Clinical Trials
Person-Centric Clinical Trials: Ethical Challenges in Recruitment and Data Transparency for Improved Outcomes
The Journal of Clinical Pharmacology 54(9) 1072–1077 © 2014, The American College of Clinical Pharmacology DOI: 10.1002/jcph.308
Dennis A. Robbins, Ph.D., M.P.H.1,2, Frederick A. Curro, D.M.D., Ph.D.3,4, and John Mattison, M.D.5
Abstract Practitioners participating in clinical studies are faced with a number of ethical issues related to recruitment, informed consent, handling and transparency of data. Practitioners educated in Good Clinical Practice, applying the philosophy of person-centricity within a network utilizing riskbased monitoring and remote data entry can provide the requisite infrastructure and oversight to support person-centric clinical studies. While “patient-centered” clinical studies allow for a broader clinical outcome perspective beyond the investigator, the person-centric approach, accounts for the comprehensiveness and complexity of how we make health and healthcare decisions. Augmenting person centricity with comparative effectiveness studies allow for the inclusion of individual data significantly contributing to the aggregation of multiple data sets about individuals and populations. This enables more powerful and personal analytics and care and everyone is afforded the opportunity and privilege to contribute to improve clinical outcomes and in controlling and containing costs. Policy and institutional investment in infrastructure are prerequisite to accommodate these opportunities, to minimize abuses, and provide pathways for analyzing alternative healthcare patterns. Data provided will be comprehensive and robust, representative of use, with safety data more easily discernible from persons with a known past medical and health history.
Introduction We have previously reported on the concept of using a practice-based research network (PBRN) for quality assured clinical studies for regulatory submission.1 The concept termed person-centric clinical trials utilizes a PBRN based on the principles of Good Clinical Practice (GCP) a fundamental requirement for regulatory submission. Person-centric clinical trials (PCCT) utilize trained practitioners in GCP who recruit patients from their practice to participate in clinical studies to improve treatment outcomes. PCCT defines the N-of-1 clinical trial and is inclusive of the person in assessing the clinical outcome. PCCT are limited by safety and reflected in removing the term “research” from PBRN and replacing it with the term “translational” that describes a Practice Based Translational Network (PBTN). Studies for consideration utilizing a PBTN would be Phase III and IV where safety has been established, comparative effectiveness studies to establish best practice and studies for additional label changes. The advantages previously described by conducting a PBTN study translate into shorter clinical development time by generating a large body of data in a relatively short amount of time increasing the frequency of identifying safety issues, providing more robust clinical data by using many investigators, using patients of record with known past medical histories to avoid unexplainable side effects, and to generalize the clinical outcomes related to comparative effectiveness studies. This manuscript discusses the role that a GCP PBTN has in providing person/patient input
into the national health care big data concept for best practice, the rationale for a practitioner to approach their patient for participation in a study and the ethical issues related to the patient’s personal health information being part of the national medical grid. Additionally, PCCTs within the paradigm of the new health care proposal mandate that the person (patient) contribute to improved treatment outcomes. The manuscript is based on the experiences of the PEARL (Practitioners Engaged in Applied Research & Learning) PBTN at New York University which has conducted more than 20 studies over the last 8 years including randomized controlled studies. The PEARL Network was built as a
1
Integrated Decisions, Ethics, Alternatives and Solutions, Imperial Beach, CA, USA 2 Director of Health Policy, PEARL Translational Network, New York University, New York, NY, USA 3 Director, PEARL Practice-Based Translational Network, New York University College of Dentistry, New York, NY, USA 4 Regulatory Affairs Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, USA 5 Medical Director, Kaiser Permanente, Pasadena, CA, USA Submitted for publication 10 January 2014; accepted 8 April 2014. Corresponding author: Frederick A. Curro, D.M.D., Ph.D.; Director, PEARL Practice-Based Translational Network; Director, Regulatory Affairs Bluestone Center for Clinical Research, New York University College of Dentistry, 380 Second Avenue, Suite 302 New York, NY 10010 Email: [email protected]
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patient-centered Network on the principles of GCP for regulatory submission incorporating risk-based monitoring and a regulatory compliant remote data entry system.
Issues in Conducting Practice-Based Translational Network Studies Recruitment of subjects frequently presents as one of the major hurdles in completing a study. Studies somehow separate patients from subjects giving the appearance of considering patients as associated with a practitioner’s office and subjects who are basically unknown to the investigator and recruited for the study. The concept of conducting a PBTN study considers the subject as a patient (person) and the investigator as the practitioner making the terms interchangeable. This concept warrants further discussion on the ethics of recruitment, IRB considerations, transparency, and consent especially with all the electronic health input currently available. The GCP component of the PEARL Network is based on clinical education of the practitioners, use and compliance of an approved remote data entry system with safeguards and clinical research associates periodically visiting the offices to ensure compliance. However, it is the question of “why should I include this person who is a patient of mine into a study” that remains the most asked by practitioners. Other issues in conducting a PBTN study are limiting the turnover of practitioners which can be costly in time and expense, performing appropriate practitioner background screens so they are not limited in scope of practice and have no negative history with regulatory agencies, practitioners having the necessary staff, and a general interest in being part of a clinical infrastructure that can educate their patients in health care literacy maintaining their self-determination.
