- Email: [email protected]
Navigating Conflicts of Interest for the Medical Device Entrepreneur
Progress in Cardiovascular Diseases 55 (2012) 316 – 320 www.onlinepcd.com
Navigating Conflicts of Interest for the Medical Device Entrepreneur Aine Donovan, Aaron V. Kaplan⁎ Ethics Institute, Dartmouth College (AD) and Cardiology Section Dartmouth Hitchcock Medical Center and the Geisel School of Medicine at Dartmouth (AVK), Lebanon, NH
Abstract
The past fifty years has witnessed dramatic progress in the understanding and treatment of patients suffering from cardiovascular disease leading to symptomatic relief and impressive increases in longevity. These advances have been due in large part to the development, study and implementation of new technology. Within interventional cardiology in particular, these advances have been driven by the availability of new technology in the form of medical devices. Successful device development efforts require close collaboration among basic scientist, clinician-inventors/ entrepreneurs, clinician-investigators and corporations. Though the role of the clinician is central to this process, these activities present important conflicts-of-interest (COIs). The purpose of this paper is to 1) characterize these conflicts, 2) provide a context from which to approach their management and 3) recommend management strategies. (Prog Cardiovasc Dis 2012;55:316-320) © 2012 Elsevier Inc. All rights reserved.
Keywords:
Medical devices; Conflicts of interest; Management strategy; Cardiovascular disease
Introduction The past fifty years has witnessed dramatic progress in the understanding and treatment of patients suffering from cardiovascular disease leading to symptomatic relief and impressive increases in longevity. These advances have been the result of many factors starting with an increased understanding of cardiovascular disease, followed by the utilization of this knowledge in the development of prevention and treatment strategies. These early insights stem from basic and clinical research funded primarily by government and philanthropic organizations. The availability of new technology (electronic, material and manufacturing) has formed the basis for the translation of these insights into viable products, requiring large investments from the pharmaceuticals, biotechnology, diagnostic and medical device sectors. Successful development Statement of Conflict of Interest: see page 320. ⁎ Address reprint requests to Aaron V. Kaplan, M.D., F.A.C.C., F.S.C.A.I., Professor of Medicine (Cardiology) and of Community & Family Medicine, Director, Dartmouth Device Development Symposia, Director of Clinical Research, Cardiology Section, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH 03756-0001. E-mail address: [email protected] (A.V. Kaplan).
0033-0620/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pcad.2012.10.008
efforts require close collaboration among basic scientist, clinician-investigators and corporations. Clinicians are central to the translational process, in the identifying and characterizing of unmet clinical needs, in the development of new products and in the evaluation their impact. Nowhere has the role of the clinician-inventor been more central to the early inventive process than in interventional cardiology. The field was born by clinician inventors most notably Andreas Grüntzig, M.D. in Switzerland. Grüntzig working in close collaboration with Hugo Schneider an engineer, developed the first balloon dilation catheters which were used in the initial angioplasty cases. Grüntzig and Scheider initially tested their product on the ‘bench top’ (often in the inventor's kitchen), then in cadavers and quickly proceeded into the patients, first within the peripheral vasculature and then within the coronary circulations. The ability of Grüntzig to effectively actualize his ideas via his collaboration with Schneider and to effectively communicate them to the vanguard of the clinical community was an essential element to launching interventional cardiology. 1 These efforts led the way for other clinician-inventors including John B. Simpson, M.D., Ph.D. (over-the-wire angioplasty balloon, atherectomy catheter and suture based closure device), and later Julio Palmaz, M.D. (inventor of the slotted tube stent) who
316
A. Donovan, A.V. Kaplan / Progress in Cardiovascular Diseases 55 (2012) 316–320
Abbreviations and Acronyms
have been essential to growth of this field. The COI = conflict of interest emergence of intervenFDA = U.S. Food and Drug tional cardiology has reAdministration quired the ability to develop and manufacFIH = First in Human ture next generation IDE = Investigative Device technology, the infraExemption structure to evaluate clinIRB = Institutional Review ically the technology Board often in the form of randomized controlled studies, as well as the regulatory apparatus to provide appropriate oversight. The cardiovascular medical device sector is now well developed and generates N 4BB USD in worldwide sales annually. Though the role of the clinician inventor is central to developing devices this role frequently presents important conflicts-of-interest (COIs). The purpose of this paper is to 1) characterize these conflicts, 2) provide a context from which to approach their management and 3) recommend management strategies.
