparison in measuring or judging content, capacity, quantity, quality, extent, or other characteristics. For example, in the United States, the American Society for Testing and Materials has served as a scientific forum for the establishment of a language of universal standards among expert scientists in testing and materials. Many of the Society's documents adopted by the International Organization for Standardization are recognized globally. Until recently, these informative documents were of only technical interest. With the development of the Common Market, however, where equivalent products may cross borders unimpeded by tariffs or duties, the role of standards changed. They not only provide technical guidance but also legally characterize the products being exchanged and are therefore termed normative standards. (The Instructions to Authors provided in each issue of The Journal of Bone and Joint Surgery is an example of a normative standard.) Because they define the goods or services being traded, they are the key to the globalization of commerce. Similarly, the standard of practice for conducting clinical trials for the regulatory approval of a medical device in one country should lead to recognition of the device's safety, performance, and ultimate approval in another. Health care is a global enterprise, and valid trials become pre-eminently important in the evaluation and approval of global medical products. To this end, the European Committee for Standardization published its document EN 540: Clinical Investigation of Medical Devices for Human Subjects, in 199313. This document covers the ethical requirements for a clinical investigation, adherence to the Declaration of Helsinki, agreement by an ethics committee, and informed patient consent. Other sections describe the plan for the clinical investigation; the roles of the sponsor, monitor, and clinical investigator; and the presentation of a final report. On March 1, 1996, the International Organization for Standardization approved ISO/DIS 14155, Clinical Investigation of Medical Devices19. This document is very similar to the document of the European Committee for Standardization, with the following exceptions: in the event of unexpected harm, the document of the European Committee for Standardization requires compensation for the subject, whereas that of the International Organization for Standardization asks for additional medical care; the document of the European Committee for Standardization does not require the reporting of all subjects, whereas that of the International Organization for Standardization requires total accountability; the document of the European Committee for Standardization guides the individual investigator, whereas that of the International Organization for Standardization guides the investigator and the institution; and the document of the European Committee for Standardization refers to the action of the medical device, whereas that of the International Organization for Standardization refers to its safety and effectiveness. Compliance with the standards is necessary to meet the essential requirements of the European Medical Device Directive, the most comprehensive regulation of medical devices ever published8. According to Article 15 of the Directive, a manufacturer may start a clinical investigation sixty days after notifying the appropriate competent authority (Ministry of Health) in the country where the study is to be conducted. The authority may, however, deny approval within that time-period if there are public-health concerns. Sponsors (manufacturers) may commence a clinical trial before the sixty-day time-period whenever the ethics committee issues a favorable opinion with respect to the investigation.
The stepwise advance of world medical research closely parallels the North American experience. In the United States, systematically conducted clinical research in the pharmaceutical industry has been regulated by the Food and Drug Administration for more than thirty years. Implantable devices such as artificial joints came under this agency's jurisdiction in 1976. Because of the long period during which regulation of the device was promulgated, clinical trials for devices span little more than ten years. Orthopaedic research outside of the United States, however, has been ongoing for more than thirty-five years, preceding even Charnley's breakthrough studies with total hip arthroplasty7. The articulation of metal alloy and polyethylene is still the basis for essentially all currently used artificial joints. Charnley's work remains the prime example for orthopaedic clinical trials because he insisted on a systematic method of training, evaluation, and follow-up. To ensure that only trained surgeons perform implantations, Charnley controlled distribution of both prostheses and instrumentation. He also developed and implemented accurate tools for postoperative evaluation of the functional (clinical) and radiographic status of recipients of implants. Perhaps Charnley's most important contribution, however, was the importance that he placed not only on short-term safety but also on long-term results, and especially his appeal to include, whenever possible, postmortem retrieval of implants for analysis and evaluation31. Long-term surveillance of patients, developed and advocated by Charnley, continues to be the cornerstone of evaluation of orthopaedic implants. The European Common Market, or the unification of Europe, started with the Treaty of Rome in 1957. This evolved through a process of subordination of the interests and laws of individual states to a common European interest. This process of mutual assent is termed harmonization. The European union authorized its members to develop new national legislation to promote safety, health, and free trade. This resulted in The New Approach to Technical Harmonization of Standards9. One of the first