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 Industry1

and Clinical Investigators 

The Use Of Clinical Holds Following Clinical Investigator 

Misconduct

This guidance represents the Food and Drug Administration’s (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).
Contains Nonbinding Recommendations

2

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the FDA’s 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 FDA’s 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 FDA’s regulations, there are a number of guidance documents available that describe FDA’s current 

thinking on good clinical practice. These include the FDA’s Guidance for Industry: E6 Good Clinical Practice 

Guidance; FDA’s Information Sheets for Institutional Review Boards and Clinical Investigators; FDA’s 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. 
Contains Nonbinding Recommendations

3

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 (Inspectiona l 

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. 
Contains Nonbinding Recommendations

4

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.
Contains Nonbinding Recommendations

5

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).
Contains Nonbinding Recommendations

6

?? 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.
Contains Nonbinding Recommendations

7

– 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, 
Contains Nonbinding Recommendations

8

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.).