317
conflict when the physician is called to an entrepreneurial endeavor, such as device development, that strives for societal as well as individual benefit. In this emerging world of the physician/entrepreneur it is beneficial to rethink the notion of professionalism for the twenty-first century. The philosopher Michael Davis provides a useful clarification, he states that Pound's definition of a profession made earning a living incidental to the profession. Older notions of professionalism were often associated with a calling, indeed the earliest understanding of the term vocation is derived from religious calling. Today's professionals adhere to the love of the chosen field, but most would not consider doing the work as a charitable calling. Professions, according to Davis, differ from charities in that they are deeply concerned about how their members earn a living, not merely that they enjoy a skill set. 5 Compensation is a significant aspect of the professional's work; the task is in determining what guidelines will assist today's physician with maintaining the highest ideals of ethical conduct that serves the good of society with fair compensation for creative endeavors.
Background Defining conflict of interest The medical profession is, by most accounts, in a state of growth and redefinition. This is not unusual for most professions but medicine, in particular, is struggling with the specifics of how to allow for growth, creativity and respect in a rapidly changing environment. The unique nature of the medical profession calls for a hard look at the ethical constraints and obligations of the physician's work life. That unique nature is, by definition, of a strongly differentiated character; the physician operates under “certain unique moral principles or norms that other professions are not bound by.” 2 But what are the characteristics that set one line of work apart from another, granting one the status of profession and the other merely work? Lawyers rely on the former Harvard Law School Dean Roscoe Pound's definition of a profession: a group of men pursuing a learned art as a common calling in the spirit of a public service 3; but Pound's definition seems thin for the medical community. Because they are entrusted with life and death issues, physicians, are called to adopt a type of internal character that protects the profession from the vagaries of ordinary business. Having this character, according to many professional ethicists, “requires individuals to commit themselves to a certain ideal and this ideal requires two standards: first, the physician is required to attain the highest level of technical competence in his or her chosen field, and second, the skills of the profession must be put to use for the good of society.” 4 But whether for society or, as more commonly thought by the medical community — the good of the patient, these two aspirational career goals seem desirable for the medical profession. And yet they pose a potential
The ethicist John Boatright defines a conflict of interest as when "a personal or institutional interest interferes with the ability of the individual or institution to act in the interest of another party, when the individual or institution has an ethical or legal obligation to act in that other party's interest." 6 To further refine the notion of COI Boatright provides three distinct variations on the idea: actual conflicts versus potential conflicts; personal versus impersonal conflicts; and individual versus organizational conflicts. In device development, the controversy often lies in the third category — individual versus organizational conflicts. Many hospitals have taken draconian measures to ensure that employees (usually physicianresearchers) are removed from the chain of potential COI by mandating disengagement at any clinical level. But it is important to recognize that organizations which include both medical services and medical research have, by the nature of their structure, built-in conflicts. As ever increasing numbers of medical professionals turn to entrepreneurial endeavors it is the responsibility of the medical community to develop policies that will maintain the public's trust while fostering the development of new therapies.
The sources of conflict in routine practice Physicians are confronted with numerous COIs in routine daily practice. These COIs emanate from activities and responsibility that extend beyond direct patient care
318
A. Donovan, A.V. Kaplan / Progress in Cardiovascular Diseases 55 (2012) 316–320
and include responsibilities to generate income, for program development and to maintain financial health of the Hospital-Institution where he/she practices. Additional COIs are encountered at university medical centers in the pursuit of their educational and research missions. Within interventional cardiology, in the training of Fellows, the responsibilities to teaching technical skills are frequently in conflict with patient responsibilities. These COIs are managed by disclosure as well as the close supervision to minimize patient risk. Conflicts also arise in the participation in clinical research where patients are subjected to unproven therapies, additional testing and risk of identification. Specific COIs arising from participation in clinical trials, include a clinician's interest in professional advancement by fulfilling publication requirements, clinical service development by obtaining access to new technology prior to competitor hospitals and research program development by generating the income associated with study conduct. These COIs are managed by formal disclosure in the form of Informed Consent performed under the aegis of Institutional Review Boards (IRB). The IRB's primary focus is to insure patient safety, proper recruitment based on informed consent and selecting studies protocols with justifiable safety profile.
