May 9, 2013

Controversial U.S. Medical Study Raises Informed Consent Questions

Regulators Scrutinize Studies Involving Human Subjects for Compliance with Existing Regulations
Holland & Knight Alert
Michael J. Werner

The recent controversy surrounding a study of newborn babies in universities across the United States demonstrates the importance of compliance with human subject protection regulations in medical research. The U.S. Department of Health and Human Services (HHS) found that many of the nation's most prestigious universities failed to adequately inform parents of newborn children enrolled in a government-funded research study of the risks associated with participation in that study. According to The New York Times, the risks of participation — which included increased chances of blindness or death — "were not properly communicated" to the parents, "depriving them of information needed to decide whether to [have their newborn babies] participate."

The sanctions these universities could face for failure to comply with federal regulations are still to be determined and could be as severe as being temporarily barred from receiving federal research funds. Regardless, the study and the institutions' reputations have been tainted. The HHS report and the attendant publicity will add to the scrutiny faced by research institutions. Thus, it is essential that universities are familiar with the regulations that govern protecting subjects in research.

Current Regulations Protect Human Medical Research Subjects

Research that is funded by U.S. government agencies, such as the National Institutes of Health (NIH), is governed by the regulations found at 45 CFR Part 46. The regulations are enforced by the HHS Office for Human Research Protection (OHRP). These regulations have been adopted by 15 federal agencies and are enforced by each agency for the research it funds with support from OHRP. FDA has similar regulations that are available at 21 CFR Part 56.

It should be noted that human subject protection rules of 45 CFR Part 46 apply to U.S.-funded research even if that research is performed in other countries. In fact, federal regulations state that federal agencies can allow local law to govern only if they find that the protections offered human subjects are issued either by sovereign states or by an organization whose function for the protection of human research subjects is internationally recognized and these protections "are at least equivalent" to those provided by U.S. regulation.1 In these cases, the agency head may approve the substitution of the foreign procedures in lieu of the procedural requirements provided in U.S. regulations.2 Thus, institutions interested in conducting research abroad must still comply with these rules.

Ethical Foundation for Human Subject Protection Regulations

U.S. human subject protection regulations have their ethical genesis in The Belmont Report, written in 1974 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The report established the basic ethical principles and guidelines to resolve ethical problems that surround the conduct of research with human subjects that are still used today.3

The report identified three principles:

  1. Autonomy/Respect for Persons. Individuals should be treated as autonomous agents and have the right to choose whether or not to participate in research.
  2. Beneficence. Research studies should maximize possible benefits to subjects and minimize possible harms.
  3. Justice. There should be equitable distribution of benefits and risks among members of society and research projects should use fair selection processes to identify subjects.

These principles remain the foundation of U.S. human subject protection regulations.

Regulatory Provisions

Institutions must analyze which of the provisions in 45 CFR Part 46 apply to an individual research project funded by U.S. government agencies. This alert focuses on rules governing when human subject regulations apply and informed consent requirements, as these were the regulations at issue in the newborn study.

When Do the Regulations Apply (45 CFR 46.101 and 45 CFR 46.102)

According to the regulations, human subject protection rules apply to "all research involving human subjects conducted, supported or otherwise subject to regulation by any federal department or agency." The regulations define "research" as a "systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge." This distinguishes research from medical care received by a patient for their own personal well-being.

The regulations also define a "human subject" as a living individual about whom an investigator conducting research "obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information." According to the regulations, "private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes ... and which the individual can reasonably expect will not be made public."4 The regulations specify that "individually identifiable" means that the identity of the subject "is or may readily be ascertained by the investigator or associated with the information". 5

The regulations specifically exempt certain research such as:

  • research conducted in established or commonly accepted educational settings, involving normal educational practices, such as research on regular and special education instructional strategies
  • research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless:
    • information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects
    • any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, or reputation
  • research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects

The full list of exempt research can be found at 45 CFR 46.101(b).

Informed Consent Requirements (45 CFR 46.116 and 45 CFR 46.117)

Voluntary informed consent is the fundamental protection in U.S. law for human research subjects. No human subject research can lawfully occur unless the investigator has obtained informed consent from the subject. Regulations specify the basic elements of informed consent. They are the following:

  1. a statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed and identification of any procedures which are experimental
  2. a description of any reasonably foreseeable risks or discomforts to the subject
  3. a description of any benefits to the subject or to others which may reasonably be expected from the research
  4. a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject
  5. a statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained
  6. for research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained
  7. an explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject
  8. a statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled6

When appropriate, one or more of the following elements of information also must be provided to each subject:

  1. a statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable
  2. anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent
  3. any additional costs to the subject that may result from participation in the research;
  4. the consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject
  5. a statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject
  6. the approximate number of subjects involved in the study7

Note that getting voluntary informed consent is not sufficient to satisfy federal regulations — the consent must be documented. Typically, this entails a written and signed form approved by an institutional review board (IRB). Alternatively, investigators can use a short written consent document stating that the elements of informed consent have been presented orally to the subject or the subject's legally authorized representative. When this method is used, there must be a witness to the oral presentation.8

Since this is seen as a crucial protection for research participants, regulators heavily scrutinize whether subjects received proper consent. In fact, based on published reports, the primary flaw in the newborn study is the lack of informed consent. That is, the parents of newborns enrolled in the research were not adequately informed of the risks of participation, especially since these risks were foreseeable.

The Role of the Institutional Review Board in Ensuring Informed Consent

Federal regulations detail the responsibilities of IRBs.9 One such role is to review research and research protocols to ensure that subjects are protected. In fact, 45 CFR 46.109 and 46.111 specify that IRBs must review informed consent processes/documents to ensure that information given to subjects meets the regulatory requirements. The IRB has the authority to require information that it believes must be given to subjects as part of informed consent including information not in the consent form that it believes would "meaningfully add to the protection" of the rights and welfare of subjects.

In the newborn study at issue, the informed consent document was approved by all 23 institutions that were study sites. At this time, it is not known if federal regulators believe the IRBs did not satisfy their responsibilities.


The specific sanctions to be faced by the U.S. institutions that were part of the newborn study have not yet been determined. But what is clear now is that the government found that these universities did not appropriately and adequately comply with federal regulations. In addition to possible penalties, this is likely to embarrass the universities and their faculty, potentially depriving them of future research opportunities and possibly exposing them to lawsuits.

Human subject research is an important activity in our society as it has the potential to produce valuable data that can be an integral part of developing many types of treatments to help people live with, overcome or be cured of numerous types of conditions and illnesses. However, this type of research faces tremendous scrutiny from regulators as well as the media because it often involves vulnerable individuals who volunteer to participate as research subjects. An institution must take extra care to comply with existing regulations to ensure that the research performed under its auspices maintains high standards.



1 45 CFR 46.101.

2FDA also requires its human subject rules be applied when U.S. companies are doing clinical trials abroad to develop marketing applications for products to be sold in the U.S.

3While the report was influenced by the Nuremberg Code established after World War II, the commission deliberately created a set of ethical principles rather than a strict behavioral code.

4 45 CFR 46.102.

5 Ibid.

6 45 CFR 46.116.

7 Ibid.

8The regulations envision a few situations when the IRB can waive the requirement for a signed consent form. They are: if the only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality; or the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

9 45 CFR 46.107-111.

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Information contained in this alert is for the general education and knowledge of our readers. It is not designed to be, and should not be used as, the sole source of information when analyzing and resolving a legal problem. Moreover, the laws of each jurisdiction are different and are constantly changing. If you have specific questions regarding a particular fact situation, we urge you to consult competent legal counsel.

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