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CONFLICT OF INTEREST ISSUES
Questions of honesty and dishonesty are a central focus of ethics. Dishonesty can be a conscious and intentional act intended to deceive or mislead. It can also be a relatively unconscious act brought about a bias induced by self-interest. Bias may enter a research study through, inter alia, patient selection, subjective physical assessment, or the interpretation of nonquantitative laboratory or imaging assessments. Such bias has all too often been associated with an investigators interest in the outcome of a study. To account for such sources of bias, many institutions, professional publications, and public agencies have developed guidelines for dealing with potential conflicts of interest.
The public health service (PHS) has recently promulgated regulations establishing standards and procedures to be followed by institutions that apply for research funding from the PHS to control issues that might arise because of conflicts of interest of investigators. Their purpose is to ensure that the design, conduct, or reporting of research funded under PHS grants will not be biased by any conflicting financial interest of those investigators responsible for the research.55 The National Science Foundation promulgated similar regulations relating to investigator financial disclosure for projects funded by National Science Foundation grants.”56 These regulations require investigators to disclose to an official designated by the institution significant financial interests (including those of their spouse and minor children) that would reasonably appear to be affected by the research proposed for funding by the PHS. Before the expenditure of funds, the institution must act to protect PHS-funded research from bias resulting from conflict of interest.
Several possible actions to manage, reduce, or eliminate such a conflict of interest are permissible under the regulations. They include public disclosure of significant financial interests, monitoring of research by independent reviewers, modification of the research plan, disqualification of the investigator from participation in the research, divestiture of significant financial interests, or severance of relationships that create actual or potential conflict.
Universities and other research institutions have responded to these regulations in various ways. Some have accepted the flexible approach to management of conflicts of interest permitted by the regulations. Others have gone far beyond the federal requirements. For example, a leading medical school prohibits a faculty member from participating in clinical research on a technology owned by a business in which the faculty member has a consulting relationship or ownership interest.57 This policy encompasses both federally funded and privately funded studies.
At least in California, the Courts have found that a physician who treats a patient in whom he also has a research interest has potentially conflicting loyalties.58 Thus to satisfy fiduciary duty and to obtain the patient’s informed consent in that state, a physician “must disclose personal interests unrelated to the patient’s health, whether research or economic, that may affect his medical judgment.”59
The desire of academic researchers to publish their work creates a tension with the need of sponsors to keep valuable data confidential. Thus the investigator should be aware of institutional policies on restriction of publication and terms of existing grants before accepting restrictions on the publication of investigational results. Clinical investigators serving as consultants to government agencies must be aware of federal conflict of interest statutes.60 State conflict of interest provisions may also apply, particularly to investigators who are employees of state institutions. The FDA has developed a rule that, while not prohibiting conflicts of interest, requires investigator financial disclosure to the agency so that it can be aware of potential sources of bias. Currently, sponsors must provide certification for all investigators in studies which the FDA uses for a determination of the efficacy of a new product that no financial arrangements with an investigator have been made where study outcome could affect compensation; that the investigator has no proprietary interest in the tested product; that the investigator does not have a significant equity interest in the sponsor of the covered study; and that the investigator has not received significant payments of other sorts. Alternatively, the sponsor must disclose the nature of such specified financial arrangements and describe steps taken to minimize the potential for bias.61
PROTECTION OF THE PUBLIC AND PRIVATE PURSE
The focus of FDA inspections of clinical investigation sites is on data integrity, not financial fraud. Yet, FDA inspectors have seen an increase in alleged cases of fraud involving investigator reimbursement funded under federal grants and contracts. Although these issues do not directly fall within the ambit of FDA jurisdiction, the agency frequently refers cases involving criminal misconduct of any form to federal prosecutors.
Professional ethics, institutional policies, and FDA regulations guide decisions concerning charging subjects for investigational drugs or devices. Both the investigational device exemption and the IND regulations permit a sponsor to charge investigators for investigational products in an amount necessary to recover costs. Investigators can pass this charge on to subjects with IRB approval and subject consent after full disclosure. In addition, investigators may charge subjects for professional medical services rendered as part of a clinical investigation.