Ethical Issues of Patient Recruitment The ethics of clinical studies have at times been historically controversial with the result of elaborate and codified oversight to secure the person involved in a study’s safety as well as their autonomy, health, and well-being. These methodologies have assured the conditions for appropriate compliance with the study protocol and protection of patient safety. The more outcome-based and value-based model of care driven by the Accountable Care Act suggest the need to achieve three goals: (i) extend the data set available for analysis; (ii) preserve data integrity; and (iii) increase the involvement of the individual person in all aspects of care and research.2 It is both possible and desirable to commingle data generated by conventional healthcare with data generated directly by the individual person, and yet preserve the integrity of the data and enhance its
1073 collective value for understanding health and driving healthier decisions. Quality assured clinical studies combining observational data from standard of care approaches with oversight to create an audit trail for documentation requires a balance for patient treatment without biasing the treatment to the study outcome. The litany of ethical issues that arise with this new approach are primarily focused on transparency, use and misuse of data and information, health care literacy, and other variables that enable the person to participate throughout the translational lifecycle from data collection and analysis to shared decision making. We have previously defined “patient-centricity” as a dynamic process through which the patient regulates the flow of information to and from him/her via multiple pathways to exercise choices consistent with his/her preferences, values, and beliefs. This fundamentally transformative concept affects how health care decisions are made and who has the authority to make them.3 This concept has evolved into “person-centricity” which builds upon and refines our earlier definition in which the individual is the “regulating fulcrum to evaluate and filter information based on evidence and best practices”. This construct shifts the mindset away from uni-dimensional models of consumer or patient empowerment, centeredness, engagement, or activation to one in which shared decision making results from both self-determination and good counsel from professional caregivers. For the purposes of this manuscript, the term “translational” refers to how new knowledge can improve the clinical outcomes of primary care providers while comparative effectiveness studies define best practices for specific health issues. There are currently many gaps between the term best practice and how physicians actually deliver care. The term “translational gap” encompasses three elements: the practice itself, the health outcome, and the cost associated with those gaps. New technologies can most effectively close these gaps by engaging the person in each of the translational processes. One critical opportunity is to better understand the social determinants of health and how best to address those risks to each individuals health as part of the systematic promotion of wellness and resilience of both individuals and their larger communities. The primary ethical question involving practice-based studies has centered on the concern that involving patients in design and execution of clinical studies would compromise the objectivity of the study or introduce conflicts of interest. While this is a complex topic with no single ‘perfect solution’, a compelling case can be made that protecting the best interest of the study participants should prevail over any other consideration. Engaging the study participants in study design and execution is increasingly considered not only most ethical, but also
1074 most practical in understanding what elements of the care process and outcomes will yield the most meaningful results, and as a byproduct improve compliance of individual persons with the study protocol they helped shape. Our experiences with the PEARL Network suggest that a hybrid practice-based conducted study is the most natural forum that can support both the best interests of the study participants and the most meaningful scientific outcomes. The literature suggests that a relatively high percentage of published study conclusions are subsequently not substantiated.4 We can only speculate whether that statistic could be improved through a more collaborative approach involving study participants.
Person-Centricity and PBTN: A Transformative Paradigm The heavy emphasis of the Affordable Care Act via its supporting Patient Centered Outcomes Research Institute (PCORI) mandates that Institutional Review Boards (IRBs) will now have to revisit the role of the “person” in clinical studies and determine if and when the element of safety may become the counterbalance or even the antithesis of person centricity.5 Conducting such studies requires a careful balance between how much responsibility and risk the “person” is willing to incur as measured by compliance versus how much the IRB is willing to allow the person to influence the outcome of a study. The outcomes may well become limited and restricted to effectiveness studies. It may also have the potential to stimulate and expand the drive and movement toward a more personalized medicine. We must also be vigilant to the concern that if the pendulum swings too far in the direction of centricity it may constrain the basic science aspect of clinical research in pursuing an understanding of the mechanism of the disease process. This concept can be further supported by the PBTN as one of its objectives is to determine optimal treatment outcomes and narrow the scientific translational and educational gap (STEG) in an ongoing and continuing bi-directional process and cultivate participation from all sides. We can minimize practitioner discomfort in recruiting a person (patient) from their practice into a randomized clinical study when we perceive that the clinical study compromises their fiduciary duty to put the participants’ best interests first. Part of that guiding ethic pivots on whether the caring physician abrogates his/her fiduciary duty when a translational study or research is added to the mix. The person must be able to explicitly trust their physician/provider to be secure in the expectation that they receive the care they need when they need it and that such care will not be compromised by any payment schemes or research agendas that may influence a doctor’s judgment. While there is nothing
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endemic to research or translational studies that compromises fiduciary duty, safeguards need to be in place so there is no appearance of impropriety and that research is being done to help improve the person, and at a minimum, ‘do no harm’.
Centricity, Informed Consent and National Medical Grid The mainstay and gold standard of person autonomy and involvement across clinical care as well as research has been “consent”. Informed consent requires understanding and appreciating the significance of the information being afforded. Informed consent is central to the principle of person-centricity. As an extension of person-centricity, it is important that we involve persons as pivots and partners in clinical translational studies and no longer restrict studies to being conducted in highly controlled sterile non-person centric environments.6 This may offer a safer alternative to the legacy of the number of black box warnings and market withdrawals by the Food and Drug Administration (FDA) over the last 10 years.7 Rather, studies should reflect outcomes based on practitioner use in real-world settings.8 PBTNs have been shown to be effective to generate point-of-care-use data when the infrastructure is designed with risk assessment oversight for IRB compliance and for data generalizability.9 Including the person in clinical assessment has added value to the traditional exclusivity of the top-down provider-only approach of interpreting clinical results. Person-centricity encompasses among other things the person’s self-determination including choices surrounding improving their health, and to maximize their wellbeing. It is inclusive and allows for accommodating a wide range the person’s chosen health care providers, health advisors, and those that comprise the person’s medical home. All of these otherwise disparate components can be easily integrated and connected via the person’s electronic health record. Further, the model supports the ability of every willing person to participate in and be an integral part of a national comprehensive health care forum in a national medical grid or network whereby the value of each person’s medical data is fully leveraged both for that individual and for every individual with conditions similar to their own. Person-centric healthcare can be extended easily to person-centric clinical studies in support of a new model of health care delivery, practice and research. Publication of study results allows every provider access to this data for optimal treatment and closing of the scientific and translational gap. Ideally every practice and every willing patient in the practice can become tethered to some grid and this becomes the minimum standard for patient inclusion for diagnosis and treatment. Providing an infrastructure to formalize this process and most
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importantly to ensure that the data contributed to the national medical grid is of a level of quality to improve clinical outcomes. Realistically not all providers will choose to be part of the system or be adequately equipped to participate in this infrastructure and accordingly questions arise with respect to quality of their data input. Incomplete participation has to be addressed to understand the implications for data quality and data integrity. We are proposing a tiered system whereby those providers who are part of a GCP infrastructure can have direct input of the national grid and those that are not part of a GCP infrastructure must have their data input queried for quality assurance. However, we must create controls to ensure ethical propriety based in consent and privacy.
