Oversight of Clinical Investigators
Action Needed to Improve Timeliness and Enhance Scope of FDA's Debarment and Disqualification Processes for Medical Product Investigators Gao ID: GAO-09-807 September 25, 2009The Food and Drug Administration (FDA) oversees the clinical investigators who conduct research involving new drugs, biologics, and medical devices to ensure that their conduct does not compromise the safety of clinical trial participants or the integrity of clinical trial data. FDA can debar or disqualify investigators who have engaged in misconduct such as submitting fraudulent data. Debarred or disqualified investigators cannot engage in certain activities related to clinical research. GAO was asked to review FDA's debarment and disqualification processes. GAO examined the length of time debarment and disqualification processes have taken and factors for those time frames, and the statutory and regulatory limitations of debarment and disqualification. GAO reviewed laws, regulations, and FDA files through November 5, 2008, for (1) all investigators, study coordinators, and sub-investigators for whom FDA pursued debarment since receiving debarment authority in 1992; and (2) all clinical investigators for whom FDA pursued disqualification since FDA adopted its current process for initiating proceedings in 1998.
More than half of the debarment proceedings in GAO's review took 4 or more years, and factors contributing to these time frames included internal control weaknesses in the debarment process and competing priorities among responsible staff. FDA has statutory authority to debar individuals who have been convicted of felonies or certain misdemeanors related to the development, approval, or regulation of a drug or biologic. For the 18 proceedings GAO reviewed, the length of time from an individual's conviction through debarment (or as of November 5, 2008, for pending proceedings) ranged from about 1 year to nearly 11 years. Factors that contributed to delays included that FDA staff faced competing priorities and FDA had not established internal controls, such as time frames for the completion of steps in the debarment process. FDA has made or planned changes that could improve timeliness (e.g., by establishing time frames in March 2009), but the effects of such actions have yet to be seen. The time taken for disqualification proceedings varied and proceedings took longer when the investigator contested disqualification. FDA may disqualify investigators who repeatedly or deliberately failed to comply with FDA regulations or submitted false information to FDA or the sponsor of a clinical trial. For the 52 disqualification proceedings GAO reviewed, the length of time from initiation of a disqualification proceeding to its conclusion (or as of November 5, 2008, for pending proceedings) ranged from 26 days to more than a decade, with about one-third taking more than 2 years. In general, the more steps taken by the investigator to contest disqualification, the longer it took to complete the proceeding. Disqualification proceedings initiated in 1998 through 2001 generally took longer than proceedings that were initiated more recently. FDA officials told us that a lack of time frames for these proceedings--an internal control weakness--may have contributed to longer proceedings. FDA made changes to its disqualification process (e.g., by establishing time frames in June 2008 and January 2009) that could further improve timeliness, but the full effect of these changes remains to be seen. FDA's debarment authority does not fully extend to involvement with medical devices, and its regulations do not extend disqualification for drugs and biologics to medical devices and vice versa. As a result, an individual may be debarred from involvement with drugs and biologics, but not from involvement with medical devices, regardless of the kind of misconduct in which the individual engaged. FDA's disqualification regulations allow an investigator who is disqualified for conduct related to drugs or biologics to serve as an investigator for medical devices; likewise, an individual who FDA disqualified for conduct related to medical devices remains able to serve as a clinical investigator for drugs and biologics.
RecommendationsOur recommendations from this work are listed below with a Contact for more information. Status will change from "In process" to "Open," "Closed - implemented," or "Closed - not implemented" based on our follow up work.
Director: Team: Phone:GAO-09-807, Oversight of Clinical Investigators: Action Needed to Improve Timeliness and Enhance Scope of FDA's Debarment and Disqualification Processes for Medical Product Investigators
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Report to Congressional Requesters:
United States Government Accountability Office:
GAO:
September 2009:
Oversight of Clinical Investigators:
Action Needed to Improve Timeliness and Enhance Scope of FDA's
Debarment and Disqualification Processes for Medical Product
Investigators:
GAO-09-807:
GAO Highlights:
Highlights of GAO-09-807, a report to congressional requesters.
Why GAO Did This Study:
The Food and Drug Administration (FDA) oversees the clinical
investigators who conduct research involving new drugs, biologics, and
medical devices to ensure that their conduct does not compromise the
safety of clinical trial participants or the integrity of clinical
trial data. FDA can debar or disqualify investigators who have engaged
in misconduct such as submitting fraudulent data. Debarred or
disqualified investigators cannot engage in certain activities related
to clinical research. GAO was asked to review FDA‘s debarment and
disqualification processes. GAO examined the length of time debarment
and disqualification processes have taken and factors for those time
frames, and the statutory and regulatory limitations of debarment and
disqualification. GAO reviewed laws, regulations, and FDA files through
November 5, 2008, for (1) all investigators, study coordinators, and
sub-investigators for whom FDA pursued debarment since receiving
debarment authority in 1992; and (2) all clinical investigators for
whom FDA pursued disqualification since FDA adopted its current process
for initiating proceedings in 1998.
What GAO Found:
More than half of the debarment proceedings in GAO‘s review took 4 or
more years, and factors contributing to these time frames included
internal control weaknesses in the debarment process and competing
priorities among responsible staff. FDA has statutory authority to
debar individuals who have been convicted of felonies or certain
misdemeanors related to the development, approval, or regulation of a
drug or biologic. For the 18 proceedings GAO reviewed, the length of
time from an individual‘s conviction through debarment (or as of
November 5, 2008, for pending proceedings) ranged from about 1 year to
nearly 11 years. Factors that contributed to delays included that FDA
staff faced competing priorities and FDA had not established internal
controls, such as time frames for the completion of steps in the
debarment process. FDA has made or planned changes that could improve
timeliness (e.g., by establishing time frames in March 2009), but the
effects of such actions have yet to be seen.