Additional conflicts encountered by the clinician-inventor-entrepreneur Input from active clinicians is central to the early clinical development of novel medical devices. This is especially the case with the development of devices that require highly refined technical skills, e.g., coronary stents, laparoscopic devices. Working closely with engineers, clinicians provide nuanced insights into anatomic as well as user interface factors essential to device performance. The successful design team typically includes one or two active clinicians who provide real time feedback during the early design phase. This includes clinician feedback from bench top, cadaveric and animal models. Through these interactions, the clinician team member obtains intimate device knowledge including a thorough understanding the limitations and failure modes of the specific device. This knowledge is important when designing the performing the initial clinical, First in Human (FIH), studies. These clinicians receive compensation typically in the form of cash and equity and this fact leads to the ‘perceived' conflict of interest. When the physician has a substantial financial interest he or she is under scrutiny for encouraging patients to participate in trials. Public perception is a critical factor in maintaining support for on-going research; without it medical organizations and sponsoring companies are in jeopardy of losing their credibility. However, the time and availability required to be an effective design team member
preclude doing this on a ‘gratis’ basis or on terms which do not exceed established thresholds for ‘significant’ compensation generating real and substantial COIs. 7 Some have advocated precluding clinicians with ‘significant’ financial interest from participating in clinical activities. 7 In general, we agree that such COIs are difficult to manage and are best avoided. However, in the case of early clinical device evaluation, especially FIH, the imperative to minimize patient risk requires the active participation of clinicians with a thorough device understanding particularly with respect to failure modes, participate in these cases. This will introduce additional COIs, which will require active management. In the design and performance of a clinical trial one needs to balance patient safety with the exigency of obtaining quality data, which addresses a clinically meaningful issue(s). This needs to be done in an adequately transparent fashion to command the trust of patients and the clinical community. Insuring safety and best of care All aspects of clinical studies are designed not to interfere with a physician's obligation to unambiguously place patient care first and foremost. The COI associated with a large financial position associated with a specific device would likely preclude a clinician from most aspects of providing care to a patient receiving the study device. This prohibition stems from confusion surrounding the physicians motivation, i.e., was driven by needs to show the device in positive light or by the needs of the patient. Protocol development Study design requires an in-depth understanding of the test device as well as the clinical aspects of the disease state. It is expected that the clinicians who have worked most closely and have the best understanding of a specific device will play a central role in the study design process. It is also understood that as with any clinical study the requisite infrastructure to perform a high quality study is in place, including independent analysis of clinical data, event adjudication and data and safety monitoring. A financial COI should not preclude a clinician from participating in the protocol development process. However, this should not include serving as the principal investigator who assumes responsibility for the trial including, but not limited to, the protocol design, execution and as well as public presentation and publication. Patient screening and consent Review of clinical data, e.g., angiography, to insure that a specific patient meets study selection criteria and
A. Donovan, A.V. Kaplan / Progress in Cardiovascular Diseases 55 (2012) 316–320
procedure planning are appropriate roles for clinician with direct ties to a device manufacturer. Direct discussion with the patient regarding the risk and benefits of a specific procedure is best left to providers without COI. This is particularly the case when the discussion is in the context of obtaining of informed consent. Providing the patient with an overview of an experimental technology highlighting the known risks and perceived benefits is central to adequately ‘informing’ the patient prior to obtaining consent. The notion of informed consent is often misunderstood in the most neutral of circumstances, but when the physician has a financial interest at stake in the care of his or her patient, the potential for real or perceived conflict rises to a new level. The ability to provide this information in a fair, transparent and balanced manner would preclude a clinician with ‘significant’ interest in the technology to be part of the consent process. Performing the procedure As with any experimental procedure, in-depth procedure planning is essential to procedural success and maintaining patient safety. In this process the role of the clinician-inventor is to provide technical assistance. It is important that clinical decisions are made by the attending physician with ultimate responsibility for the patient's care. It would be inappropriate for a physician with ‘significant’ interest in specific device to take on this responsibility. In the planning process, it is important to clearly delineate the specific role of each team member. Data management In addition to insuring patient safety, insuring data integrity is paramount to the clinical study process. As such, clinicians with COI should be precluded from direct data entry. It is important to highlight that these suggestions are specific to early clinical device evaluation, in particular FIH studies. As the focus of the evaluation changes during the development process, the role of clinicians with significant COI changes. The primary focus of FIH studies is establishing proof-of-concept. As the focus of development naturally evolves from proof-of-concept, to demonstrating generalized safety and effectiveness, it is anticipated that the role of the clinician with COI would evolve as well. Case study As outlined above, there are different strategies to manage COI. The default strategies employed by many