Consent and Privacy—Changing Perspectives Due to Electronic Health People have the right to determine what they wish with their own bodies and persons and each of us has an imaginary sphere of privacy that surrounds and protects us. When we share that privacy with a limited few we speak then not of privacy but of confidentiality. Our privacy right was articulated as early as our Constitution and in legal contexts was articulated more profoundly as early as 1890 in the Harvard Law review but was never conceived to be absolute and has limitations. In this article, the authors Samuel Warren and Louis Brandeis argued that the common law “has always evolved to meet the changing needs of society and provide new protections in today’s information age as one lost the ability for personal health information to be obtained and used without one’s permission, that is one’s consent to allow one to do or use what in the absence of that consent would not be permissible”.10 Without engaging the person and without the person participating in a major way how can there be any assurance that such information is accurate and complete or know if and to what extent they are willing to share information or agree to a procedure that in the absence of consent would not be tolerated. Moreover how can the person or for that matter anyone be assured that the data is good and actionable. Data should be relevant to the purpose for which it was collected and should be accurate, complete and current as needed for that purpose”.11 Furthermore a purpose specification principle indicating that purposes for the collection of personal information should be disclosed before collection and its limited to that collection.10 Persons should be apprised not only of intended use but also be able to restrict that use, revise and review information and remain active participants in the information gathering and dissemination processes. They should be assured that reasonable safeguards and protections are in place and honored. They should be insulated from the insecurity of inadequate security and be vigilant to guard against
1075 misappropriation, unauthorized secondary use, distortion of data and breaches of confidentiality. To make consent meaningful we must get beyond the limiting and most primitive expressions of consent while at the same time understand both the ethical and legal aspects of the consent process. Consent from both an ethical and legal perspective is a permission that allows one to do what in the absence of that consent would not be otherwise permitted or tolerated. The failure to secure consent from a legal aspect would result in battery and from an ethical standpoint a violation of one’s autonomy or self-determination. The fundamental legal foundation of consent is based on the concept of materiality that is the extent to which this specific person would understand and appreciate the significance of the information being afforded. This obviously goes beyond a reasonable person’s standard because it is a specific person who exercises a consent which is derived from two Latin words Con and Sentire. Con means together or with and sentire means both to know and to feel possessing both cognitive and affective dimensions. Thus, the researcher or clinician must be able to transmit knowledge and to some extent feel with the person to best ensure that the patient understands and appreciates the content and significance of the information being afforded and what that means for that specific person. We must not become confused to believe that consent is something one gets or obtains as if it were a discrete static legal transaction, as if it were a fait accompli, something over and done with and once done is set in stone. Rather like clinical care and research, consent must be a continuous, dynamic, and ongoing process that can and should be upgraded as new information accrues or conditions change. This is consistent with the nature of both clinical care and clinical research. The dynamic process of clinical care and/or research in which probabilities and uncertainties are transformed into reasoned judgments on the basis of evidence that it presents is gained dynamically over time. This supports the self-determination and intent of the person and keeps the person informed and less vulnerable to unexpected events. By adding the qualifying adjective “informed” to consent we generate a species of consent which is much more specific and possesses different standards than for example implied consent. Informed consent is a process in which when the person participates in a practice-based study related to improved clinical outcomes such as a comparative effectiveness study where the information transferred is somewhat continuous. It also mandates that risk and benefits be shared, probabilities, alternatives available and the risk of not participating in the process. Consent may be given specifically or globally by the person to allow certain information related to their health care to be shared by a central health information platform to be part of a big data set for improved clinical outcomes.
1076 Person-centric health care delivery and person-centric clinical research mandate that providers practice according to the principles of good clinical practice (GCP) so that the data that is submitted to the grid is of added value. This process only enhances the quality of health care delivery by reducing risk and improving safety and provides a level of consistency by members of the practice or more expansive medical home. This ensures that health care delivery is in the best interests of the person. This process also minimizes/diminishes any ethical issues that are brought into question. Widespread sharing of information poses a host of challenges and opportunities. The issues of secondary use by third parties such as insurers and employers, research access to personal healthy data and information without notice or consent and potential sequelae associated with stigmatizing conditions head the list of concerns.12 Consent as permission to protecting the right and virtue of privacy faces some challenges in the big data arena. Large simple GCP studies creating large-scale data are “crucial for the future of medicine, (and especially for translating genomics research)”. To this end, “the public needs not only to be assured that threats of government exploitation are kept in check, but that the more pedestrian concerns of leaks to insurance providers, employers, or even friends are also prevented. We are faced with challenges to balance the desires to make the information available for biomedical research and to protect it to a reasonable degree.13 De-identification, essentially the process of removing personal identifiers from collected data to support the use of personal information while concealing the identity of the source with the goal of preventing re-identification is touted as the sine qua known of protection for those who are willing to share their data for purposes of research and improving our knowledge base for health and health caring.14 Yet in today’s digital age knowing a specific lab test at a certain time with a certain value could be easily retrievable and reidentifiable.14 When information that is secured for a primary reason such as direct patient care is “re-used for any other purpose” such as research quality control, CER marketing or the like we speak of the “tradeoff between the virtues of protecting individual patient privacy and the virtues of secondary use notably clinical research”.14 The surest way, the sole way, to ensure absolute privacy is to “lock down information so tightly that no one could use it”.14 However the digital age has pretty much invalidated the assurance of protected information in that it can be re-identified. In fact as the authors note “machine re-identification of de-identified data sets is an increasingly trivial pursuit for modern computers”.14 These authors argue “secondary use has the potential to bring better care to entire populations” this public interest component is key to understanding the complexity and challenges in this