The time taken for disqualification proceedings varied and proceedings
took longer when the investigator contested disqualification. FDA may
disqualify investigators who repeatedly or deliberately failed to
comply with FDA regulations or submitted false information to FDA or
the sponsor of a clinical trial. For the 52 disqualification
proceedings GAO reviewed, the length of time from initiation of a
disqualification proceeding to its conclusion (or as of November 5,
2008, for pending proceedings) ranged from 26 days to more than a
decade, with about one-third taking more than 2 years. In general, the
more steps taken by the investigator to contest disqualification, the
longer it took to complete the proceeding. Disqualification proceedings
initiated in 1998 through 2001 generally took longer than proceedings
that were initiated more recently. FDA officials told us that a lack of
time frames for these proceedings”an internal control weakness”may have
contributed to longer proceedings. FDA made changes to its
disqualification process (e.g., by establishing time frames in June
2008 and January 2009) that could further improve timeliness, but the
full effect of these changes remains to be seen.
FDA‘s debarment authority does not fully extend to involvement with
medical devices, and its regulations do not extend disqualification for
drugs and biologics to medical devices and vice versa. As a result, an
individual may be debarred from involvement with drugs and biologics,
but not from involvement with medical devices, regardless of the kind
of misconduct in which the individual engaged. FDA‘s disqualification
regulations allow an investigator who is disqualified for conduct
related to drugs or biologics to serve as an investigator for medical
devices; likewise, an individual who FDA disqualified for conduct
related to medical devices remains able to serve as a clinical
investigator for drugs and biologics.
What GAO Recommends:
To improve its oversight, the Commissioner of FDA should pursue
extending FDA‘s debarment authority; extend disqualification to include
drugs, biologics, and medical devices; and ensure the timely completion
of debarment and disqualification proceedings. FDA agreed with GAO‘s
recommendations.
View [hyperlink, http://www.gao.gov/products/GAO-09-807] or key
components. For more information, contact Marcia Crosse at (202) 512-
7114 or crossem@gao.gov.
[End of section]
Contents:
Letter:
Background:
More than Half of Debarment Proceedings Took 4 or More Years, and Type
of Debarment Pursued, Internal Control Weaknesses, and Competing
Priorities Contributed to Longer Proceedings:
Times Taken for Disqualification Proceedings Varied and Factors Such as
Clinical Investigators' Contesting Disqualification and Internal
Control Weaknesses May Have Contributed to Longer Proceedings:
FDA's Debarment Authority Does Not Fully Extend to Involvement with
Devices and Regulations Allow Disqualified Clinical Investigators to
Conduct Trials for Other Investigational Medical Products:
Conclusions:
Recommendations for Executive Action:
Agency Comments:
Appendix I: Scope and Methodology:
Appendix II: Selected Features of Debarment and Disqualification:
Appendix III: Debarment Proceedings Completed or Pending from May 13,
1992, through September 9, 2008:
Appendix IV: Types of Misconduct Cited in Proposal to Debar Letters:
Appendix V: Disqualification Proceedings Initiated from January 1,
1998, through September 9, 2008:
Appendix VI: Types of Alleged Misconduct Cited in FDA's Initiation of
Disqualification Proceedings:
Appendix VII: Comments from the Department of Health and Human
Services:
Appendix VIII: GAO Contact and Staff Acknowledgments:
Table:
Table 1: Examples of Misconduct Allegations Cited in NIDPOE Letters:
Figures:
Figure 1: FDA's Debarment Process for Individuals:
Figure 2: FDA's Disqualification Process for Clinical Investigators:
Figure 3: Time Taken for Completed and Pending Debarment Proceedings:
Figure 4: Lengths of Time for the 11 Completed Debarment Proceedings by
Type of Debarment:
Figure 5: Time Taken for Completed and Pending Disqualification
Proceedings:
Figure 6: Time Taken for Disqualification Proceedings Initiated in 1998
through 2001, 2002 through 2005, and 2006 through 2008:
Figure 7: Time Taken to Complete Disqualification Proceedings:
Abbreviations:
CBER: Center for Biologics Evaluation and Research:
CDER: Center for Drug Evaluation and Research:
CDRH: Center for Devices and Radiological Health:
FDA: Food and Drug Administration:
NIDPOE: Notice of Initiation of Disqualification Proceedings and
Opportunity to Explain:
NOOH: Notice of Opportunity for Hearing:
[End of section]
United States Government Accountability Office:
Washington, DC 20548:
September 25, 2009:
The Honorable Joe Barton:
Ranking Member:
Committee on Energy and Commerce:
House of Representatives:
The Honorable Greg Walden:
Ranking Member:
Subcommittee on Oversight and Investigations:
Committee on Energy and Commerce:
House of Representatives:
The Food and Drug Administration (FDA) has oversight responsibilities
for clinical investigators who conduct research involving
investigational medical products--including drugs, biologics, and
devices[Footnote 1]--to ensure that their conduct does not compromise
the quality or integrity of clinical trial data or the safety of
clinical trial participants. The quality or integrity of the clinical
trial data that FDA uses to determine whether an investigational
medical product is safe and effective for the U.S. market can be
compromised by misconduct, such as falsification of these results, and
the safety of clinical trial participants can be jeopardized by
misconduct, such as failing to obtain their informed consent. For
example, if a clinical investigator falsifies data or fails to report
trial participants' adverse reactions to an investigational drug,
flawed data could be used to assert the drug's safety and the drug
could potentially endanger the health of those who take it. Timely
action against individuals who engage in such misconduct is a key
component of effective oversight.
