**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](#i.-purpose) {#i.-purpose-1 .TOC-1}

# II. BACKGROUND [2](#ii.-background) {#ii.-background-2 .TOC-1}

## A. What Are a Clinical Investigator\'s Responsibilities? [2](#a.-what-are-a-clinical-investigators-responsibilities) {#a.-what-are-a-clinical-investigators-responsibilities-2 .TOC-2}

## B. What Actions Can FDA Take to Address Clinical Investigator Misconduct? [3](#b.-what-actions-can-fda-take-to-address-clinical-investigator-misconduct) {#b.-what-actions-can-fda-take-to-address-clinical-investigator-misconduct-3 .TOC-2}

## C. How Can FDA Protect Human Subjects Following the Discovery of Clinical Investigator Misconduct? [4](#c.-how-can-fda-protect-human-subjects-following-the-discovery-of-clinical-investigator-misconduct) {#c.-how-can-fda-protect-human-subjects-following-the-discovery-of-clinical-investigator-misconduct-4 .TOC-2}

# III. USE OF CLINICAL HOLDS TO PROTECT HUMAN SUBJECTS [4](#iii.-use-of-clinical-holds-to-protect-human-subjects) {#iii.-use-of-clinical-holds-to-protect-human-subjects-4 .TOC-1}

## A. What Is a Clinical Hold? [4](#a.-what-is-a-clinical-hold) {#a.-what-is-a-clinical-hold-4 .TOC-2}

## B. Under What Circumstances Would FDA Consider Imposing A Clinical Hold Following Discovery Of Clinical Investigator Misconduct? [5](#b.-under-what-circumstances-would-fda-consider-imposing-a-clinical-hold-following-discovery-of-clinical-investigator-misconduct) {#b.-under-what-circumstances-would-fda-consider-imposing-a-clinical-hold-following-discovery-of-clinical-investigator-misconduct-5 .TOC-2}

### 1. Before an enforcement action is initiated [5](#before-an-enforcement-action-is-initiated) {#before-an-enforcement-action-is-initiated-5 .TOC-3}

### 2. After an enforcement action is initiated [6](#after-an-enforcement-action-is-initiated) {#after-an-enforcement-action-is-initiated-6 .TOC-3}

## C. What Steps Will FDA Take Before Imposing A Clinical Hold to Protect Subjects from Investigator Misconduct? [7](#c.-what-steps-will-fda-take-before-imposing-a-clinical-hold-to-protect-subjects-from-investigator-misconduct) {#c.-what-steps-will-fda-take-before-imposing-a-clinical-hold-to-protect-subjects-from-investigator-misconduct-7 .TOC-2}

## D. When Will FDA Lift a Clinical Hold that Was Imposed to Protect Subjects from Investigator Misconduct? [7](#d.-when-will-fda-lift-a-clinical-hold-that-was-imposed-to-protect-subjects-from-investigator-misconduct) {#d.-when-will-fda-lift-a-clinical-hold-that-was-imposed-to-protect-subjects-from-investigator-misconduct-7 .TOC-2}

Guidance for Industry[^1]

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.

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).

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. 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 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;

-   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;

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-   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:

> -- 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, 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.).

[^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).

[^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>.

[^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]: 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]: This list is not intended to be all-inclusive.