319
institutions is avoidance, i.e., avoiding the activity and eliminating the potential for COI. The risk of this approach is that it may simply drive away clinical research and innovation from centers which are best equipped to carry out the research. Furthermore, in the case of academic institutions, faculty who are eager to delve into new and innovative research may be thwarted by an overly restrictive approach limiting the role of the researcher, resulting in a loss of talented faculty. This has been one reason that FIH research as a rule is no longer performed in the U.S. We thought it would be instructive to use a fictional case study to further demonstrate how a strategy of active management can be utilized to allow for participation without resorting to recusal. This case involves participation of an academic center in a randomized control trial evaluating a first-in-class bioerodible coronary stent. The proposed Trial is performed under an Investigative Device Exemption (IDE) which was granted by the FDA to study the stent as part of the approval process. On faculty within the Cardiology Section, is the inventor of the stent who also serves on the Board of The Company that developed the stent, and he holds a significant equity position. Via an agreement with the institution and The Company, the faculty member provides consulting services which include providing guidance in study selection criteria, technical advice regarding Stent usage and proctoring at other clinical sites. It was recognized by the members of the Cardiology Section that participation in this Study would present significant COIs, as such it was decided to explore strategies to actively manage these COIs rather than to simply abstain from study participation. Working with the Chief Quality and Compliance Officer, the following rules were instituted prospectively to address and manage COIs generated by study participation. The Faculty Member/Inventor would recuse himself from the following aspects of this Trial: • Serving as Principal Investigator or Co-Principal Investigator • Participation in the Consenting process • Participation in data acquisition • Representing the Institution during negotiations with The Company For the purposes of this Trial, the Faculty Member/ Inventor would be treated as if he were a full-time company employee. All reasonable efforts would be made to remove him from providing care to study patients. Despite these efforts, there were some scenarios in which the Faculty Member/Inventor would be required to provide care, e.g., when taking call for the Cardiac Catheterization Laboratory and while attending in the Cardiac Care Unit. If this were to occur, the Faculty Member/Inventor would make the Principal Investigator at the Institution aware. Furthermore,
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if a patient already under the care of the Faculty Member/ Inventor was felt to be appropriate for the Trial, the Faculty Member/Inventor would refer the patient to the Principal Investigator or Co-Principal Investigator who would discuss study participation with the patient. In doing so the Faculty Member/Inventor will disclose his/her Conflictof-Interest to the patient. It is important to note that these measures were agreed upon and implemented prior to study participation and was disclosed to the IRB. Conclusions Conflict of interest is an inevitable aspect of cardiovascular medical device development. It is neither right nor wrong, it is merely a fact and as a fact of the profession it must be managed. The medical community has at stake its reputation and patient goodwill, these are inestimable public goods that we ignore at our own peril. The encouragement of creative advances in device development is essential to the future of the profession, but it must proceed with the following cautions. In conclusion, the successful medical device development requires, the in depth participation of clinician entrepreneurs. These clinician entrepreneurs frequently have financial connection with the companies developing these devices. These interest and activities present significant COIs which demand active management based on the following guiding principles: 1. Insuring patient care decisions are made by senior clinicians without COI. 2. Restricting the clinician entrepreneur's role to technical aspects focused on the case selection and the procedure performance.
3. Developing a COI management plan in a prospective manner with oversight from outside the clinician entrepreneur's Clinical Section in concert with the institution's IRB. We believe that following these guiding principles provides a means for academic centers and clinicalentrepreneurs to provide technical guidance necessary for the effective early evaluation of emerging medical devices. Finding this balance is key to maximizing the potential of next generation technology while maintaining the public's trust both of which are integral to success going forward. Statement of Conflict of Interests and Disclosures Dr. Kaplan is an active interventional cardiologist and medical device entrepreneur. He is a Founder and a Director of Tryton Medical, Inc. a venture back start-up company developing a specialized stent to treat bifurcation lesions within the coronary vasculature. References 1. Monagan D, Williams DO, editors. Journey into the Heart. New York, NY: Gotham Books; 2007. Chapter 7. 2. Whitman J. Reclaiming the medical profession: the military profession as a model. Prof Ethics. 1995;4(1):5. 3. Davis M. Profession, code and ethics. Ashgate; 2000. p. 3. 4. Whitman J. Reclaiming the medical profession: the military profession as a model. Prof Ethics. 1995;4(1):5. 5. Davis M. Profession, code and ethics. Ashgate; 2000. p. 4. 6. Boatright J. Financial services. In: Davis M, editor. Conflict of interest in the professions. Oxford University Press; 2001. p. 217-236. 7. Baim DS, Donovan A, Smith JJ, et al. Medical device development: A balanced approach to managing conflicts of interest encountered by physicians. Catheter Cardiovasc Interv. 2007;69:655-664.