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area. Yet, “understanding what information is being collected can help individuals make choices about what information to share, and whom to trust with that information. And whether to rely on their expectations about what will happen to their information”.14 A PBTN can integrate a person/patient’s health and health care data reflecting point-of-care as well as wellness and prevention and provide many other advantages. Such a network exemplified by Practitioners Engaged in Applied Research & Learning (PEARL) was designed as an interdisciplinary GCP network that included patient reported outcomes (PROs) with studies designed that were person-centric and could best accommodate this shift.14 Patients of record with the practitioner/investigator’s office are more willing to participate in a study especially if it can benefit them as the issue of trust has already been established. PBTNs can generate large amounts of data depending upon its membership and the data is from providers who know the past medical history of a given individual so that side effects can be assessed in context with the patient’s history and not reported as an isolated event. The point-ofcare-data generated in actual use, both for efficacy and safety, will be more robust as PBTNs are well suited for pharmacovigilance and surveillance for they are more likely to identify an adverse side effect for a person/ patient than for a subject recruited to the study with no past medical history. Provider/patient participation in large simple studies, observational studies, retrospective and prospective studies and limited randomized clinical studies are considered for the generation of data. Where safety is an issue a controlled environment is required. All studies discussed are assumed to be approved by an IRB. The focus on recruitment from a practice resides in presenting the informed consent to the patient so it is objective, nonbiased and of relative equal risk as standard of care treatment. If the risks of treatment are similar across all treatment groups then the process of randomization becomes an operational task. The concept provides that everyone be a part of the HIPAA compliant national data base; contribute to improved health care delivery and that research data be extended to the private practice sector. We have enriched the concept of patient-centered care by changing the conceptual framework as evidenced by changing the word research to translational, describing the participants as patients not subjects and then further elevating the term patient to person. Additionally, the importance of formalizing observational data has been reported on by the IOM to broaden the clinical outcome perspective beyond that of the investigator and to lessen the controlled environment of traditional studies.14,15 The infrastructure needed to support the integrity of such studies resides in a network designed with the principals of good
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clinical practice.16 The concept that every person has the opportunity to participate in a “big data” base that is constantly being analyzed in real-time to maximize a patient’s clinical outcome is dependent upon both the patient’s health care literacy and transparency of the health care system and is of itself an ethical question to be answered. Some of the positive ethical elements of making the person part of the process are that they better understand the dynamics of a given condition for which a translational study is being performed and for which they are being treated thereby enhancing both their knowledge and inclusion. The format of clinical studies has been evolving to be more inclusive of the person in the assessment of treatment for their condition. Randomized controlled clinical studies may be too controlled and not representative of real use and subsequently early signaling of adverse reactions are missed. PBTNs can serve as an infrastructure to not only deliver information, care and clinical insight but also to document clinical outcomes from both the practitioner as well as the person’s (patient’s) perspective.
Conclusion Clinical studies to be in compliance with the new mandate of patient or person centricity may now extend beyond the traditional boundaries of controlled environments to include practitioner’s offices. The larger the input into the health care database the more predictable will be the clinical outcome. Thus, every person has a chance to participate in optimizing the Nation’s health care outcomes and not only creating a data base related to disease management but by considering the “person” and the continued input of health information we can have a health care policy based on wellness and prevention and early symptoms of disease for early intervention. PBTNs can serve as a model for positive based ethics that ensures trust, accountability and integrity. When we speak of ethics and the PBTN we refer to those overriding principles that protect the person and support the dignity of the research person, subject or patient as well as refer to the propriety of performing or not performing certain research. Further we must respond to transparency in respect to the disclosure of conflicts of interest by the practitioner and stakeholders. We need to be crystal clear about what should be transparent and the manner in which our actions harmonize or conflict with such a framework. Establishing a guiding ethic to offer some logic, process, and justification of how we handle these matters is in order. Such a guiding ethic should define how we determine right, wrong, and propriety.17 As already noted, the PBTN concept can serve many roles to the health caring professions and the consumer. The question of participating in a CER study under the auspices of a GCP PBTN should be viewed as fulfilling the obligation to contribute to person safety, new
1077 knowledge and cost control. Person centricity would be supported with the guidance document on person reported outcomes. With persons and health care providers working together not only the awareness of health care will be raised but also optimal treatment will be provided. All these are keys to a better life, better science and the ability to make better and more astute decisions. Declaration of Conflicting Interests The authors report no conflict of interests.