As part of its oversight activities, FDA can take actions against
clinical investigators who have engaged in certain types of misconduct;
debarment and disqualification are two such actions. FDA has express
statutory authority to debar individuals--including clinical
investigators and the sub-investigators and study coordinators who work
for them[Footnote 2]--who have been convicted of certain crimes or who
have engaged in certain misconduct related to the development or
approval of any drug or biologic.[Footnote 3] For example, FDA can
debar an individual convicted of a felony in connection with submitting
fraudulent data for nonexistent clinical trial participants or
falsifying a report to conceal a failure to conduct a clinical trial as
required. Debarred individuals cannot provide services to the drug or
biologic industry as a clinical investigator, sub-investigator, study
coordinator, or in any other capacity. Under FDA's regulations, the
agency may disqualify clinical investigators who repeatedly or
deliberately failed to comply with FDA regulations or who repeatedly or
deliberately submitted false information to FDA or the sponsor of the
clinical trial in a required report. For example, FDA can disqualify a
clinical investigator who failed to obtain informed consent from
clinical trial participants. Disqualified clinical investigators are
prohibited from receiving one or more types of investigational medical
products, which include drugs, biologics, and devices, and as a result,
they are prevented from serving as clinical investigators for clinical
trials of these products. FDA posts on its Web site lists of those
individuals whom the agency has debarred or disqualified. Sponsors of
applications for new drugs and biologics must certify that debarred
individuals did not provide services to them, and sponsors of
investigational medical products may not provide these products to
investigators who have been disqualified to receive them.
Reports of some delays in debarring or disqualifying clinical
investigators and questions about the scope of FDA's debarment and
disqualification activities have focused attention on FDA's oversight
of clinical investigators.[Footnote 4] Previous reports have noted
weaknesses in other aspects of FDA's oversight of clinical
investigators. We previously reported that FDA's oversight efforts may
allow violations of protections to clinical trial participants to go
undetected because FDA inspected only a small percentage of the sites
where clinical trials were conducted and FDA typically carried out
these inspections after clinical trials were concluded.[Footnote 5] The
Department of Health and Human Services's Office of Inspector General
previously reported on weaknesses in FDA's oversight of clinical
trials, including a lack of clear, specific guidance and inconsistency
across FDA components in their responses to inspectional findings.
[Footnote 6] You asked us to review factors contributing to delays in
FDA's debarment and disqualification proceedings. This report discusses
(1) the length of time FDA's debarment proceedings have taken and the
factors contributing to the length of time they have taken, (2) the
length of time FDA's disqualification proceedings have taken and the
factors contributing to the length of time they have taken, and (3)
statutory and regulatory limitations to debarment and disqualification.
To determine how long FDA's debarment proceedings have taken and to
identify factors that contributed to the length of time they have
taken, we reviewed FDA's files regarding all clinical investigators,
sub-investigators, and study coordinators whom FDA pursued or
considered pursuing for debarment from the time that it was given
authority to do so on May 13, 1992, through September 9, 2008.[Footnote
7] To identify these individuals, we reviewed information about FDA's
debarment proceedings from Federal Register notices (including proposal
to debar letters, which FDA uses to initiate debarment actions, and
debarment orders, which FDA uses to complete debarment actions) and
FDA's Web site, and obtained additional information from FDA about
individuals whom FDA pursued or considered pursuing for debarment. We
identified 18 proceedings--13 involving clinical investigators and 5
involving study coordinators.[Footnote 8] For each proceeding, we
reviewed relevant files in the FDA center that initiated the debarment
action--either the Center for Drug Evaluation and Research (CDER) for
misconduct related to drugs or the Center for Biologics Evaluation and
Research (CBER) for misconduct related to biologics--and in FDA's
Division of Dockets Management, which maintains publicly available
information about debarment proceedings. To determine the length of
time each completed debarment proceeding took, we calculated the number
of calendar days from the date of the individual's conviction (or, if
the individual's conviction occurred before FDA received debarment
authority, from the date when FDA received debarment authority--May 13,
1992) through publication of the debarment order in the Federal
Register.[Footnote 9] For debarment proceedings that were pending at
the time of our file review, we calculated the number of calendar days
through the last day of our file review (Nov. 5, 2008).[Footnote 10] To
identify factors that contributed to the length of time FDA's debarment
proceedings have taken, we analyzed the information we obtained from
FDA's files and obtained additional information from FDA officials (for
example, by asking what occurred during long intervals for which we saw
no documented activity). We examined laws, regulations, and guidance to
determine whether there were criteria relevant to the times taken by
debarment proceedings. We also examined internal control standards,
which include the need to establish policies and procedures to help
ensure effective and efficient operations.[Footnote 11] We also
interviewed FDA officials, including those involved with FDA's
Debarment Working Group, which was formed by FDA to review FDA's
debarment process, including the length of debarment proceedings.
To determine how long FDA's disqualification proceedings have taken and
identify factors that contributed to the length of time they have
taken, we reviewed FDA's files regarding all clinical investigators for
whom FDA pursued disqualification by issuing a Notice of Initiation of
Disqualification Proceedings and Opportunity to Explain (NIDPOE) letter
from January 1, 1998, through September 9, 2008, for conduct related to
drugs, biologics, or devices, whether these clinical investigators were
ultimately disqualified or not.[Footnote 12] To identify these
individuals, we reviewed information about FDA's disqualification
proceedings from FDA's Web site and obtained additional information
from FDA about individuals for whom FDA pursued disqualification. We
identified 52 proceedings. For each proceeding, we reviewed relevant
files in the FDA center that initiated the disqualification proceeding--
CDER for drugs, CBER for biologics, or the Center for Devices and
Radiological Health (CDRH) for devices--as well as in other FDA offices
that maintained files relating to these disqualification proceedings.
These other offices included the Office of Enforcement, the Office of
the Ombudsman, and the Good Clinical Practice Program, an office within
FDA responsible for coordinating policies for the conduct of clinical
trials of FDA-regulated products that involve human participants.