such standards that was promulgated dealt with the conduct of clinical trials. Before harmonization, European countries carried out their clinical research individually, with no greater over-all objective than the ultimate regulatory or marketing interests of the local sponsor. Previously, the specifications governing the conduct of medical research in Europe were, by and large, less stringent than those imposed in the United States by the Food and Drug Administration. In fact, the Food and Drug Administration's requirement that a medical device or drug have a cleared (approved-for-marketing) status before it is exported served as a safety net to countries outside of the United States14. Several European countries have distinguished themselves in the area of orthopaedic clinical research. The Scandinavian countries all have voluntary implant registries in which patients having a total joint arthroplasty are enrolled. These registries function under sponsorship of the national orthopaedic societies, the most successful of which has been the Swedish total joint registry. Recently released survivorship results include more than 136,000 cases22. This type of proactive database construction, performed voluntarily by orthopaedic practitioners, has resulted in a seminal contribution to orthopaedic research. In Scandinavian countries, a standardized approach to the practice of medicine as it applies to clinical research also yields a consistency in practice across institutional lines. In Norway, for example, approval of research by an ethics committee (analogous to an institutional review board in the United States) in any institution enjoys reciprocation throughout the entire country. In Canada, the Health Protection Branch governs issues of orthopaedic research. To grant Clinical Trials Status to a product, this protective body requires a filing process resembling the full application procedure mandated by the Food and Drug Administration in the United States, except for clinical data. After an application has been submitted, however, oversight with regard to the design of the protocol and regulatory review are less stringent. Moreover, no monitoring of ongoing clinical research is required in Canada. Investigational testing must have approval from institutional ethics committees when appropriate, must take place in appropriate settings, and must be conducted by qualified investigators. Common patient-consent forms must be used by all investigators and should contain the names of the agencies that will have access to the data. The Japanese Pharmaceutical Affairs Bureau, within the Medical Devices Division of the Ministry of Health, dictates requirements for clinical research. More onerous than the clinical regulations, however, are the preclinical requirements, which are more numerous when the sponsor is a foreign entity. Japan, however, has a more practical approach to the evaluation of results of clinical trials. The merits of the data that are collected are determined by whether the data have "been published at a scientific meeting or . . . in a scientific journal or equivalent publication."20 Thus, Japanese authorities clearly recognize the important role of the scientific community in policing itself throughout the peer-review process. The personal rights of subjects are held in accordance with the Declaration of Helsinki and the Counsel of the Science Council of Japan. Thus, an institutional review board composed of five members reviews the validity of conducting a trial in accordance with the study protocol and verifies that informed consent of subjects has been appropriately obtained.
While the process of clinical trials of medical devices according to EN 540 is straightforward in Europe, the procedures in the United States are less clear and have substantial regulatory overtones. Most studies are conducted with the purpose of broadening indications or providing additional claims for devices that already have been approved. Far fewer studies are conducted to provide a basis for Premarket Approval, especially for devices defined as being associated with substantial risk. Relatively little clinical research has been carried out to formally develop new or vastly improved devices categorized as being associated with significant risk.
Often, the necessity to conduct extensive clinical studies in the United States can be attributed to the classification scheme adopted by the Medical Device Amendments of 197625. These Amendments placed all existing medical devices into one of three classes. Class-I devices are deemed low risk and require no performance standards or special controls. They are exempt from most Food and Drug Administration restrictions. Class-II devices also are exempt from restrictions, but they require conformance to special controls, such as labeling requirements, postmarket surveillance, and performance standards. Class-III devices are those deemed by the Food and Drug Administration to pose the greatest risk; they require substantial controls and Premarket Approval. Since May 1976, new technology, or a new application of existing technology, has caused a device to be earmarked as class III, requiring clinical trials. Unfortunately, the risk-benefit ratio for a device frequently bears no relation to its classification, nor does the complexity of the device affect its chosen class. For example, the Food and Drug Administration took more than ten years to approve a breast-sensor diagnostic product consisting of a lubricant enclosed by two sealed plastic sheets. The device was ruled class III because no substantially equivalent pre-amendment devices existed28. Such rigid application of the rules leads to the classification of inherently safe, simple devices with those posing the greatest risks to patients. The classification scheme in Europe is much more reasonable and does not address pre-amendment or preregulatory status.
