Guidance for Industry and Clinical 
Investigators 
 
The Use of Clinical Holds Following 
Clinical  
 
Investigator Misconduct
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
September 2004 
  Guidance for Industry and Clinical 
Investigators 
 
The Use of Clinical Holds Following 
Clinical  
 
Investigator Misconduct
 
 
 
Additional copies of this guidance are available from: 
Office of Communication, Training and 
Manufacturers Assistance (HFM-40) 
Center for Biologics Evaluation and Research 
Food and Drug Administration 
1401 Rockville Pike, Rockville, MD 20852-1448 
Phone:  800-835-4709 or 301-827-1800 
Internet:  http://www.fda.gov/cber/guidelines.htm 
or 
Office of Training and Communication 
Division of Communications Management 
Drug Information Branch, HFD-210 
Center for Drug Evaluation and Research 
Food and Drug Administration 
5600 Fishers Lane, Rockville, MD  20857 
Phone:  301-827-4573 
Internet:  http://www.fda.gov/cder/guidance/index.htm 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
 September 2004
  Table of Contents 
 
I.  PURPOSE...............................................................................................................................1 
II.  BACKGROUND....................................................................................................................2 
A.  What Are a Clinical Investigator's Responsibilities?............................................................2 
B.  What Actions Can FDA Take to Address Clinical Investigator Misconduct?.......................3 
C.  How Can FDA Protect Human Subjects Following the Discovery of Clinical Investigator 
Misconduct?.................................................................................................................................4 
III.  USE OF CLINICAL HOLDS TO PROTECT HUMAN SUBJECTS..............................4 
A.  What Is a Clinical Hold?......................................................................................................4 
B.  Under What Circumstances Would FDA Consider Imposing A Clinical Hold Following 
Discovery Of Clinical Investigator Misconduct?...........................................................................5 
1. Before an enforcement action is initiated.................................................................................5 
2. After an enforcement action is initiated....................................................................................6 
C.  What Steps Will FDA Take Before Imposing A Clinical Hold to Protect Subjects from 
Investigator Misconduct?.............................................................................................................7 
D.  When Will FDA Lift a Clinical Hold that Was Imposed to Protect Subjects from 
Investigator Misconduct?.............................................................................................................7 
 
 
  Contains Nonbinding Recommendations 
1
Guidance for Industry   
and Clinical Investigators  
 
The Use Of Clinical Holds Following Clinical Investigator 
Misconduct 
 
 
This guidance represents the Food and Drug Administrations (FDA's) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
the FDA or the public. You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the appropriate FDA staff.  If you cannot identify the appropriate FDA staff, 
call the appropriate number listed on the title page of this guidance. 
 
 
 
I.  PURPOSE 
 
This guidance provides information on one use by the Food and Drug Administration (FDA) of 
its authority to impose a clinical hold on a study or study site if FDA finds that human subjects 
are or would be exposed to an unreasonable and significant risk of illness or injury.  Specifically, 
this guidance describes circumstances in which FDA may impose a clinical hold based on 
credible evidence that a clinical investigator conducting the study has committed serious 
violations of FDA regulations on clinical trials of human drugs and biologics, including 21 CFR 
Parts 312, 50, and 56, or has submitted false information to FDA or the sponsor in any required 
report. FDA may consider imposing a clinical hold in these situations where necessary to protect 
human subjects in the study from an unreasonable and significant risk of illness or injury. Such a 
clinical hold may be imposed on the study in which the misconduct occurred or on other studies 
of drugs or biological products in which the clinical investigator is directly involved or proposed 
to be involved. Although FDA has authority to take various enforcement actions against a 
clinical investigator who commits serious violations of FDA regulations, these actions may not 
be completed swiftly enough to protect human subjects who may be at risk in ongoing studies 
conducted by the investigator. Where the investigator's misconduct appears to pose an ongoing 
threat to the safety and welfare of such subjects, imposition of a full or partial clinical hold on 
ongoing or proposed studies of human drugs or biological products may be appropriate.  See 21 
CFR 312.42(b)(1)(i), 312.42(b)(2)(i), 312.42(b)(3)(iii), and 312.42(b)(4)(i).  This guidance does 
not address other circumstances in which FDA may impose a clinical hold if FDA finds that 
human subjects are or would be exposed to an unreasonable and significant risk of illness or 
injury, including when there is no evidence of clinical investigator misconduct or a serious 
regulatory violation.  This guidance finalizes the draft guidance of the same title dated April 
2002. 
                                                 
1 This guidance was developed by the Center for Drug Development and Research (CDER) and the Center for 
Biologics Evaluation and Research (CBER) in consultation with the Office of the Commissioner (OC). 
  1 Contains Nonbinding Recommendations 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  
The use of the word should in FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
This section describes the responsibilities of clinical investigators, the process for bringing an 
enforcement action for serious clinical investigator misconduct, and the need for a more rapid 
means of protecting human subjects after serious misconduct has been discovered. 
 