[Footnote 13] To determine the length of time each completed
disqualification proceeding took, we calculated the number of calendar
days from the date of issuance of the NIDPOE letter through the
completion of the disqualification proceeding. For disqualification
proceedings that were pending at the time of our file review, we
calculated the number of calendar days through the last day of our file
review (Nov. 5, 2008). To identify factors that contributed to the
length of time FDA's disqualification proceedings have taken, we
analyzed the information we obtained from FDA's files and obtained
additional information from FDA officials (for example, by asking what
occurred during long intervals for which we saw no documented
activity). To determine whether the length of time taken for
disqualification proceedings changed during the years covered in our
review, we divided disqualification proceedings into three groups based
on the date that FDA issued the NIDPOE letter--those initiated before
2002, those initiated in 2002 through 2005, and those initiated after
2005. We examined laws, regulations, guidance, and standards for
internal control to determine whether there were criteria relevant to
the times taken by disqualification proceedings. We also interviewed
FDA officials, including those in each of the offices in which we
reviewed disqualification files.
To identify statutory and regulatory limitations to debarment and
disqualification, we reviewed relevant laws, regulations, and guidance;
reviewed files documenting FDA's debarment and disqualification
proceedings; and interviewed FDA officials involved with debarment and
disqualification. We conducted this performance audit from June 2008 to
September 2009, in accordance with generally accepted government
auditing standards. Those standards require that we plan and perform
the audit to obtain sufficient, appropriate evidence to provide a
reasonable basis for our findings and conclusions based on our audit
objectives. We believe that the evidence obtained provides a reasonable
basis for our findings and conclusions based on our audit objectives.
For additional information about our scope and methodology, see
appendix I.
Background:
FDA has responsibilities for overseeing clinical investigators who
conduct clinical trials of investigational medical products, including
drugs, biologics, and devices. As part of its oversight activities, FDA
can take actions such as debarment or disqualification against
investigators and other individuals who have engaged in certain types
of misconduct.
FDA's Oversight of Clinical Investigators:
FDA oversees clinical investigators to ensure that they comply with
federal regulations governing the conduct of clinical trials. These
regulations, which are intended to protect the quality and integrity of
the clinical trial data and the safety of clinical trial participants,
include requirements for the following:
* Obtaining informed consent from clinical trial participants,
* Obtaining approval for conducting a clinical trial from an
institutional review board that has been tasked with reviewing that
trial's protections for participants,[Footnote 14]
* Following the research plan for the clinical trial (including a
protocol) that was approved by the institutional review board,
* Reporting adverse events associated with the clinical trial, and:
* Submitting reports.
FDA can disqualify clinical investigators who repeatedly or
deliberately violate applicable regulations or who repeatedly or
deliberately submit false information in a required report, and in some
cases, an individual's misconduct may result in a criminal conviction,
providing a basis for debarment. FDA's debarment and disqualification
proceedings each consist of a series of steps involving actions taken
by FDA and by the affected individual. These steps provide the
individual with an opportunity to contest the charges against him or
her. The number of steps involved for each proceeding can vary
depending, for example, on whether the individual chooses to contest
the charges by providing information or arguments against debarment or
disqualification.
Debarment:
Under the Generic Drug Enforcement Act of 1992,[Footnote 15] FDA has
authority to debar individuals--including clinical investigators, sub-
investigators, and study coordinators--who have been convicted of
certain crimes, or engaged in other misconduct, related to the
development, approval, or regulation of any drug or biologic from
involvement with drugs and biologics.[Footnote 16] (FDA does not have
comparable authority with regard to an individual involved in the
medical device industry.) There are two types of debarment, and if
based on a criminal conviction, debarment must be initiated within 5
years of the date of conviction:
* Mandatory. Debarment is mandatory--and permanent--when FDA finds that
an individual has been convicted of a felony under federal law for
misconduct relating to the development or approval of any drug or
biologic, or otherwise relating to the regulation of any drug or
biologic.[Footnote 17]
* Permissive. FDA may, but is not required to, seek permissive
debarment--which is not permanent--under certain other conditions, for
example, if the individual was convicted of a felony under state law
for conduct related to the development or approval of any drug or
biologic.[Footnote 18] For permissive debarment, FDA must determine
that debarment is appropriate and determine the period of debarment by
considering factors such as the nature and seriousness of the offense
or offenses involved. An individual may be permissively debarred for up
to 5 years for each offense. If the individual is permissively debarred
for multiple offenses, the Commissioner of FDA may determine whether
debarment periods will run concurrently or consecutively.[Footnote 19]
As shown in figure 1, FDA's debarment process involves multiple
possible steps. The process starts when FDA learns of an individual's
conviction, determines that it provides a basis for debarment, and
drafts a proposal to debar letter. For the debarment proceedings we
reviewed, the relevant FDA center (CDER for drugs or CBER for
biologics) was responsible for determining if there was a basis for
debarment and drafting the proposal to debar letter, with input from
the Office of the Chief Counsel.[Footnote 20] FDA provides the
individual with a notice of its proposal to debar and provides an
opportunity for a formal hearing to demonstrate why he or she should
not be debarred.[Footnote 21] If the individual requests a hearing, he
or she must provide information on disputed issues of material fact to
justify a hearing, such as whether the individual was actually
convicted as alleged in the notice and, if so, whether this conviction
provides a basis for debarment. FDA evaluates this information and
determines whether to grant a hearing. If the FDA Commissioner
determines that there is no substantial issue of material fact, then he
or she denies the hearing and debars the individual by issuing an order
of debarment. FDA publishes a debarment order in the Federal Register.