In the United States, the process of regulatory approval for some class-II medical devices (those that can be cleared for marketing by a 510-k submission when substantial equivalence to a pre-enactment device can be demonstrated to the satisfaction of the Food and Drug Administration) and virtually all class-III medical devices can be arduous. (A 510-k is a notification provision by which a company advises the Food and Drug Administration that the device that it wishes to sell does not require a Premarket Approval Application. The device that is subject to the 510-k provision must be substantially equivalent to lawfully marketed devices.) The foremost factor contributing to this situation is the requirement for the clinical data to support the submission of these devices to the Food and Drug Administration. The generation of clinical data for all medical devices categorized as significant-risk devices, including orthopaedic implants, involves a rigid set of procedures and guidelines. The Food and Drug Administration has the right to request clinical data to demonstrate the safety and efficacy of these devices for alleviating the conditions for which they are indicated. The Food and Drug Administration frequently exercises its right to require clinical data for so-called new orthopaedic implants. Before a clinical trial of a significant-risk device can begin, the trial's sponsor must submit an application for an Investigational Device Exemption. The application (submission) for such an exemption consists of (1) identification of the sponsor; (2) complete reports on all previous investigations of the significant-risk device; (3) an investigative plan that covers the purpose of the investigation (including the intended use of the device and the objectives and duration of the investigation), a detailed protocol describing the methodology to be used and an analysis of the scientific soundness of the protocol, an itemized description of the device (including its composition and principle of operation), and any laboratory or preclinical safety studies that have been done (including those mandated by Good Laboratory Practices, which are broad Food and Drug Administration regulations designed to ensure that the sponsor of the study adequately addresses the quality of the non-clinical laboratory study); (4) a description of the manufacture and handling of the significant-risk device sufficient to prove that it was manufactured in compliance with the design-control provisions of the Good Manufacturing Practice regulations; (5) identification of investigators and the means used to identify them as qualified to conduct the study; (6) identification of institutional review boards reviewing and approving the investigative plan; (7) names of institutions where the investigational device will be used; (8) the amount (if any) charged for the device and an explanation of why the sale does not constitute commercialization; (9) a claim for exclusion from an environmental assessment or an environmental assessment statement; (10) information showing that any risk associated with the clinical trial is counterbalanced by a commensurate or larger benefit to the patient or the health-care system in general (this information also must show, within reason, that the device is effective when used in the intended manner); (11) copies of all labeling; (12) copies of all informed-consent forms and informational materials to be provided to subjects; and (13) any other relevant information that the Food and Drug Administration requests. Much of the data included in an Investigational Device Exemption normally are generated by a prudent manufacturer during the development process. When included in a submission, however, the information is subjected to scrutiny for adherence to technical and regulatory detail beyond that normally anticipated. Sponsors and investigators must generate data and prepare the results of their studies with this level of scrutiny in mind or they may not gain approval of an Investigational Device Exemption. Thus, the time to gain approval of an Investigational Device Exemption is generally much longer than the prescribed statutory thirty-day time-frame.
Investigational Device Exemptions require extensive record-keeping. The necessary records include all correspondence with other sponsors, monitors, investigators, institutional review boards, and the Food and Drug Administration. Also required are agreements signed by investigators, informed-consent forms signed by patients in the presence of witnesses, patient records, periodic progress reports, and the final study report. The study's sponsor also must maintain shipment and disposition records of all devices, including the lot number of the device and whether it was used for a patient, returned to the sponsor, or destroyed (and the method of destruction, if applicable). If the study was completed but was not used to support a Premarket Approval submission, or if it was terminated for any reason, the investigative records must be kept for the duration of the study plus an additional two years. If the study is used to support a Premarket Approval submission, the records must be kept for at least two years after they are no longer needed to support the submission. These record-keeping mandates apply to the clinicians involved in the study as well as to its sponsor. Clearly, the filing and conduct of an Investigational Device Exemption is not to be entered into lightly. Although the Food and Drug Administration describes the review period for the Investigational Device Exemption as having little consequence, the time-consuming and expensive preparation for submission must be performed meticulously. A hidden consequence of too little preparation is that failure to follow the applicable regulations in detail may result in both a punitive action against the sponsor of the work and a likelihood that the work will not result in an approvable submission. Only after the Food and Drug Administration has reviewed and approved the submission is the sponsor permitted to undertake the really time-consuming and costly part of the Investigational Device Exemption process: the clinical trial itself. The entire concept of the Investigational Device Exemption or Premarket Approval regulations presumes that the subject of the investigation (the device) is completely developed before it is ever placed in contact with a patient. However, this is not always so in reality. Usually, a device goes through the four phases, as noted earlier, from the time of its conception through its evolutionary stages, while simultaneously undergoing the battery of testing required for an application for an Investigational Device Exemption. Implanted devices often are subject to additional modifications in the early stages of application in humans. Unfortunately, no latitude exists in the original construction of the regulations for such modifications based on human testing. To conduct such work legally, many companies therefore resort to stretching the regulations for a custom device (a unique item designed for an individual patient) to apply to what would best be described as a pilot phase of an Investigational Device Exemption study29. Regulations for custom devices were not designed for this purpose, and the Food and Drug Administration strongly suggests that companies conduct Investigational Device Exemption feasibility studies instead of seeking coverage under custom-device regulations.