References 1. Curro FA, Robbins DA, Millenson ML, Fox CH, Naftolin F. Person-centric clinical trials: an opportunity for the good clinical practice (GCP)-practice-based research network. J Clin Pharmacol. 2013;53(10):1091–1094. 2. Patient Protection and Affordable Care Act Health Related Portions of the Health Care and Education Reconciliation Act of 2010, http:// housedocs.house.gov/energycommerce/ppacacon.pdfcontent-detail. html. Published 2010. Accessed January 9, 2014. 3. Robbins DA, Curro FA, Fox CH. Defining patient-centricity: opportunities, challenges, and implications for clinical care and research. Ther Innov Regul Sci. 2013;47(3):349–355. 4. Ioannidis JA. Contradicted and initially stronger effects in highly cited clinical research. JAMA. 2005;294(2):218–228. DOI: 10.1001/ jama.294.2.218. 5. American Recovery and Reinvestment Act of (H.R.1). http:// www.gpo.gov/fdsys/pkg/PLAW-111publ5/pdf/PLAW-111publ5. pdf. Published 2009. Accessed January 9, 2014. 6. Grossman J, Mackenzie FJ. The randomized controlled trial: gold standard, or merely standard. Perspect Biol Med. 2005;48(4):516– 534. PubMed PMID: 16227664. 7. Carpenter D, Zucker EJ, Avorn J. Drug-Review deadlines and safety problems. N Eng. J. Med. 2008;358(13):1354–1361. 8. Green LA, Fryer GE, Yawn BP, Lanier D, Dovey SM. The ecology of medical care revisited. NEJM. 2001;344:2021–2025. 9. Curro FA, Thompson VP, Naftolin F, et al. PBRN infrastructure design for institutional review board risk assessment and generalizability of clinical results. Ther Innov Regul Sci. 2013;47(1):82–89. 10. Richards NM. The puzzle of brandeis, privacy and speech. Vand L Rev. 2010;63(5):1295–1332. 11. Koontz L. Information Privacy in the Evolving Healthcare Environment. Chicago, IL: HIMSS; 2013. Chapter 1. 12. Koontz L. Information Privacy in the Evolving Healthcare Environment. Chicago, IL: HIMSS; 2013. Chapter 6. 13. Mark G, Dov G. .Proceed with Caution. The Scientist. http://www. the-scientist.com/?articles.view/articleNo/37592/title/Proceed-withCaution. Published October 1, 2013; Accessed January 9, 2014 . 14. Koontz L. Information Privacy in the Evolving Healthcare Environment. Chicago, IL: HIMSS; 2013. Chapter 9. 15. Institute of Medicine. Observational Studies in Learning a Health Care System. Workshop presented at the National Academy of Sciences, Washington, D.C. http://iom.edu/Activities/Quality/VSRT/2013APR-25. aspx. Published April 25th, 2013. Accessed January 9, 2014. 16. FDA Guidance Information. http://www.fda.gov/scienceresearch/ specialtopics/runningclinicaltrials/guidancesinformationsheetsandnotices/default.htm. Published August 5, 2010. Accessed January 9, 2014. 17. Robbins D, Wilson TW. In Praise of Transparency and Opacity in Healthcare. Person Safety & Quality Healthcare. http://www.psqh. com/novdec06/ethics.html. Published November/December 2006. Accessed January 9, 2014.
Person-Centric Clinical Trials: Ethical Challenges in Recruitment and Data Transparency for Improved Outcomes
The Journal of Clinical Pharmacology 54(9) 1072–1077 © 2014, The American College of Clinical Pharmacology DOI: 10.1002/jcph.308
Dennis A. Robbins, Ph.D., M.P.H.1,2, Frederick A. Curro, D.M.D., Ph.D.3,4, and John Mattison, M.D.5
Abstract Practitioners participating in clinical studies are faced with a number of ethical issues related to recruitment, informed consent, handling and transparency of data. Practitioners educated in Good Clinical Practice, applying the philosophy of person-centricity within a network utilizing riskbased monitoring and remote data entry can provide the requisite infrastructure and oversight to support person-centric clinical studies. While “patient-centered” clinical studies allow for a broader clinical outcome perspective beyond the investigator, the person-centric approach, accounts for the comprehensiveness and complexity of how we make health and healthcare decisions. Augmenting person centricity with comparative effectiveness studies allow for the inclusion of individual data significantly contributing to the aggregation of multiple data sets about individuals and populations. This enables more powerful and personal analytics and care and everyone is afforded the opportunity and privilege to contribute to improve clinical outcomes and in controlling and containing costs. Policy and institutional investment in infrastructure are prerequisite to accommodate these opportunities, to minimize abuses, and provide pathways for analyzing alternative healthcare patterns. Data provided will be comprehensive and robust, representative of use, with safety data more easily discernible from persons with a known past medical and health history.
Introduction We have previously reported on the concept of using a practice-based research network (PBRN) for quality assured clinical studies for regulatory submission.1 The concept termed person-centric clinical trials utilizes a PBRN based on the principles of Good Clinical Practice (GCP) a fundamental requirement for regulatory submission. Person-centric clinical trials (PCCT) utilize trained practitioners in GCP who recruit patients from their practice to participate in clinical studies to improve treatment outcomes. PCCT defines the N-of-1 clinical trial and is inclusive of the person in assessing the clinical outcome. PCCT are limited by safety and reflected in removing the term “research” from PBRN and replacing it with the term “translational” that describes a Practice Based Translational Network (PBTN). Studies for consideration utilizing a PBTN would be Phase III and IV where safety has been established, comparative effectiveness studies to establish best practice and studies for additional label changes. The advantages previously described by conducting a PBTN study translate into shorter clinical development time by generating a large body of data in a relatively short amount of time increasing the frequency of identifying safety issues, providing more robust clinical data by using many investigators, using patients of record with known past medical histories to avoid unexplainable side effects, and to generalize the clinical outcomes related to comparative effectiveness studies. This manuscript discusses the role that a GCP PBTN has in providing person/patient input
into the national health care big data concept for best practice, the rationale for a practitioner to approach their patient for participation in a study and the ethical issues related to the patient’s personal health information being part of the national medical grid. Additionally, PCCTs within the paradigm of the new health care proposal mandate that the person (patient) contribute to improved treatment outcomes. The manuscript is based on the experiences of the PEARL (Practitioners Engaged in Applied Research & Learning) PBTN at New York University which has conducted more than 20 studies over the last 8 years including randomized controlled studies. The PEARL Network was built as a
1
Integrated Decisions, Ethics, Alternatives and Solutions, Imperial Beach, CA, USA 2 Director of Health Policy, PEARL Translational Network, New York University, New York, NY, USA 3 Director, PEARL Practice-Based Translational Network, New York University College of Dentistry, New York, NY, USA 4 Regulatory Affairs Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, USA 5 Medical Director, Kaiser Permanente, Pasadena, CA, USA Submitted for publication 10 January 2014; accepted 8 April 2014. Corresponding author: Frederick A. Curro, D.M.D., Ph.D.; Director, PEARL Practice-Based Translational Network; Director, Regulatory Affairs Bluestone Center for Clinical Research, New York University College of Dentistry, 380 Second Avenue, Suite 302 New York, NY 10010 Email: [email protected]
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patient-centered Network on the principles of GCP for regulatory submission incorporating risk-based monitoring and a regulatory compliant remote data entry system.