Figure 1: FDA's Debarment Process for Individuals:
[Refer to PDF for image: illustration]
FDA staff learn that individual was convicted of a crime and determine
whether to pursue debarment (mandatory or permissive):
FDA issues a proposal to debar letter, describing the conviction and
misconduct and offering an opportunity for a formal hearing[A]:
Individual does not submit a timely request or declines the opportunity
for a hearing:
Debarred.
Individual requests a formal hearing by the specified date; Request for
hearing is Not Granted[B]:
* FDA Commissioner or delegate makes decision:
- Not debarred;
- Debarred.
Individual requests a formal hearing by the specified date; Request for
hearing is Granted:
Formal hearing conducted and presiding officer makes recommendation:
* FDA Commissioner or delegate makes decision:
- Not debarred;
- Debarred.
Source: GAO.
Notes: This figure presents the major steps that could be involved in
the debarment proceedings we reviewed. These proceedings involved
clinical investigators, sub-investigators, and study coordinators for
whom FDA pursued or considered pursuing debarment from May 13, 1992,
through September 9, 2008. The number of steps involved for a
proceeding can vary depending, for example, on whether the individual
chooses to contest the charges by requesting a hearing. All clinical
investigators, sub-investigators, and study coordinators whom FDA
pursued or considered pursuing for debarment as of the last date of our
file review (November 5, 2008) had been convicted of a crime.
[A] Proposal to debar letters specify that if the individual chooses to
respond, he or she must submit a written notice of request for a formal
hearing within 30 days of receiving the letter and must submit
information on which the individual relies to justify a hearing within
60 days of receiving the letter.
[B] When a request for a hearing is denied, the FDA Commissioner (or
delegate) generally issues a decision that includes both a denial of
the hearing and a debarment order.
[End of figure]
Debarred individuals are prohibited from involvement with drugs and
biologics. Debarment does not preclude such individuals from serving in
any capacity to an entity that intends to market or is marketing a
medical device or other FDA-regulated product, such as food additives
or cosmetics.
An individual's debarment can end when the individual's permissive
debarment period has ended or if FDA terminates the individual's
debarment. FDA may terminate debarment if, for example, the conviction
that served as the basis for the individual's debarment is reversed.
[Footnote 22]
Disqualification:
Under federal regulations, FDA may disqualify clinical investigators
from receiving investigational drugs, biologics, or devices if they
repeatedly or deliberately failed to comply with pertinent FDA
regulations or repeatedly or deliberately submitted false information
to FDA or the sponsor of the clinical trial in a required
report.[Footnote 23] Sub-investigators and study coordinators cannot be
disqualified by FDA under current regulations. FDA initiates
disqualification proceedings based on allegations of misconduct
detected during an inspection of a clinical investigator.[Footnote 24]
Before issuing a NIDPOE letter, FDA staff evaluate information gathered
during the inspection, obtain additional clarifying information as
necessary (including, in some cases, information obtained from other
inspections), determine whether their observations provide a foundation
for initiation of a disqualification proceeding, and, if so, draft the
NIDPOE letter with input from FDA's Office of the Chief Counsel. The
misconduct alleged in the NIDPOE letter may have occurred years before
the inspection.
As shown in figure 2, FDA's disqualification process involves multiple
possible steps. FDA initiates a disqualification proceeding against a
clinical investigator by providing the investigator with a NIDPOE
letter.[Footnote 25] The NIDPOE letter details FDA's allegations of
misconduct and provides the investigator an opportunity to respond in
writing or to meet informally with FDA officials to discuss the
allegations. It also provides the investigator with the option of
concluding the disqualification proceeding by entering into a consent
agreement with FDA. The investigator and FDA may enter a consent
agreement at any time before the Commissioner reaches a decision.
Figure 2: FDA's Disqualification Process for Clinical Investigators:
[Refer to PDF for image: illustration]
FDA center issues a Notice of Initiation of Disqualification
Proceedings and Opportunity to Explain (NIDPOE) letter to a clinical
investigator[A]:
1) Disqualified: Investigator enters into a consent agreement;
disqualification process ends[B].
2) Investigator submits information in writing by the specified date;
Written materials:
FDA center evaluates information provided by investigator (in writing
and/or at the conference) and determines that the investigator‘s
explanation is satisfactory:
Disqualification process ends; investigator is not disqualified;
and/or:
3) Investigator requests an informal conference by the specified date;
Informal conference:
FDA center evaluates information provided by investigator (in writing
and/or at the conference) and determines that the investigator‘s
explanation is not satisfactory:
Go to step 5.
4) Investigator does not submit a timely request or declines to respond
in writing or in an informal conference.
5) FDA issues a Notice of Opportunity for Hearing (NOOH) letter.
6) FAD issues NOOH[C]:
7) Disqualified: Investigator enters into a consent agreement;
disqualification process ends[B]; or:
8) Investigator requests a regulatory hearing by the specified date.
Request for hearing is not granted[D]:
Go to step 10.
Request for hearing is granted:
Regulatory hearing conducted and presiding officer issues report; Go to
step 10; or:
Disqualified: Investigator enters into a consent agreement;
disqualification process ends[B].
9) Investigator does not submit a timely request or declines the
opportunity for a hearing.
10) FDA Commissioner or delegate makes decision[E]:
Not disqualified: Disqualification process ends; investigator is not
disqualified; or:
Disqualified: Disqualification process ends; investigator is
disqualified.
Source: GAO.
Notes: This figure presents the major steps that could be involved in
disqualification proceedings we reviewed that were initiated by FDA
using a NIDPOE letter from January 1, 1998, through September 9, 2008.
The number of steps involved for a proceeding can vary depending, for
example, on whether the individual chooses to contest the charges by
requesting a hearing. For the purposes of this report, we treat consent
agreements that restrict clinical investigators' activities as a form
of disqualification.
