FDA believes that, in some situations, clinical investigator misconduct may be sufficiently serious to conclude that human subjects under that investigator's care are or would be exposed to an unreasonable and significant risk of illness or injury. FDA anticipates that the use of clinical holds in instances of misconduct will be infrequent. In this section, FDA provides guidance on the circumstances in which the agency could reach such a conclusion and impose a clinical hold on the study or study sites in which an investigator is involved. Still, FDA may impose a clinical hold on a study or study site whenever it finds that human subjects are or would be exposed to an unreasonable and significant risk of illness or injury. The grounds for imposition of a clinical hold need not include a finding of misconduct or a violation of a regulation.

1. Before an enforcement action is initiated

After FDA obtains evidence about investigator misconduct, but before a decision to bring an enforcement action in federal court or to issue a NIDPOE letter has been made, there may or may not be reason to believe that human subjects under the care of the investigator are or would be exposed to an unreasonable and significant risk of illness or injury. At this stage in an inquiry into investigator misconduct, FDA would consider two factors in deciding whether to issue a clinical hold.

First, FDA would look at the nature of the violation and its significance for the rights, safety and welfare of human subjects. Certain types of violations may pose such a significant threat to subjects in the trial that suspending that part of the trial under the investigator is justified, even where the investigation into the violations is at an early stage. For example, FDA may conclude that suspending the trial is necessary to protect subjects from a significant and unreasonable risk of illness or injury, if FDA finds evidence of one or more of the following.

• Failure to report serious or life-threatening adverse events;
• Serious protocol violations, such as enrolling subjects who do not meet the entrance criteria because they have conditions that put them at increased risk from the investigational drug, or failing to carry out critical safety evaluations;
• Repeated or deliberate failure to obtain adequate informed consent, including:
  - Falsification of consent forms;
  - Repeated or deliberate failure to disclose serious risks of the investigational drug in the informed consent process;
• Falsification of study safety data;
• Failure to obtain IRB review and approval for significant protocol changes; and
• Failure to adequately supervise the clinical trial such that human subjects are or would be exposed to an unreasonable and significant risk of illness or injury.

Conversely, some types of violations would be less likely to justify a clinical hold at an early stage in FDA's investigation. For example, certain kinds of record-keeping violations would be unlikely to suggest such a significant risk of illness or injury to subjects in the trial that a clinical hold would be justified.

Second, FDA would consider the degree of certainty that there has been investigator misconduct that poses a significant risk to subjects. Nonetheless, protecting the safety of subjects is of great importance, and even preliminary (e.g. pre-inspectional information provided to FDA by the IRB, sponsor or other parties), but credible evidence raising concerns that subjects may be placed at substantial risk may warrant a hold while further information is being obtained.

2. After an enforcement action is initiated

In general, when FDA concludes that there is sufficient evidence of repeated or deliberate violations of the regulations or of repeated of deliberate submission of false information to take an enforcement action, it typically will issue a NIDPOE letter and begin a disqualification proceeding. In this case there will be a strong presumption that human subjects are or would be exposed to an unreasonable and significant risk of illness or injury. The types of violations that warrant the issuance of NIDPOE letters are always significant and, with rare exceptions, jeopardize the rights, safety and welfare of the subjects involved. Those exceptions involve violations that compromise data integrity alone without jeopardizing subjects. Minor violations of an investigator's responsibilities do not alone give rise to a NIDPOE letter. One or more of the following types of violations may give rise to NIDPOE letters, and may also give rise to clinical holds if the circumstances show that the violations pose a significant risk to subjects:

• Repeated or deliberate failure to obtain or document informed consent from human subjects, which may include:
  - Repeated or deliberate omission of a description of serious risks of the experimental therapy when obtaining informed consent;
  - Repeated or deliberate failure to provide informed consent in a language understandable to the subject;
• Repeated or deliberate failure to limit administration of the investigational article to those subjects under the investigator's supervision;
• Repeated or deliberate failure to comply with conditions placed on the study by the IRB, sponsor, or FDA;
• Repeated or deliberate failure to obtain review of a study plan by an IRB, the body responsible for overseeing the rights,safety and welfare of human subjects;
• Repeated or deliberate failure to follow the signed investigator statement or protocol, e.g., by enrolling subjects who should have been excluded because of concomitant illnesses that put those subjects at greater risk;
• Repeated or deliberate failure to maintain accurate study records or submit required adverse event reports to the sponsor;
• Repeated or deliberate falsification or concealment of study records, e.g., by substituting in study records the results of biological samples from subjects who met the inclusion criteria for samples of subjects who did not meet the inclusion criteria, or by fabricating subjects; and
• Repeated or deliberate failure to adequately supervise the clinical trial such that human subjects are or would be exposed to an unreasonable and significant risk or injury.

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