Issues in Conducting Practice-Based Translational Network Studies Recruitment of subjects frequently presents as one of the major hurdles in completing a study. Studies somehow separate patients from subjects giving the appearance of considering patients as associated with a practitioner’s office and subjects who are basically unknown to the investigator and recruited for the study. The concept of conducting a PBTN study considers the subject as a patient (person) and the investigator as the practitioner making the terms interchangeable. This concept warrants further discussion on the ethics of recruitment, IRB considerations, transparency, and consent especially with all the electronic health input currently available. The GCP component of the PEARL Network is based on clinical education of the practitioners, use and compliance of an approved remote data entry system with safeguards and clinical research associates periodically visiting the offices to ensure compliance. However, it is the question of “why should I include this person who is a patient of mine into a study” that remains the most asked by practitioners. Other issues in conducting a PBTN study are limiting the turnover of practitioners which can be costly in time and expense, performing appropriate practitioner background screens so they are not limited in scope of practice and have no negative history with regulatory agencies, practitioners having the necessary staff, and a general interest in being part of a clinical infrastructure that can educate their patients in health care literacy maintaining their self-determination.
Ethical Issues of Patient Recruitment The ethics of clinical studies have at times been historically controversial with the result of elaborate and codified oversight to secure the person involved in a study’s safety as well as their autonomy, health, and well-being. These methodologies have assured the conditions for appropriate compliance with the study protocol and protection of patient safety. The more outcome-based and value-based model of care driven by the Accountable Care Act suggest the need to achieve three goals: (i) extend the data set available for analysis; (ii) preserve data integrity; and (iii) increase the involvement of the individual person in all aspects of care and research.2 It is both possible and desirable to commingle data generated by conventional healthcare with data generated directly by the individual person, and yet preserve the integrity of the data and enhance its
1073 collective value for understanding health and driving healthier decisions. Quality assured clinical studies combining observational data from standard of care approaches with oversight to create an audit trail for documentation requires a balance for patient treatment without biasing the treatment to the study outcome. The litany of ethical issues that arise with this new approach are primarily focused on transparency, use and misuse of data and information, health care literacy, and other variables that enable the person to participate throughout the translational lifecycle from data collection and analysis to shared decision making. We have previously defined “patient-centricity” as a dynamic process through which the patient regulates the flow of information to and from him/her via multiple pathways to exercise choices consistent with his/her preferences, values, and beliefs. This fundamentally transformative concept affects how health care decisions are made and who has the authority to make them.3 This concept has evolved into “person-centricity” which builds upon and refines our earlier definition in which the individual is the “regulating fulcrum to evaluate and filter information based on evidence and best practices”. This construct shifts the mindset away from uni-dimensional models of consumer or patient empowerment, centeredness, engagement, or activation to one in which shared decision making results from both self-determination and good counsel from professional caregivers. For the purposes of this manuscript, the term “translational” refers to how new knowledge can improve the clinical outcomes of primary care providers while comparative effectiveness studies define best practices for specific health issues. There are currently many gaps between the term best practice and how physicians actually deliver care. The term “translational gap” encompasses three elements: the practice itself, the health outcome, and the cost associated with those gaps. New technologies can most effectively close these gaps by engaging the person in each of the translational processes. One critical opportunity is to better understand the social determinants of health and how best to address those risks to each individuals health as part of the systematic promotion of wellness and resilience of both individuals and their larger communities. The primary ethical question involving practice-based studies has centered on the concern that involving patients in design and execution of clinical studies would compromise the objectivity of the study or introduce conflicts of interest. While this is a complex topic with no single ‘perfect solution’, a compelling case can be made that protecting the best interest of the study participants should prevail over any other consideration. Engaging the study participants in study design and execution is increasingly considered not only most ethical, but also
1074 most practical in understanding what elements of the care process and outcomes will yield the most meaningful results, and as a byproduct improve compliance of individual persons with the study protocol they helped shape. Our experiences with the PEARL Network suggest that a hybrid practice-based conducted study is the most natural forum that can support both the best interests of the study participants and the most meaningful scientific outcomes. The literature suggests that a relatively high percentage of published study conclusions are subsequently not substantiated.4 We can only speculate whether that statistic could be improved through a more collaborative approach involving study participants.
Person-Centricity and PBTN: A Transformative Paradigm The heavy emphasis of the Affordable Care Act via its supporting Patient Centered Outcomes Research Institute (PCORI) mandates that Institutional Review Boards (IRBs) will now have to revisit the role of the “person” in clinical studies and determine if and when the element of safety may become the counterbalance or even the antithesis of person centricity.5 Conducting such studies requires a careful balance between how much responsibility and risk the “person” is willing to incur as measured by compliance versus how much the IRB is willing to allow the person to influence the outcome of a study. The outcomes may well become limited and restricted to effectiveness studies. It may also have the potential to stimulate and expand the drive and movement toward a more personalized medicine. We must also be vigilant to the concern that if the pendulum swings too far in the direction of centricity it may constrain the basic science aspect of clinical research in pursuing an understanding of the mechanism of the disease process. This concept can be further supported by the PBTN as one of its objectives is to determine optimal treatment outcomes and narrow the scientific translational and educational gap (STEG) in an ongoing and continuing bi-directional process and cultivate participation from all sides. We can minimize practitioner discomfort in recruiting a person (patient) from their practice into a randomized clinical study when we perceive that the clinical study compromises their fiduciary duty to put the participants’ best interests first. Part of that guiding ethic pivots on whether the caring physician abrogates his/her fiduciary duty when a translational study or research is added to the mix. The person must be able to explicitly trust their physician/provider to be secure in the expectation that they receive the care they need when they need it and that such care will not be compromised by any payment schemes or research agendas that may influence a doctor’s judgment. While there is nothing
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endemic to research or translational studies that compromises fiduciary duty, safeguards need to be in place so there is no appearance of impropriety and that research is being done to help improve the person, and at a minimum, ‘do no harm’.