In 1984, the American Society for Artificial Internal Organs authored a citizens' petition requesting that the Food and Drug Administration rewrite a portion of the Investigational Device Exemption regulations. The Society wanted the Food and Drug Administration to permit the conduct of investigations that were limited to a maximum of ten patients at one clinical site. Such investigations would test the feasibility of a device in its final stages of development, unencumbered by the requirements of the full-scale scrutiny of an Investigational Device Exemption. Under the proposal of the American Society for Artificial Internal Organs, the institutional review boards would shoulder more responsibility to ensure the safety of patients. The Food and Drug Administration responded to the citizens' petition with a guidance document professing to show how Investigational Device Exemption regulations could be used, without modification, to provide the regulatory basis for feasibility studies. Regrettably, the Investigational Device Exemption regulations under which these studies would be conducted do not lend themselves to such small-scale examinations. Supporting-documentation requirements of full-scale studies still are necessary for feasibility studies. Also, there is still an expectation that the feasibility study will be conducted according to a protocol describing exactly how end points will be evaluated and statistical significance will be achieved. Actually, feasibility studies are almost always too small to have statistical significance. In addition, the other Investigational Device Exemption regulatory requirements are far too extensive for this mechanism to be viable in the final-design stages of the development of a device. Feasibility studies further delay the interminable process of Premarket Approval in the United States.
The time required to conduct a clinical trial of a significant-risk medical device, such as an orthopaedic implant, in the United States is a function of several variables in the investigative plan: the number of patients fitting the criteria for inclusion who are available at the investigative sites chosen, the likelihood of patients agreeing to become subjects in the clinical trial, the number of patients required to achieve the level of statistical significance dictated by the Food and Drug Administration, whether a current or a historical control is used, and the follow-up period to which both the sponsor and the Food and Drug Administration have agreed. In general, a clinical trial with a total enrollment of 200 to 300 patients will involve ten to fifteen study sites with ten to thirty patients per site. The enrollment of patients varies from site to site and is determined by the number of eligible patients routinely seen at that site. Depending on the rate of enrollment, the accrual may take from one to three years. It is likely to take longer if concurrent rather than historical controls are required because of the competition for qualified patients to meet the mandated number of control subjects. (Historical controls are a previous series of patients who should be comparable with the patients being managed with the investigational device and who may or may not have received an active intervention. Concurrent controls are patients under the direct care of the study investigator who are assigned to an intervention other than the investigational device.) Added to this time is that necessary for follow-up. For most orthopaedic implants, the Food and Drug Administration has mandated a two-year follow-up period with examinations performed at intervals during that time. Including the follow-up period, the total time required for a clinical trial could be three to five years from the time of approval of the Investigational Device Exemption to the time of the final study report. The preparation time required for submission of the Investigational Device Exemption is, of course, added onto this period. Thus, it is not unusual for the preclinical and clinical studies necessary to prepare a submission for a significant-risk orthopaedic implant to take approximately seven years, at a total of $700,000 to $1 million in direct and indirect costs. Because of the nature of the statistical analyses to which the clinical data are subjected, the Food and Drug Administration exerts strong pressure to use narrow criteria for inclusion to achieve a more homogeneous patient population. Narrowing of these criteria, however, also results in slower enrollment of patients, higher costs, and diminished real indications for use of the device after it has been approved. These limited indications often result in reduced market potential for the approved device. Because of the time that elapses, from the inception of a new device's development, to the completion of the clinical trial, to the final authorization of the Premarket Approval or the 510-k submission of equivalency, to a marketed product, a newly approved device often has little or no market value23. This devaluation is due to limited indications and the tendency for newer technology to bypass the new device during clinical trials. For a company of any size to pursue development of an orthopaedic implant that requires an Investigational Device Exemption and Premarket Approval or an Investigational Device Exemption and a 510-k, the intended market must be large enough to justify the cost, time, and risk.