[A] NIDPOE letters specify that if the clinical investigator chooses to
respond, he or she must request an informal conference or indicate an
intention to submit a written reply within 15 days and provide the
written reply within 30 days of receiving the letter.
[B] The clinical investigator and FDA may enter into a consent
agreement, terminating the disqualification process, at any time before
the Commissioner reaches a decision.
[C] Notice of Opportunity for Hearing (NOOH) letters specify that if
the clinical investigator chooses to request a regulatory hearing, he
or she must do so within 10 business days of receiving the letter.
[D] When a request for a hearing is denied, the FDA Commissioner (or
delegate) issues a decision that includes both a denial of the hearing
and a notice of disqualification.
[E] Prior to rendering a decision, the Commissioner (or the
Commissioner's delegate) may, on his or her own initiative or at the
request of the clinical investigator or center, review a decision by
the presiding officer to deny a hearing, or to deny review of a
particular issue during a hearing, because there is no genuine and
substantial issue of fact to be resolved.
[End of figure]
If the clinical investigator provides a timely explanation in response
to a NIDPOE letter in a written response or in an informal conference,
the investigator's explanation is evaluated by the FDA center (CDER for
drugs, CBER for biologics, or CDRH for devices) that initiated the
disqualification proceeding and the center's legal counsel. To evaluate
the information presented by the investigator, FDA staff may collect
additional information (which could include conducting an additional
inspection). If the center finds the investigator's explanation for all
of the allegations in the NIDPOE letter satisfactory, the
disqualification proceeding is concluded and the investigator is not
disqualified. Otherwise, FDA provides the investigator with an
opportunity for a regulatory hearing to show why he or she should not
be disqualified by issuing a Notice of Opportunity for Hearing (NOOH)
letter, which details the allegations of misconduct that were included
in the NIDPOE letter to which the investigator did not provide a
satisfactory explanation.[Footnote 26] If the investigator requests a
hearing, he or she must submit evidence of a genuine and substantial
issue of fact that would warrant a regulatory hearing. FDA evaluates
this information and determines whether to grant a hearing or not. If
the Commissioner determines that there is no genuine and substantial
issue of fact, then he or she denies the request for a hearing and
decides whether to disqualify the investigator. If a regulatory hearing
is held, a presiding officer issues a report with a recommendation to
the Commissioner, who makes the final decision about whether to
disqualify the investigator. The presiding officer and Commissioner are
assisted by FDA attorneys who are not associated with the center that
initiated the disqualification proceeding.
Clinical investigators who are disqualified through a Commissioner's
decision (without entering into a consent agreement) are disqualified
from receiving either investigational drugs and biologics or
investigational devices, depending on the type of product with which
the misconduct was associated. For those investigators who are
disqualified through a consent agreement, because the investigator may
negotiate the terms of disqualification with FDA, the terms of such
consent agreements vary and may include restrictions on the
investigator's research activities.[Footnote 27] For example, the
negotiated consent agreement might allow the individual to continue as
a clinical investigator, but limit the number of clinical trials in
which the investigator can participate at any one time.
Disqualification does not preclude serving as a sub-investigator or
study coordinator unless the terms of the consent agreement include
such restrictions.
Clinical investigators who have been disqualified may apply to be
reinstated as eligible to again receive investigational medical
products. If disqualification was through a Commissioner's decision,
disqualification is permanent unless the clinical investigator requests
reinstatement, and the Commissioner determines that the investigator
has presented adequate assurances that the investigator will use
investigational medical products in compliance with pertinent FDA
regulations.[Footnote 28] If the investigator's disqualification was
based on a consent agreement that restricted the investigator's
activities for a specified period of time, reinstatement requires FDA's
determination that the investigator met the terms of the consent
agreement.
For additional information about debarment and disqualification, see
appendix II.
More than Half of Debarment Proceedings Took 4 or More Years, and Type
of Debarment Pursued, Internal Control Weaknesses, and Competing
Priorities Contributed to Longer Proceedings:
More than half of the debarment proceedings we reviewed took 4 or more
years, and permissive proceedings generally took longer than mandatory
proceedings. Factors such as internal control weaknesses and competing
priorities were associated with longer proceedings. The agency has made
or plans to make changes to its debarment policies and procedures that
may improve the timeliness of debarment proceedings, but the effect of
these changes remains to be seen.
More than Half of Debarment Proceedings Took 4 or More Years:
The 18 debarment proceedings we reviewed took from just over 1 year to
more than a decade, with more than half taking 4 or more years.
[Footnote 29] Of these 18 debarment proceedings--which were all of the
proceedings FDA pursued or considered pursuing against clinical
investigators, sub-investigators, and study coordinators since FDA
obtained debarment authority in 1992--FDA completed 11 proceedings as
of November 5, 2008. As shown in figure 3, the length of time to
complete these 11 debarment proceedings--from an individual's
conviction through the publication of a debarment order in the Federal
Register[Footnote 30]--ranged from just over 1 year to just over 6
years, with a median of 4.4 years.[Footnote 31] In addition to these 11
completed proceedings, FDA was pursuing or considering pursuing
debarment for 7 clinical investigators and study coordinators. The
length of time taken for these seven pending debarment proceedings--
from an individual's conviction through the last day of our file
review--ranged from just over 1 year to nearly 11 years, with a median
of 3.3 years.[Footnote 32]
Figure 3: Time Taken for Completed and Pending Debarment Proceedings:
[Refer to PDF for image: two pie-charts]
Completed debarment proceedings (11 proceedings):
0-2 years (2): 18%;
2-4 years (2): 18%;
4-6 years (6): 55%;
6+ years (1): 9%.
Pending debarment proceedings (7 proceedings):
0-2 years (2): 29%;
2-4 years (2): 29%;
4-6 years (1): 14%;
6+ years (2): 29%.
Source: GAO analysis.