Centricity, Informed Consent and National Medical Grid The mainstay and gold standard of person autonomy and involvement across clinical care as well as research has been “consent”. Informed consent requires understanding and appreciating the significance of the information being afforded. Informed consent is central to the principle of person-centricity. As an extension of person-centricity, it is important that we involve persons as pivots and partners in clinical translational studies and no longer restrict studies to being conducted in highly controlled sterile non-person centric environments.6 This may offer a safer alternative to the legacy of the number of black box warnings and market withdrawals by the Food and Drug Administration (FDA) over the last 10 years.7 Rather, studies should reflect outcomes based on practitioner use in real-world settings.8 PBTNs have been shown to be effective to generate point-of-care-use data when the infrastructure is designed with risk assessment oversight for IRB compliance and for data generalizability.9 Including the person in clinical assessment has added value to the traditional exclusivity of the top-down provider-only approach of interpreting clinical results. Person-centricity encompasses among other things the person’s self-determination including choices surrounding improving their health, and to maximize their wellbeing. It is inclusive and allows for accommodating a wide range the person’s chosen health care providers, health advisors, and those that comprise the person’s medical home. All of these otherwise disparate components can be easily integrated and connected via the person’s electronic health record. Further, the model supports the ability of every willing person to participate in and be an integral part of a national comprehensive health care forum in a national medical grid or network whereby the value of each person’s medical data is fully leveraged both for that individual and for every individual with conditions similar to their own. Person-centric healthcare can be extended easily to person-centric clinical studies in support of a new model of health care delivery, practice and research. Publication of study results allows every provider access to this data for optimal treatment and closing of the scientific and translational gap. Ideally every practice and every willing patient in the practice can become tethered to some grid and this becomes the minimum standard for patient inclusion for diagnosis and treatment. Providing an infrastructure to formalize this process and most
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importantly to ensure that the data contributed to the national medical grid is of a level of quality to improve clinical outcomes. Realistically not all providers will choose to be part of the system or be adequately equipped to participate in this infrastructure and accordingly questions arise with respect to quality of their data input. Incomplete participation has to be addressed to understand the implications for data quality and data integrity. We are proposing a tiered system whereby those providers who are part of a GCP infrastructure can have direct input of the national grid and those that are not part of a GCP infrastructure must have their data input queried for quality assurance. However, we must create controls to ensure ethical propriety based in consent and privacy.
Consent and Privacy—Changing Perspectives Due to Electronic Health People have the right to determine what they wish with their own bodies and persons and each of us has an imaginary sphere of privacy that surrounds and protects us. When we share that privacy with a limited few we speak then not of privacy but of confidentiality. Our privacy right was articulated as early as our Constitution and in legal contexts was articulated more profoundly as early as 1890 in the Harvard Law review but was never conceived to be absolute and has limitations. In this article, the authors Samuel Warren and Louis Brandeis argued that the common law “has always evolved to meet the changing needs of society and provide new protections in today’s information age as one lost the ability for personal health information to be obtained and used without one’s permission, that is one’s consent to allow one to do or use what in the absence of that consent would not be permissible”.10 Without engaging the person and without the person participating in a major way how can there be any assurance that such information is accurate and complete or know if and to what extent they are willing to share information or agree to a procedure that in the absence of consent would not be tolerated. Moreover how can the person or for that matter anyone be assured that the data is good and actionable. Data should be relevant to the purpose for which it was collected and should be accurate, complete and current as needed for that purpose”.11 Furthermore a purpose specification principle indicating that purposes for the collection of personal information should be disclosed before collection and its limited to that collection.10 Persons should be apprised not only of intended use but also be able to restrict that use, revise and review information and remain active participants in the information gathering and dissemination processes. They should be assured that reasonable safeguards and protections are in place and honored. They should be insulated from the insecurity of inadequate security and be vigilant to guard against
1075 misappropriation, unauthorized secondary use, distortion of data and breaches of confidentiality. To make consent meaningful we must get beyond the limiting and most primitive expressions of consent while at the same time understand both the ethical and legal aspects of the consent process. Consent from both an ethical and legal perspective is a permission that allows one to do what in the absence of that consent would not be otherwise permitted or tolerated. The failure to secure consent from a legal aspect would result in battery and from an ethical standpoint a violation of one’s autonomy or self-determination. The fundamental legal foundation of consent is based on the concept of materiality that is the extent to which this specific person would understand and appreciate the significance of the information being afforded. This obviously goes beyond a reasonable person’s standard because it is a specific person who exercises a consent which is derived from two Latin words Con and Sentire. Con means together or with and sentire means both to know and to feel possessing both cognitive and affective dimensions. Thus, the researcher or clinician must be able to transmit knowledge and to some extent feel with the person to best ensure that the patient understands and appreciates the content and significance of the information being afforded and what that means for that specific person. We must not become confused to believe that consent is something one gets or obtains as if it were a discrete static legal transaction, as if it were a fait accompli, something over and done with and once done is set in stone. Rather like clinical care and research, consent must be a continuous, dynamic, and ongoing process that can and should be upgraded as new information accrues or conditions change. This is consistent with the nature of both clinical care and clinical research. The dynamic process of clinical care and/or research in which probabilities and uncertainties are transformed into reasoned judgments on the basis of evidence that it presents is gained dynamically over time. This supports the self-determination and intent of the person and keeps the person informed and less vulnerable to unexpected events. By adding the qualifying adjective “informed” to consent we generate a species of consent which is much more specific and possesses different standards than for example implied consent. Informed consent is a process in which when the person participates in a practice-based study related to improved clinical outcomes such as a comparative effectiveness study where the information transferred is somewhat continuous. It also mandates that risk and benefits be shared, probabilities, alternatives available and the risk of not participating in the process. Consent may be given specifically or globally by the person to allow certain information related to their health care to be shared by a central health information platform to be part of a big data set for improved clinical outcomes.