Navigating Conflicts of Interest for the Medical Device Entrepreneur Aine Donovan, Aaron V. Kaplan⁎ Ethics Institute, Dartmouth College (AD) and Cardiology Section Dartmouth Hitchcock Medical Center and the Geisel School of Medicine at Dartmouth (AVK), Lebanon, NH
Abstract
The past fifty years has witnessed dramatic progress in the understanding and treatment of patients suffering from cardiovascular disease leading to symptomatic relief and impressive increases in longevity. These advances have been due in large part to the development, study and implementation of new technology. Within interventional cardiology in particular, these advances have been driven by the availability of new technology in the form of medical devices. Successful device development efforts require close collaboration among basic scientist, clinician-inventors/ entrepreneurs, clinician-investigators and corporations. Though the role of the clinician is central to this process, these activities present important conflicts-of-interest (COIs). The purpose of this paper is to 1) characterize these conflicts, 2) provide a context from which to approach their management and 3) recommend management strategies. (Prog Cardiovasc Dis 2012;55:316-320) © 2012 Elsevier Inc. All rights reserved.
Keywords:
Medical devices; Conflicts of interest; Management strategy; Cardiovascular disease
Introduction The past fifty years has witnessed dramatic progress in the understanding and treatment of patients suffering from cardiovascular disease leading to symptomatic relief and impressive increases in longevity. These advances have been the result of many factors starting with an increased understanding of cardiovascular disease, followed by the utilization of this knowledge in the development of prevention and treatment strategies. These early insights stem from basic and clinical research funded primarily by government and philanthropic organizations. The availability of new technology (electronic, material and manufacturing) has formed the basis for the translation of these insights into viable products, requiring large investments from the pharmaceuticals, biotechnology, diagnostic and medical device sectors. Successful development Statement of Conflict of Interest: see page 320. ⁎ Address reprint requests to Aaron V. Kaplan, M.D., F.A.C.C., F.S.C.A.I., Professor of Medicine (Cardiology) and of Community & Family Medicine, Director, Dartmouth Device Development Symposia, Director of Clinical Research, Cardiology Section, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH 03756-0001. E-mail address: [email protected] (A.V. Kaplan).
0033-0620/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pcad.2012.10.008
efforts require close collaboration among basic scientist, clinician-investigators and corporations. Clinicians are central to the translational process, in the identifying and characterizing of unmet clinical needs, in the development of new products and in the evaluation their impact. Nowhere has the role of the clinician-inventor been more central to the early inventive process than in interventional cardiology. The field was born by clinician inventors most notably Andreas Grüntzig, M.D. in Switzerland. Grüntzig working in close collaboration with Hugo Schneider an engineer, developed the first balloon dilation catheters which were used in the initial angioplasty cases. Grüntzig and Scheider initially tested their product on the ‘bench top’ (often in the inventor's kitchen), then in cadavers and quickly proceeded into the patients, first within the peripheral vasculature and then within the coronary circulations. The ability of Grüntzig to effectively actualize his ideas via his collaboration with Schneider and to effectively communicate them to the vanguard of the clinical community was an essential element to launching interventional cardiology. 1 These efforts led the way for other clinician-inventors including John B. Simpson, M.D., Ph.D. (over-the-wire angioplasty balloon, atherectomy catheter and suture based closure device), and later Julio Palmaz, M.D. (inventor of the slotted tube stent) who
316
A. Donovan, A.V. Kaplan / Progress in Cardiovascular Diseases 55 (2012) 316–320
Abbreviations and Acronyms
have been essential to growth of this field. The COI = conflict of interest emergence of intervenFDA = U.S. Food and Drug tional cardiology has reAdministration quired the ability to develop and manufacFIH = First in Human ture next generation IDE = Investigative Device technology, the infraExemption structure to evaluate clinIRB = Institutional Review ically the technology Board often in the form of randomized controlled studies, as well as the regulatory apparatus to provide appropriate oversight. The cardiovascular medical device sector is now well developed and generates N 4BB USD in worldwide sales annually. Though the role of the clinician inventor is central to developing devices this role frequently presents important conflicts-of-interest (COIs). The purpose of this paper is to 1) characterize these conflicts, 2) provide a context from which to approach their management and 3) recommend management strategies.
