Subject Selection and Protection

Traditionally, ethical considerations in clinical research have focused on the protection of human research subjects. The Declaration of Helsinki provides that it is the duty of the physician in medical research to protect the life, health, privacy and dignity of the human subject. Additionally, the subjects must be volunteers and informed participants in the research project. American Medical Association (AMA) ethical principle E-2.071 provides further that participants should be drawn from the qualifying population in the general geographic area of the trial and not based on the participant’s ethnicity, race, gender or economic status. Criteria for including or excluding potential study participants should be based on sound scientific principles. As such, although the burdens of research should not fall disproportionately on socioeconomically disadvantaged populations, such populations should not be categorically excluded or discouraged from research protocols.

Federal law requires that institutions performing Department of Health and Human Services (HHS) conducted or supported non-exempt research studies involving human subjects have such research reviewed and approved by an Institutional Review Board (IRB). The IRB’s goal is to help ensure that the rights and welfare of human research subjects are protected. Research studies regulated by the federal Food and Drug Administration (FDA) involving human subjects also requires that such studies be reviewed and approved by an IRB. Under these regulations, medical researchers must demonstrate, among other things, to the IRB’s satisfaction, the following:

·  Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects.

·  Risks to subjects are minimized.

·  The selection of the subjects is equitable.

·  The possibility of coercion or undue influence is minimized.

·  Informed consent will be sought from each prospective subject.

Such additional information may be required to be given to subjects where the IRB determines that such information would meaningfully add to the protection of the rights and welfare of the subjects.

Additionally, there are very stringent requirements under federal law concerning payments made to subjects for recruitment purposes and the contents of advertising and marketing materials, which must be reviewed prior to their dissemination for recruitment of study participants. The funding agency, such as HHS, may also impose additional conditions as necessary for the protection of human subjects.

Informed Consent

Under federal law, investigators must obtain the informed consent of the individual subject or the subject’s representative before involving such subject in research. The informed consent form must include a number of disclosures, such as:

·  A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation in the research study; and a description of the procedures that will need to be followed, as well as identification of any experimental procedures.

·  A description of any reasonably foreseeable discomforts or risks to the subject.

·  A description of any benefits to the subject or others which may reasonably be expected from the subject’s participation in the research study.

·  A disclosure of appropriate alternative courses of treatment or procedures that may be advantageous to the subject.

·  A statement describing confidentiality of records and permissible disclosures under applicable law, including the Health Insurance Portability and Accountability Act of 1996 (HIPAA).

·  An explanation regarding the payment of compensation or the availability of treatment in the event of injury in connection with research involving more than minimal risk.

·  An explanation of whom to contact regarding questions concerning the research, including the rights of the subject and in the event of research-related injuries.

·  A statement that participation in the research study is voluntary, that refusal to participate will not result in any penalty or loss of benefits to which the subject is otherwise entitled and that the subject may discontinue participation at any time without penalty or loss of such benefits.

Additional disclosures under the informed consent form may be required depending upon the study, such as termination of the subject’s participation, consequences of subject withdrawal and additional costs to the subject that may result from participation in the study.

Privacy and Confidentiality

The HIPAA privacy regulations (Privacy Rule) prohibit a covered entity, including health care providers from using or disclosing protected health information (PHI) except as permitted or required by the Privacy Rule. A health care provider may use and disclose PHI for research, regardless of the source of funding of the research, provided that the health care provider obtains documentation that an alteration to, or waiver – in whole or in part – of the subject’s authorization required under the Privacy Rule has been approved by either an IRB or privacy board. In the event that such a waiver or alteration is not obtained, the health care provider must obtain the subject’s authorization prior to the use or disclosure of PHI of the subject.

Where no waiver of, or alteration to, the authorization requirement is obtained, such authorization may be combined with the subjects informed consent form. The informed consent form would have to specifically identify the uses and disclosures of the PHI, request authorization of the subject for such use or disclosure, permit the health care provider to condition the provision of research-related treatment on the provision of an authorization and otherwise comply with the requirements of the Privacy Rule. Where certain standards under the Privacy Rule are met, reviews preparatory to research and research on decedent’s information would not require the subject’s authorization under HIPAA. State laws and regulations may, however, still require that the consent of the subject be obtained prior to any release of medical information of the subject in connection with the research.

Conflicts of Interest

FDA regulations require sponsors to disclose certain financial interests of clinical investigators. The purpose of such disclosures is to allow FDA to assess the reliability of the clinical data. Sponsors seeking marketing approval for products are required to certify that investigators do not have certain financial interests, or to disclose those interests to the FDA. Concerns have grown that financial conflicts of interest in research, derived from financial relationships between the sponsors and investigators and the financial interests they create, may affect the rights and welfare of human subjects in research. Accordingly, on May 12, 2004, HHS published a guidance document regarding financial relationships and interests in research involving human subjects. Specifically, HHS provides a variety of methods that may be used by investigators to manage or mitigate conflicts of interest created by financial relationships of the parties involved in the research.

In its guidance, HHS recommends that investigators conducting research involving human subjects consider the potential effects that a financial relationship of any kind may have on the research or on interactions with research subjects, as well as necessary actions to take. HHS recommends that where a potential conflict of interest exists because of a financial relationship, an investigator should consider taking, as applicable, the following actions:

·  Including information in the informed consent document, such as: (1) the source of funding and funding arrangements for the conduct and review of the research; or (2) information about a financial arrangement of an institution or an investigator and how it is being managed.

·  Using special measures to modify the informed consent process when a potential or actual financial conflict exists, such as: (1) having another individual who does not have a potential or actual conflict of interest involved in the consent process, especially when a potential or actual conflict of interest could influence the tone, presentation or type of information presented during the consent process; or (2) using independent monitoring of the research.

Fee Splitting and Referrals

Generally, the AMA considers the offer or receipt of payment in return for the referral of study participants as unethical. AMA ethical principle E-6.03 provides that the offering or accepting of payment for referring patients to research studies (i.e., a finder’s fee) is unethical. In response to requests for clarification, the Council on Ethical and Judicial Affairs indicated that it is unethical for physicians to receive any kind of compensation in return for the referral of patients to health care facilities, which includes referrals for research studies. Additionally, state anti-referral and anti-fraud and abuse laws, including fee splitting laws, may be broad enough to encompass the payment of a finder’s fee for study participants, thereby prohibiting such arrangements.

Medical research involving human subjects potentially offers great benefits to science and our society as a whole. In working to achieve these benefits, medical researchers may be presented with significant legal and ethical challenges. In order to minimize any potential liability, medical researchers should be aware of their obligations, as well as the duties and responsibilities of sponsors, research organizations and others involved in the research process.