A.  What Are a Clinical Investigator's Responsibilities? 
 
The regulations governing the conduct of clinical trials by clinical investigators are intended to 
assure adequate protection of the rights, safety, and welfare of subjects involved in those trials, 
as well as the quality and integrity of the resulting data, while at the same time providing 
sufficient flexibility for clinical research.2  A brief description of the specific responsibilities of 
investigators follows. 
 
Clinical investigators are responsible for protecting the rights, safety and welfare of human 
subjects in the studies they conduct (21 CFR 312.60, 21 CFR Parts 50 and 56). Among other 
things, investigators must assure that an Institutional Review Board (IRB) that complies with 
FDA regulations conducts initial and continuing ethical review of the study (21 CFR Part 56 and 
 312.66). An investigator must notify the IRB of changes in the research activity or 
unanticipated problems involving risks to human subjects or others, and must not make any 
changes in the protocol without IRB and sponsor approval, unless necessary to eliminate 
apparent immediate hazards to human subjects (21 CFR 312.66). An investigator must also 
obtain informed consent from each subject who participates in the study (21 CFR 312.60 and 21 
CFR Part 50). 
 
Clinical investigators are responsible for following the signed investigator statement (Form FDA 
1572) (21 CFR 312.60). The investigator's signed statement includes a commitment to: (1) 
follow the study protocol, and to make changes only after notifying the sponsor, unless necessary 
to protect the rights, safety or welfare of the subjects; (2) personally conduct or supervise the 
research; and (3) inform subinvestigators and others assisting in the conduct of the investigation 
of their obligations in meeting these commitments (21 CFR 312.53(c)). Clinical investigators are 
also responsible for following the investigational plan (21 CFR 312.60). 
                                                 
2 In addition to FDAs regulations, there are a number of guidance documents available that describe FDAs current 
thinking on good clinical practice.  These include the FDAs Guidance for Industry: E6 Good Clinical Practice 
Guidance; FDAs Information Sheets for Institutional Review Boards and Clinical Investigators; FDAs Guidance 
for Industry: Computerized Systems Used in Clinical Trials.  A more comprehensive listing of useful guidances on 
good clinical practice can be found at the following web sites:  http://www.fda.gov/oc/gcp, 
http://www..fda.gov/cder/guidances, and http://www.fda.gov/cber/guidelines.htm.   
  2 Contains Nonbinding Recommendations 
 
Clinical investigators must ensure that the investigational drug is administered only to study 
subjects under the supervision of the investigator or a subinvestigator responsible to the 
investigator (21 CFR 312.61). Finally, clinical investigators must keep required records of the 
study and make required reports to the sponsor of the investigation (21 CFR 312.62 and 312.64). 
An investigator must prepare and maintain adequate case histories, including documentation of 
informed consent, and keep records of disposition of the drug (21 CFR 312.62). These records 
must be maintained for 2 years from the date FDA approves a marketing application for the drug 
under study or if FDA does not approve the drug or no application is filed for the drug, from the 
date the study is discontinued and FDA is informed (Id.). The investigator must make several 
types of reports to the sponsor, including progress reports, safety reports (prompt reports of 
adverse events, and immediate reports of alarming effects), and a final report (21 CFR 312.64). 
The investigator must also report his or her financial interests to the sponsor to permit 
assessment of conflicts of interest (Id.). 
 