317
conflict when the physician is called to an entrepreneurial endeavor, such as device development, that strives for societal as well as individual benefit. In this emerging world of the physician/entrepreneur it is beneficial to rethink the notion of professionalism for the twenty-first century. The philosopher Michael Davis provides a useful clarification, he states that Pound's definition of a profession made earning a living incidental to the profession. Older notions of professionalism were often associated with a calling, indeed the earliest understanding of the term vocation is derived from religious calling. Today's professionals adhere to the love of the chosen field, but most would not consider doing the work as a charitable calling. Professions, according to Davis, differ from charities in that they are deeply concerned about how their members earn a living, not merely that they enjoy a skill set. 5 Compensation is a significant aspect of the professional's work; the task is in determining what guidelines will assist today's physician with maintaining the highest ideals of ethical conduct that serves the good of society with fair compensation for creative endeavors.
Background Defining conflict of interest The medical profession is, by most accounts, in a state of growth and redefinition. This is not unusual for most professions but medicine, in particular, is struggling with the specifics of how to allow for growth, creativity and respect in a rapidly changing environment. The unique nature of the medical profession calls for a hard look at the ethical constraints and obligations of the physician's work life. That unique nature is, by definition, of a strongly differentiated character; the physician operates under “certain unique moral principles or norms that other professions are not bound by.” 2 But what are the characteristics that set one line of work apart from another, granting one the status of profession and the other merely work? Lawyers rely on the former Harvard Law School Dean Roscoe Pound's definition of a profession: a group of men pursuing a learned art as a common calling in the spirit of a public service 3; but Pound's definition seems thin for the medical community. Because they are entrusted with life and death issues, physicians, are called to adopt a type of internal character that protects the profession from the vagaries of ordinary business. Having this character, according to many professional ethicists, “requires individuals to commit themselves to a certain ideal and this ideal requires two standards: first, the physician is required to attain the highest level of technical competence in his or her chosen field, and second, the skills of the profession must be put to use for the good of society.” 4 But whether for society or, as more commonly thought by the medical community — the good of the patient, these two aspirational career goals seem desirable for the medical profession. And yet they pose a potential
The ethicist John Boatright defines a conflict of interest as when "a personal or institutional interest interferes with the ability of the individual or institution to act in the interest of another party, when the individual or institution has an ethical or legal obligation to act in that other party's interest." 6 To further refine the notion of COI Boatright provides three distinct variations on the idea: actual conflicts versus potential conflicts; personal versus impersonal conflicts; and individual versus organizational conflicts. In device development, the controversy often lies in the third category — individual versus organizational conflicts. Many hospitals have taken draconian measures to ensure that employees (usually physicianresearchers) are removed from the chain of potential COI by mandating disengagement at any clinical level. But it is important to recognize that organizations which include both medical services and medical research have, by the nature of their structure, built-in conflicts. As ever increasing numbers of medical professionals turn to entrepreneurial endeavors it is the responsibility of the medical community to develop policies that will maintain the public's trust while fostering the development of new therapies.
The sources of conflict in routine practice Physicians are confronted with numerous COIs in routine daily practice. These COIs emanate from activities and responsibility that extend beyond direct patient care
318
A. Donovan, A.V. Kaplan / Progress in Cardiovascular Diseases 55 (2012) 316–320
and include responsibilities to generate income, for program development and to maintain financial health of the Hospital-Institution where he/she practices. Additional COIs are encountered at university medical centers in the pursuit of their educational and research missions. Within interventional cardiology, in the training of Fellows, the responsibilities to teaching technical skills are frequently in conflict with patient responsibilities. These COIs are managed by disclosure as well as the close supervision to minimize patient risk. Conflicts also arise in the participation in clinical research where patients are subjected to unproven therapies, additional testing and risk of identification. Specific COIs arising from participation in clinical trials, include a clinician's interest in professional advancement by fulfilling publication requirements, clinical service development by obtaining access to new technology prior to competitor hospitals and research program development by generating the income associated with study conduct. These COIs are managed by formal disclosure in the form of Informed Consent performed under the aegis of Institutional Review Boards (IRB). The IRB's primary focus is to insure patient safety, proper recruitment based on informed consent and selecting studies protocols with justifiable safety profile.