Notes: This figure presents, for clinical investigators, sub-
investigators, and study coordinators, the length of time from
conviction to completion for the 11 completed debarment proceedings and
the length of time from conviction to November 5, 2008, for the 7
pending debarment proceedings. For two completed proceedings, the
length of time was measured from the date when FDA received debarment
authority (May 13, 1992) to completion because the clinical
investigator was convicted before FDA received debarment authority.
None of the debarment proceedings we reviewed took exactly 2 years or
any exact multiple of 2 years to complete. Numbers of proceedings are
shown in parentheses. Percentages for pending debarment proceedings do
not add up to 100 percent due to rounding.
[End of figure]
Debarment Proceedings Generally Took Longer If They Involved Permissive
Debarment or If the Individual Contested Debarment:
We found that permissive debarment proceedings generally took longer
than mandatory proceedings. Of the 11 completed debarment proceedings,
5 were permissive debarment proceedings that took 4 or more years from
conviction to debarment, with a median of 5.0 years. In contrast, six
completed mandatory debarment proceedings took from just over 1 year to
just over 6 years from conviction to debarment, with a median of 3.1
years. As shown in figure 4, the greatest difference between permissive
and mandatory debarments was in the time it took to draft the proposal
to debar letter. For each permissive proceeding, FDA took more than 2
years from when the agency began drafting the proposal to debar letter
to issuance of the proposal; for each of the five mandatory proceedings
for which FDA recorded the date on which it began drafting the proposal
to debar letter, this step took less than 9 months.[Footnote 33]
Figure 4: Lengths of Time for the 11 Completed Debarment Proceedings by
Type of Debarment:
[Refer to PDF for image: stacked horizontal bar graph]
Permissive proceeding: A;
Conviction to initial draft of proposal to debar letter: 0.8 years;
Initial draft of proposal to debar letter to issuance of proposal to
debar letter: 2.2 years;
Conviction to initial draft of proposal to debar letter: 1.1 years;.
Permissive proceeding: B;
Conviction to initial draft of proposal to debar letter: 1.6 years;
Initial draft of proposal to debar letter to issuance of proposal to
debar letter: 2.6 years;
Conviction to initial draft of proposal to debar letter: 0.8 years.
Permissive proceeding: C;
Conviction to initial draft of proposal to debar letter: 1.8 years;
Initial draft of proposal to debar letter to issuance of proposal to
debar letter: 2.8 years;
Conviction to initial draft of proposal to debar letter: 0.5 years.
Permissive proceeding: D;
Conviction to initial draft of proposal to debar letter: 1.8 years;
Initial draft of proposal to debar letter to issuance of proposal to
debar letter: 2.8 years;
Conviction to initial draft of proposal to debar letter: 0.4 years.
Permissive proceeding: E;
Conviction to initial draft of proposal to debar letter: 1.8 years;
Initial draft of proposal to debar letter to issuance of proposal to
debar letter: 2.8 years;
Conviction to initial draft of proposal to debar letter: 0.6 years.
Mandatory proceeding: F[A];
Conviction to initial draft of proposal to debar letter: 0.5 years;
Initial draft of proposal to debar letter to issuance of proposal to
debar letter: 0.2 years;
Conviction to initial draft of proposal to debar letter: 0.5 years;.
Mandatory proceeding: G;
Conviction to initial draft of proposal to debar letter: 0.4 years;
Initial draft of proposal to debar letter to issuance of proposal to
debar letter: 0.3 years;
Conviction to initial draft of proposal to debar letter: 0.7 years.
Mandatory proceeding: H;
Conviction to initial draft of proposal to debar letter: and:
Initial draft of proposal to debar letter to issuance of proposal to
debar letter: less than 1.2[B] years;
Conviction to initial draft of proposal to debar letter: 0.7 years.
Mandatory proceeding: I;
Conviction to initial draft of proposal to debar letter: 1.8 years;
Initial draft of proposal to debar letter to issuance of proposal to
debar letter: 2.8 years;
Conviction to initial draft of proposal to debar letter: 0.4 years.
Mandatory proceeding: J;
Conviction to initial draft of proposal to debar letter: 2.2 years;
Initial draft of proposal to debar letter to issuance of proposal to
debar letter: 0.7 years;
Conviction to initial draft of proposal to debar letter: 1.5 years.
Mandatory proceeding: K[A];
Conviction to initial draft of proposal to debar letter: 0.5 years;
Initial draft of proposal to debar letter to issuance of proposal to
debar letter: 0.1 years;
Conviction to initial draft of proposal to debar letter: 5.5 years.
Source: GAO analysis.
Notes: Proceedings A through E represent five completed permissive
debarment proceedings and proceedings F through K represent six
completed mandatory debarment proceedings for clinical investigators,
study coordinators, and a sub-investigator. For each proceeding, the
amount of time taken (in years) from FDA's initial draft of the
proposal to debar letter to issuance of the letter is presented.
[A] The date on which FDA received debarment authority, May 13, 1992,
was used instead of the conviction date to calculate the length of time
from conviction to the initial draft of the proposal to debar letter
because the individual was convicted prior to May 13, 1992.
[B] FDA's file for this proceeding did not indicate when FDA began
drafting the proposal to debar letter. FDA took 1.2 years from
conviction to FDA's issuance of the proposal to debar letter, so the
time that elapsed from FDA's initial draft of the proposal to debar
letter to issuance of the letter was less than 1.2 years.