In doing so, however, the clinician-investigator must avoid the temptation to bill for nonapproved investigational studies using the billing code for a related approved procedure. For example, before newer technetium-based myocardial perfusion agents were approved, billing a federal program such as Medicare for an investigational study of these agents as a previously approved “thallium scan” which may have demonstrated comparable data would, nevertheless, have subjected an investigator to civil and criminal liability under the federal false claims act. The Health Insurance Portability and Accountability Act of 1966 created a new and independent federal crime of “health care fraud” covering any scheme to defraud or obtain by false pretenses money or property of any health care benefit program, public or private.62 The penalties are severe. The False Claims Act applies to research grants and payments for medical care. For clinical studies funded with federal grant money, the investigator should be aware that material false statements in a grant application may create liability under the Act.63
PROTECTION OF PRIVATE FINANCIAL INTERESTS
It is now generally recognized that principals of public companies have a fiduciary responsibility to their shareholders that prevents them from personal enrichment at the shareholders expense by misuse of non-public data that may have a material effect on the company’s share price. It is less well recognized that such responsibility may extend to clinical investigators and others involved in medical research. A clinical investigator conducting research for a sponsor undertakes a fiduciary duty not to use research data, which can be regarded as the sponsor’s property, for his or her own benefit. The results of clinical studies often have significant impact on the price of publicly traded securities of the sponsor, particularly if the sponsor is a relatively young start-up biomedical company. Clinical investigators generally sign an agreement not to disclose nonpublic data provided by the company or produced in the course of company-sponsored research. This agreement imposes a contractual duty of confidentiality on the investigator, enforceable by the sponsor in the courts. In addition, a physician-investigator can be considered an “insider” of a publicly traded company under laws of the Securities and Exchange Commission. Such laws are intended to promote a “level playing field” for investors who trade in the securities of public companies by preventing those with nonpublic information, which might affect the value of a security, from profiting unfairly. These laws create a duty, enforced by the Securities and Exchange Commission and the courts, for the physician-investigator who is acting for a publicly traded sponsor not to “front-run” the public announcement of such research findings and act on this privileged information for personal gain.
Violation of this duty can be expensive. For example, a physician investigator and his research fellow were recently charged under the Insider Trading Sanctions Act of 1984 with tipping their friends to the failure of a critical trial of their sponsor’s product. This confidential information enabled the group to avoid substantial losses in the sponsor’s stock by selling it before the results of the study were publicly announced. The physician responsible for the study agreed to pay a civil penalty equal to the avoided stock losses of more than $160,000, even though he had not himself traded in the stock.64 Under principles recently established by the Supreme Court, an investigator could also violate insider trading provisions by using a sponsor’s nonpublic data without notifying the sponsor to profit in the stock of a competitor of the sponsor.65
Ethical and Legal Obligations of Clinical Investigators
Clinical investigators assume unique responsibilities in research studies involving human subjects, responsibilities that differ materially from those in routine healthcare. Historical example of the horrific consequences of the failure of individual ethics and Western political trends have encouraged the development of formal rules for most aspects of human experimentation. Researchers assume a non-delegable legal and ethical duty to ensure that the research process is carried out in compliance with applicable laws, regulations, and formal ethical standards. These are derived from a variety of governmental and institutional sources. Professional, personal, and financial penalties for noncompliance are severe. Standards for ethical behavior in healthcare are still evolving and new problems are likely to be posed by emerging technologies and by the increasingly dominant role of institutional structures driven by economic considerations. But, perhaps all this was prefigured by Socrates, whom the Athenians judged harshly for his pursuit of moral truth.: “What is piety? That is an enquiry which I shall never be weary of pursuing…” |
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Original Business Thinking for the Life Sciences |
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Allan M. Green, MD, PhD, JD, LLC Attorney at Law |
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FDA Regulations for Clinical Investigators: A Summary (Part 3) |
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Allan M. Green, MD,PhD,JD Neil Steinmetz, MD, JD |
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