Many manufacturers in the United States have found a solution for these problems. Rather than perform Investigational Device Exemption-based feasibility studies or stretch custom-device regulations to provide a regulatory basis for final-design modifications of devices, many now conduct virtually all clinical trials outside of the United States. This permits the iterative evolution of the device with minimum impediment. In Europe, the products can gain premarket approval in all countries of the European Economic Area (Common Market members and associated countries). Sometimes, the data can be used to support a Food and Drug Administration Premarket Approval submission. The result is easier introduction of new or markedly improved medical devices into the other geographical regions hosting the clinical studies of the device. This solution, however, leads to exclusion of the United States from the benefits of many innovations in medical devices, even when the manufacturer is located within United States borders. It is clearly possible, then, that many potentially valuable, innovative products will never be available in the United States16. Furthermore, because engineering technical support must garner early clinical feedback in order to make iterative changes in a device during the course of the trial, technical support and manufacturing could also move overseas. Today, medical devices introduced as new in the United States increasingly are variations on a theme established by earlier devices.
In conclusion, the conduct of orthopaedic clinical trials is based on the ethical considerations of the Declaration of Helsinki and the recognized need for long-term clinical-outcome data. Practically, however, local, regional, or national regulations and reimbursement issues also affect clinical studies. Conducting a clinical trial also requires a substantial amount of both time and money. Concerns about the indications for use in product-labeling certainly are unjustified for the surgeon who selects the product on the basis of the best interest of the patient. The European harmonized and integrated approach to clinical trials based on normative standards is appealing. The requirements are agreed-on, risk-based classification of devices and labeling systems; process transparency; and predictability of the harmonized regulatory process. The approach has been considered carefully and has been subjected to peer review, and it should prove to be very successful. The validity of the European approach has proved persuasive to manufacturers of devices in the United States as they move both clinical studies and medical innovations to Europe.
Recommendations guiding physicians in biomedical research involving human subjects. Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964, and amended by the 29th World Medical Assembly, Tokyo, Japan, October 1975; the 35th World Medical Assembly, Venice, Italy, October 1983; and the 41st World Medical Assembly, Hong Kong, September 1989.
Introduction The Declaration of Geneva of the World Medical Association binds the physician with the words, "The Health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient." The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the understanding of the aetiology and pathogenesis of disease. In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. This applies especially to biomedical research. Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects. In the field of biomedical research a fundamental distinction must be recognized between medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific and without implying direct diagnostic or therapeutic value to the person subjected to the research. Special caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected. Because it is essential that the results of laboratory experiments be applied to human beings to further scientific knowledge and to help suffering humanity, the World Medical Association has prepared the following recommendations as a guide to every physician in biomedical research involving human subjects. They should be kept under review in the future. It must be stressed that the standards as drafted are only a guide to physicians all over the world. Physicians are not relieved from criminal, civil and ethical responsibilities under the laws of their own countries.
I. Basic Principles 2. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted for consideration, comment and guidance to a specially appointed committee independent of the investigator and the sponsor provided that this independent committee is in conformity with the laws and regulations of the country in which the research experiment is performed. 3. Biomedical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given his or her consent. 4. Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject. 5. Every biomedical research project involving human subjects should be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interests of science and society. 6. The right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject. 7. Physicians should abstain from engaging in research projects involving human subjects unless they are satisfied that the hazards involved are believed to be predictable. Physicians should cease any investigation if the hazards are found to outweigh the potential benefits. 8. In public |
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