Additional conflicts encountered by the clinician-inventor-entrepreneur Input from active clinicians is central to the early clinical development of novel medical devices. This is especially the case with the development of devices that require highly refined technical skills, e.g., coronary stents, laparoscopic devices. Working closely with engineers, clinicians provide nuanced insights into anatomic as well as user interface factors essential to device performance. The successful design team typically includes one or two active clinicians who provide real time feedback during the early design phase. This includes clinician feedback from bench top, cadaveric and animal models. Through these interactions, the clinician team member obtains intimate device knowledge including a thorough understanding the limitations and failure modes of the specific device. This knowledge is important when designing the performing the initial clinical, First in Human (FIH), studies. These clinicians receive compensation typically in the form of cash and equity and this fact leads to the ‘perceived' conflict of interest. When the physician has a substantial financial interest he or she is under scrutiny for encouraging patients to participate in trials. Public perception is a critical factor in maintaining support for on-going research; without it medical organizations and sponsoring companies are in jeopardy of losing their credibility. However, the time and availability required to be an effective design team member
preclude doing this on a ‘gratis’ basis or on terms which do not exceed established thresholds for ‘significant’ compensation generating real and substantial COIs. 7 Some have advocated precluding clinicians with ‘significant’ financial interest from participating in clinical activities. 7 In general, we agree that such COIs are difficult to manage and are best avoided. However, in the case of early clinical device evaluation, especially FIH, the imperative to minimize patient risk requires the active participation of clinicians with a thorough device understanding particularly with respect to failure modes, participate in these cases. This will introduce additional COIs, which will require active management. In the design and performance of a clinical trial one needs to balance patient safety with the exigency of obtaining quality data, which addresses a clinically meaningful issue(s). This needs to be done in an adequately transparent fashion to command the trust of patients and the clinical community. Insuring safety and best of care All aspects of clinical studies are designed not to interfere with a physician's obligation to unambiguously place patient care first and foremost. The COI associated with a large financial position associated with a specific device would likely preclude a clinician from most aspects of providing care to a patient receiving the study device. This prohibition stems from confusion surrounding the physicians motivation, i.e., was driven by needs to show the device in positive light or by the needs of the patient. Protocol development Study design requires an in-depth understanding of the test device as well as the clinical aspects of the disease state. It is expected that the clinicians who have worked most closely and have the best understanding of a specific device will play a central role in the study design process. It is also understood that as with any clinical study the requisite infrastructure to perform a high quality study is in place, including independent analysis of clinical data, event adjudication and data and safety monitoring. A financial COI should not preclude a clinician from participating in the protocol development process. However, this should not include serving as the principal investigator who assumes responsibility for the trial including, but not limited to, the protocol design, execution and as well as public presentation and publication. Patient screening and consent Review of clinical data, e.g., angiography, to insure that a specific patient meets study selection criteria and
A. Donovan, A.V. Kaplan / Progress in Cardiovascular Diseases 55 (2012) 316–320
procedure planning are appropriate roles for clinician with direct ties to a device manufacturer. Direct discussion with the patient regarding the risk and benefits of a specific procedure is best left to providers without COI. This is particularly the case when the discussion is in the context of obtaining of informed consent. Providing the patient with an overview of an experimental technology highlighting the known risks and perceived benefits is central to adequately ‘informing’ the patient prior to obtaining consent. The notion of informed consent is often misunderstood in the most neutral of circumstances, but when the physician has a financial interest at stake in the care of his or her patient, the potential for real or perceived conflict rises to a new level. The ability to provide this information in a fair, transparent and balanced manner would preclude a clinician with ‘significant’ interest in the technology to be part of the consent process. Performing the procedure As with any experimental procedure, in-depth procedure planning is essential to procedural success and maintaining patient safety. In this process the role of the clinician-inventor is to provide technical assistance. It is important that clinical decisions are made by the attending physician with ultimate responsibility for the patient's care. It would be inappropriate for a physician with ‘significant’ interest in specific device to take on this responsibility. In the planning process, it is important to clearly delineate the specific role of each team member. Data management In addition to insuring patient safety, insuring data integrity is paramount to the clinical study process. As such, clinicians with COI should be precluded from direct data entry. It is important to highlight that these suggestions are specific to early clinical device evaluation, in particular FIH studies. As the focus of the evaluation changes during the development process, the role of clinicians with significant COI changes. The primary focus of FIH studies is establishing proof-of-concept. As the focus of development naturally evolves from proof-of-concept, to demonstrating generalized safety and effectiveness, it is anticipated that the role of the clinician with COI would evolve as well. Case study As outlined above, there are different strategies to manage COI. The default strategies employed by many