B.  What Actions Can FDA Take to Address Clinical Investigator Misconduct? 
 
If an inspection conducted by FDA reveals that a clinical investigator has committed violations 
of FDA's regulations, FDA generally will notify the investigator of the violations and take 
appropriate follow-up action. This notification may consist of the Form FDA 483 (Inspectional 
Observations) issued at the close of this inspection, or it may be in the form of a Warning Letter.  
In some cases, an investigator's agreement to correct the violations may be sufficient to resolve 
the matter.  Where FDA finds that there have been serious violations of the investigator's 
obligations, and corrective action by the investigator cannot resolve the matter, FDA may 
conclude that it is appropriate to initiate an enforcement action against the investigator. First, if 
the inspectional findings indicate that the investigator has repeatedly or deliberately violated 
FDA regulations or repeatedly or deliberately submitted false information, FDA may move to 
disqualify the investigator from conducting future studies regulated by FDA. Second, FDA may 
initiate a civil or criminal enforcement action in federal court. Such actions can take several 
months and frequently years to complete. 
 
To disqualify a clinical investigator, FDA must go through an administrative process involving 
an opportunity for hearing (21 CFR 312.70). When a Center (i.e., CBER or CDER) has reviewed 
the inspectional findings and determined that there is evidence of repeated or deliberate 
violations or repeated or deliberate submission of false information, and that the pattern or 
severity of the misconduct warrants agency action, the Center issues a Notice of Initiation of 
Disqualification Proceedings and Opportunity to Explain (NIDPOE) letter, which furnishes the 
investigator with written notice of the matter and offers the investigator an opportunity to explain 
the matter in writing, or, at the option of the investigator, in an informal conference. If an 
informal conference is held, the investigator may bring an attorney. If, after hearing the 
investigator's explanation, the Center still believes that the investigator's actions meet the 
threshold for disqualification, the Center must offer the investigator an opportunity for a 
regulatory hearing, whose procedures are governed by 21 CFR Part 16 (21 CFR 312.70). The 
investigator may enter into a consent agreement or may request a hearing. At a regulatory 
hearing, the investigator may offer the testimony of witnesses, documentary evidence, and 
supporting briefs. After the hearing, the presiding officer issues a report or decision on whether 
the investigator has repeatedly or deliberately violated the regulations and should be disqualified. 
  3 Contains Nonbinding Recommendations 
The report is forwarded to the Commissioner, who then issues a Commissioner's decision on 
disqualification (21 CFR Part 16). The investigator may appeal the Commissioner's decision in 
federal court. A disqualification proceeding generally takes many months or years to complete. 
 
C.  How Can FDA Protect Human Subjects Following the Discovery of Clinical 
Investigator Misconduct? 
 
Initiation of an enforcement action in federal court or a disqualification proceeding does not by 
itself halt an investigator's participation in clinical trials. Until an investigator is disqualified by 
FDA, the investigator remains free to participate in ongoing and new clinical investigations. 
There are, however, instances in which the investigator's misconduct appears to pose an ongoing 
risk to the safety and welfare of the human subjects under the care of that investigator. For 
example, where an investigator is found to have failed to monitor subjects for signs of serious 
toxicity associated with the experimental therapy, or falsified eligibility data, FDA may conclude 
that subjects under that investigator's care are at risk. Under such circumstances, protection of 
subjects may demand a more rapid intervention than would be offered by an enforcement action 
or a disqualification proceeding. As discussed above, an effective means of acting promptly to 
protect human subjects after the discovery of serious investigator misconduct is to impose a 
clinical hold on those studies or study sites involving the investigator.  
 
 
III.  USE OF CLINICAL HOLDS TO PROTECT HUMAN SUBJECTS 
 
A.  What Is a Clinical Hold? 
 
A clinical hold is an order by FDA that immediately suspends or imposes restrictions on an 
ongoing or proposed clinical study. FDA has promulgated regulations authorizing clinical holds 
for studies involving drugs and biological products (21 CFR 312.42). Section 312.42(a) provides 
the scope and effect of a clinical hold order: 
 
A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical 
investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or 
more of the investigations covered by an IND. When a proposed study is placed on clinical hold, 
subjects may not be given the investigational drug. When an ongoing study is placed on clinical 
hold, no new subjects may be recruited to the study and placed on the investigational drug; 
patients already in the study should be taken off therapy involving the investigational drug 
unless specifically permitted by FDA in the interest of patient safety. 
 