1076 Person-centric health care delivery and person-centric clinical research mandate that providers practice according to the principles of good clinical practice (GCP) so that the data that is submitted to the grid is of added value. This process only enhances the quality of health care delivery by reducing risk and improving safety and provides a level of consistency by members of the practice or more expansive medical home. This ensures that health care delivery is in the best interests of the person. This process also minimizes/diminishes any ethical issues that are brought into question. Widespread sharing of information poses a host of challenges and opportunities. The issues of secondary use by third parties such as insurers and employers, research access to personal healthy data and information without notice or consent and potential sequelae associated with stigmatizing conditions head the list of concerns.12 Consent as permission to protecting the right and virtue of privacy faces some challenges in the big data arena. Large simple GCP studies creating large-scale data are “crucial for the future of medicine, (and especially for translating genomics research)”. To this end, “the public needs not only to be assured that threats of government exploitation are kept in check, but that the more pedestrian concerns of leaks to insurance providers, employers, or even friends are also prevented. We are faced with challenges to balance the desires to make the information available for biomedical research and to protect it to a reasonable degree.13 De-identification, essentially the process of removing personal identifiers from collected data to support the use of personal information while concealing the identity of the source with the goal of preventing re-identification is touted as the sine qua known of protection for those who are willing to share their data for purposes of research and improving our knowledge base for health and health caring.14 Yet in today’s digital age knowing a specific lab test at a certain time with a certain value could be easily retrievable and reidentifiable.14 When information that is secured for a primary reason such as direct patient care is “re-used for any other purpose” such as research quality control, CER marketing or the like we speak of the “tradeoff between the virtues of protecting individual patient privacy and the virtues of secondary use notably clinical research”.14 The surest way, the sole way, to ensure absolute privacy is to “lock down information so tightly that no one could use it”.14 However the digital age has pretty much invalidated the assurance of protected information in that it can be re-identified. In fact as the authors note “machine re-identification of de-identified data sets is an increasingly trivial pursuit for modern computers”.14 These authors argue “secondary use has the potential to bring better care to entire populations” this public interest component is key to understanding the complexity and challenges in this
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area. Yet, “understanding what information is being collected can help individuals make choices about what information to share, and whom to trust with that information. And whether to rely on their expectations about what will happen to their information”.14 A PBTN can integrate a person/patient’s health and health care data reflecting point-of-care as well as wellness and prevention and provide many other advantages. Such a network exemplified by Practitioners Engaged in Applied Research & Learning (PEARL) was designed as an interdisciplinary GCP network that included patient reported outcomes (PROs) with studies designed that were person-centric and could best accommodate this shift.14 Patients of record with the practitioner/investigator’s office are more willing to participate in a study especially if it can benefit them as the issue of trust has already been established. PBTNs can generate large amounts of data depending upon its membership and the data is from providers who know the past medical history of a given individual so that side effects can be assessed in context with the patient’s history and not reported as an isolated event. The point-ofcare-data generated in actual use, both for efficacy and safety, will be more robust as PBTNs are well suited for pharmacovigilance and surveillance for they are more likely to identify an adverse side effect for a person/ patient than for a subject recruited to the study with no past medical history. Provider/patient participation in large simple studies, observational studies, retrospective and prospective studies and limited randomized clinical studies are considered for the generation of data. Where safety is an issue a controlled environment is required. All studies discussed are assumed to be approved by an IRB. The focus on recruitment from a practice resides in presenting the informed consent to the patient so it is objective, nonbiased and of relative equal risk as standard of care treatment. If the risks of treatment are similar across all treatment groups then the process of randomization becomes an operational task. The concept provides that everyone be a part of the HIPAA compliant national data base; contribute to improved health care delivery and that research data be extended to the private practice sector. We have enriched the concept of patient-centered care by changing the conceptual framework as evidenced by changing the word research to translational, describing the participants as patients not subjects and then further elevating the term patient to person. Additionally, the importance of formalizing observational data has been reported on by the IOM to broaden the clinical outcome perspective beyond that of the investigator and to lessen the controlled environment of traditional studies.14,15 The infrastructure needed to support the integrity of such studies resides in a network designed with the principals of good
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clinical practice.16 The concept that every person has the opportunity to participate in a “big data” base that is constantly being analyzed in real-time to maximize a patient’s clinical outcome is dependent upon both the patient’s health care literacy and transparency of the health care system and is of itself an ethical question to be answered. Some of the positive ethical elements of making the person part of the process are that they better understand the dynamics of a given condition for which a translational study is being performed and for which they are being treated thereby enhancing both their knowledge and inclusion. The format of clinical studies has been evolving to be more inclusive of the person in the assessment of treatment for their condition. Randomized controlled clinical studies may be too controlled and not representative of real use and subsequently early signaling of adverse reactions are missed. PBTNs can serve as an infrastructure to not only deliver information, care and clinical insight but also to document clinical outcomes from both the practitioner as well as the person’s (patient’s) perspective.
Conclusion Clinical studies to be in compliance with the new mandate of patient or person centricity may now extend beyond the traditional boundaries of controlled environments to include practitioner’s offices. The larger the input into the health care database the more predictable will be the clinical outcome. Thus, every person has a chance to participate in optimizing the Nation’s health care outcomes and not only creating a data base related to disease management but by considering the “person” and the continued input of health information we can have a health care policy based on wellness and prevention and early symptoms of disease for early intervention. PBTNs can serve as a model for positive based ethics that ensures trust, accountability and integrity. When we speak of ethics and the PBTN we refer to those overriding principles that protect the person and support the dignity of the research person, subject or patient as well as refer to the propriety of performing or not performing certain research. Further we must respond to transparency in respect to the disclosure of conflicts of interest by the practitioner and stakeholders. We need to be crystal clear about what should be transparent and the manner in which our actions harmonize or conflict with such a framework. Establishing a guiding ethic to offer some logic, process, and justification of how we handle these matters is in order. Such a guiding ethic should define how we determine right, wrong, and propriety.17 As already noted, the PBTN concept can serve many roles to the health caring professions and the consumer. The question of participating in a CER study under the auspices of a GCP PBTN should be viewed as fulfilling the obligation to contribute to person safety, new
1077 knowledge and cost control. Person centricity would be supported with the guidance document on person reported outcomes. With persons and health care providers working together not only the awareness of health care will be raised but also optimal treatment will be provided. All these are keys to a better life, better science and the ability to make better and more astute decisions. Declaration of Conflicting Interests The authors report no conflict of interests.
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