319
institutions is avoidance, i.e., avoiding the activity and eliminating the potential for COI. The risk of this approach is that it may simply drive away clinical research and innovation from centers which are best equipped to carry out the research. Furthermore, in the case of academic institutions, faculty who are eager to delve into new and innovative research may be thwarted by an overly restrictive approach limiting the role of the researcher, resulting in a loss of talented faculty. This has been one reason that FIH research as a rule is no longer performed in the U.S. We thought it would be instructive to use a fictional case study to further demonstrate how a strategy of active management can be utilized to allow for participation without resorting to recusal. This case involves participation of an academic center in a randomized control trial evaluating a first-in-class bioerodible coronary stent. The proposed Trial is performed under an Investigative Device Exemption (IDE) which was granted by the FDA to study the stent as part of the approval process. On faculty within the Cardiology Section, is the inventor of the stent who also serves on the Board of The Company that developed the stent, and he holds a significant equity position. Via an agreement with the institution and The Company, the faculty member provides consulting services which include providing guidance in study selection criteria, technical advice regarding Stent usage and proctoring at other clinical sites. It was recognized by the members of the Cardiology Section that participation in this Study would present significant COIs, as such it was decided to explore strategies to actively manage these COIs rather than to simply abstain from study participation. Working with the Chief Quality and Compliance Officer, the following rules were instituted prospectively to address and manage COIs generated by study participation. The Faculty Member/Inventor would recuse himself from the following aspects of this Trial: • Serving as Principal Investigator or Co-Principal Investigator • Participation in the Consenting process • Participation in data acquisition • Representing the Institution during negotiations with The Company For the purposes of this Trial, the Faculty Member/ Inventor would be treated as if he were a full-time company employee. All reasonable efforts would be made to remove him from providing care to study patients. Despite these efforts, there were some scenarios in which the Faculty Member/Inventor would be required to provide care, e.g., when taking call for the Cardiac Catheterization Laboratory and while attending in the Cardiac Care Unit. If this were to occur, the Faculty Member/Inventor would make the Principal Investigator at the Institution aware. Furthermore,
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if a patient already under the care of the Faculty Member/ Inventor was felt to be appropriate for the Trial, the Faculty Member/Inventor would refer the patient to the Principal Investigator or Co-Principal Investigator who would discuss study participation with the patient. In doing so the Faculty Member/Inventor will disclose his/her Conflictof-Interest to the patient. It is important to note that these measures were agreed upon and implemented prior to study participation and was disclosed to the IRB. Conclusions Conflict of interest is an inevitable aspect of cardiovascular medical device development. It is neither right nor wrong, it is merely a fact and as a fact of the profession it must be managed. The medical community has at stake its reputation and patient goodwill, these are inestimable public goods that we ignore at our own peril. The encouragement of creative advances in device development is essential to the future of the profession, but it must proceed with the following cautions. In conclusion, the successful medical device development requires, the in depth participation of clinician entrepreneurs. These clinician entrepreneurs frequently have financial connection with the companies developing these devices. These interest and activities present significant COIs which demand active management based on the following guiding principles: 1. Insuring patient care decisions are made by senior clinicians without COI. 2. Restricting the clinician entrepreneur's role to technical aspects focused on the case selection and the procedure performance.
3. Developing a COI management plan in a prospective manner with oversight from outside the clinician entrepreneur's Clinical Section in concert with the institution's IRB. We believe that following these guiding principles provides a means for academic centers and clinicalentrepreneurs to provide technical guidance necessary for the effective early evaluation of emerging medical devices. Finding this balance is key to maximizing the potential of next generation technology while maintaining the public's trust both of which are integral to success going forward. Statement of Conflict of Interests and Disclosures Dr. Kaplan is an active interventional cardiologist and medical device entrepreneur. He is a Founder and a Director of Tryton Medical, Inc. a venture back start-up company developing a specialized stent to treat bifurcation lesions within the coronary vasculature. References 1. Monagan D, Williams DO, editors. Journey into the Heart. New York, NY: Gotham Books; 2007. Chapter 7. 2. Whitman J. Reclaiming the medical profession: the military profession as a model. Prof Ethics. 1995;4(1):5. 3. Davis M. Profession, code and ethics. Ashgate; 2000. p. 3. 4. Whitman J. Reclaiming the medical profession: the military profession as a model. Prof Ethics. 1995;4(1):5. 5. Davis M. Profession, code and ethics. Ashgate; 2000. p. 4. 6. Boatright J. Financial services. In: Davis M, editor. Conflict of interest in the professions. Oxford University Press; 2001. p. 217-236. 7. Baim DS, Donovan A, Smith JJ, et al. Medical device development: A balanced approach to managing conflicts of interest encountered by physicians. Catheter Cardiovasc Interv. 2007;69:655-664.