A clinical hold may be complete or partial.3 Delay or suspension of all clinical work under an 
IND is considered a complete clinical hold. Delay or suspension of only part of the clinical work 
under an IND is considered a partial clinical hold. A partial clinical hold could, for example, be 
                                                 
3 The terms complete clinical hold and partial clinical hold can be found and are further described in FDA's 
Guidance for Industry: Submitting and Reviewing Complete Responses to Clinical Holds October 2000.  
(http://www.fda.gov/cder/guidance/index.htm).  Complete clinical hold means a delay or suspension of all clinical 
work requested under an IND.  Partial clinical hold means a delay or suspension of only part of the clinical work 
requested under the IND (e.g., a specific protocol or part of a protocol is not allowed to proceed; however, other 
protocols or part of the protocol are allowed to proceed under the IND. 
 
  4 Contains Nonbinding Recommendations 
imposed to delay or suspend one of several protocols in an IND, a part of a protocol, or a specific 
study site in a multi-site investigation. 
 
FDA's regulation authorizing clinical holds on studies of drugs and biological products sets forth 
grounds for imposing a hold. Those grounds vary depending on the nature of the study.4  For all 
types of studies, however, FDA may impose a clinical hold if it finds that "[h]uman subjects are 
or would be exposed to an unreasonable and significant risk of illness or injury" (21 CFR 
312.42(b)(1)(i), (b)(2)(i), (b)(3)(i)(A), (b)(3)(ii)(E)(2), (b)(4)(i), (b)(5)(i), (b)(6)(i)). 
 
B.  Under What Circumstances Would FDA Consider Imposing A Clinical Hold 
Following Discovery Of Clinical Investigator Misconduct? 
 
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; 
                                                 
4 The types of studies covered by  312.42 include: Phase 1 studies,  312.42(b)(1), Phase 2 and 3 studies,  
312.42(b)(2), proposed and ongoing treatment use,  312.42(b)(3)(i)(iii), studies that are not designed to be adequate 
and well-controlled,  312.42(b)(4), studies involving an exception from informed consent under  50.24,  
312.42(b)(5), and studies involving an exception from informed consent under  50.23,  
 312.42(b)(6). 
 
  5 Contains Nonbinding Recommendations 
?? 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:5 
 
?? Repeated or deliberate failure to obtain or document informed consent from human 
subjects, which may include: 
                                                 
5 This list is not intended to be all-inclusive. 
 
  6 Contains Nonbinding Recommendations 
 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. 
 
C.  What Steps Will FDA Take Before Imposing A Clinical Hold to Protect 
Subjects from Investigator Misconduct? 
 
The general regulations governing clinical holds require that, where FDA concludes that there 
may be grounds for imposing a clinical hold, "FDA will, unless patients are exposed to 
immediate and serious risk, attempt to discuss and satisfactorily resolve the matter with the 
sponsor before issuing the clinical hold order" (21 CFR 312.42(c)). If possible, as in all cases 
where a clinical hold is considered, FDA will contact the sponsor and attempt to resolve the 
matter in a way that adequately protects study subjects before imposing a clinical hold, following 
the timeframes described in companion guidances and regulations (e.g., Guidance with Industry: 
Formal Meetings with Sponsors and Applicants for PDUFA Products and 21 CFR 312.42(e) 
respectively).   In those cases where an inspection appears necessary to resolve issues, FDA will 
make every effort to ensure that the inspections are completed in a timely manner. 
 
D.  When Will FDA Lift a Clinical Hold that Was Imposed to Protect Subjects 
from Investigator Misconduct? 
 
FDA will lift a clinical hold imposed to protect subjects from investigator misconduct when the 
grounds for the hold no longer apply. The sponsor of the affected study may, while the clinical 
hold is in place, present evidence to FDA to show that it has taken steps to protect study subjects, 
  7 Contains Nonbinding Recommendations 
e.g., by replacing the investigator who is charged with the misconduct or, for example, in the 
case of a sponsor-investigator, by submitting a monitoring plan. If FDA concludes, based on this 
evidence, that the study subjects are no longer exposed to an unreasonable and significant risk of 
illness or injury, the hold will be lifted. In all instances, if a sponsor of a study that has been 
placed on clinical hold requests in writing that the clinical hold be removed and responds to the 
issues identified in the clinical hold order, FDA will respond in writing to the sponsor within 30 
calendar days of receipt of the request and response (21 CFR 312.42(e)). FDA will either 
remove or maintain the clinical hold and will state the reasons for its decision (Id.). 
 
 
  8