[End of figure]
According to FDA officials, the difference in the times taken between
permissive and mandatory proceedings, including the difference in the
times taken to draft proposal to debar letters, reflects the complexity
of the statute and necessary analysis, including deciding the period of
permissive debarment. FDA officials told us that the statutory standard
for permissive debarment is more complex than the statutory standard
for mandatory debarment, and that it may take more time to determine
how a situation involving misconduct relates to the statutory standard
for permissive debarment. They told us that the need to conduct an
extensive analysis of a state felony conviction to determine which
counts could provide a basis for permissive debarment was one factor
that contributed to the time that elapsed between FDA's initial
drafting of the proposal to debar letter and the date on which the
letter was issued in two permissive debarment proceedings. In one of
the proceedings, just over 2.5 years elapsed between the initial draft
of the proposal to debar letter and the date on which it was issued,
and in the other proceeding, which was still pending as of the last
date of our file review, nearly 3 years elapsed.
We also found that debarment proceedings in which the individual
contested debarment generally took longer to complete.[Footnote 34]
Five of the 18 proceedings we reviewed involved individuals who
responded to FDA's proposal to debar letter by requesting a formal
hearing to contest debarment. These proceedings took from 6 months to
about 6 years, with a median of 2.2 years, from FDA's issuance of a
proposal to debar letter to debarment.[Footnote 35] In contrast, there
were nine debarment proceedings in which the individual received a
proposal to debar letter, but did not contest debarment. These took
from nearly 6 months to 1.5 years, with a median of 9.6 months--about
one-third of the time taken for the proceedings in which the individual
requested a hearing--from FDA's issuance of a proposal to debar letter
to debarment.[Footnote 36] For example, in one proceeding that took
just over 6 years from conviction to debarment, the clinical
investigator contested debarment by submitting a hearing request in
which the individual raised constitutional arguments about FDA's
proposal to debar. In that proceeding, it took more than 5 years and 4
months for FDA to complete the proceeding after the individual
submitted the hearing request. According to FDA officials, the need to
evaluate these legal arguments contributed to the delay.
Internal Control Weaknesses and Competing Priorities Contributed to
Longer Debarment Proceedings:
FDA identified several factors that contributed to the length of time
taken to complete the debarment proceedings we reviewed. These factors
included a lack of systematic procedures to help ensure timely
communication of information relevant to debarment (such as conviction
information) and a lack of policies and procedures that established
time frames for debarment actions. These factors are related to
weaknesses in FDA's internal controls for debarment proceedings. In
addition, for almost all of the proceedings, FDA cited limited
resources due to competing priorities as a factor that contributed to
the length of time taken to complete the proceedings.
FDA did not have systematic procedures for ensuring timely
communication of relevant information about individuals who were
convicted of crimes that could serve as the basis for debarment.
Internal control standards specify that information should be
communicated to those who need it in a form and within a time frame
that enables them to carry out their operational responsibilities. FDA,
however, did not have systematic procedures for ensuring timely
communication of information that could be relevant to debarment and
the informal procedures for communicating such information were not
effective. FDA officials told us that communication between the center
staff responsible for debarment and other FDA staff having information
on convictions that might serve as a basis for debarment occurred on an
informal basis (for example, by sending an e-mail a few times a year to
other FDA staff) and that such communication may not have been
sufficient for obtaining relevant information in a timely manner. For
example, FDA officials told us that the CDER staff responsible for
debarment did not learn of one clinical investigator's December 2003
conviction (through a plea agreement) for submitting a fraudulent
medical license to a sponsor (that subsequently submitted it to FDA)
until August 2007, about 3 years and 9 months after the conviction.
Other FDA staff, however, were aware of the investigator's conviction
in 2003. The Office of Criminal Investigations had been involved in the
investigator's conviction. In addition, as a part of the plea
agreement, CDER entered into a consent agreement in which the
investigator agreed to be disqualified from receiving investigational
drugs and biologics (and other products).[Footnote 37] When asked to
explain why the staff responsible for debarment learned of the
conviction years after other FDA staff, FDA officials said that there
may have been confusion about which CDER staff should obtain conviction
information and that such confusion may have contributed to this delay.
After we completed our file review, FDA issued a proposal to debar
letter to the investigator on November 26, 2008, about 1 year and 3
months after CDER staff responsible for debarment learned of the
conviction, and published a debarment order in the Federal Register on
June 12, 2009. Although the investigator, who was not incarcerated, was
disqualified from serving as a clinical investigator for drugs,
biologics, devices, and other FDA-regulated products, the investigator
was not prohibited by FDA from being involved in research in any other
capacity (for example, as a sub-investigator or study coordinator)
until the investigator was debarred in June 2009.
FDA officials involved with debarment told us that debarment
proceedings were also delayed because FDA did not have established time
frames for its completion of its actions in debarment proceedings.
Implementation of appropriate policies and procedures to mitigate risks
(such as the risk associated with failure to debar someone in a timely
way) is one element of establishing appropriate internal controls. The
only time frame related to FDA's completion of any action involved in a
debarment proceeding at the time of our file review was the statutory
limit requiring that a debarment action be initiated within 5 years of
a date of conviction.[Footnote 38] As a result, FDA officials lacked
common expectations about how long completion of specific actions
should take, expectations that would establish a basis for them to
elevate concerns if actions were not completed in a timely manner. For
example, if center staff became concerned about the length of time the
Office of the Chief Counsel was taking to review a draft proposal to
debar letter, they had no written time frames against which to compare
the time taken, and no clearly established basis for elevating their
concern about the time taken to facilitate completion of that review.
In addition to factors related to internal control weaknesses, FDA
officials told us that limited resources for debarment actions due to
competing priorities contributed to the length of time taken for
debarment proceedings. For 14 of the 18 proceedings we reviewed, FDA
officials told us that the proceeding was delayed because of competing
priorities. For example, they said that the officials responsible for
drafting the proposal to debar letters had other responsibilities,
including drafting regulations and responding to citizen petitions.
They also said that the Office of the Chief Counsel's review of key
documents, such as debarment orders, was delayed because of competing
responsibilities, such as participating in litigation. FDA officials
told us that competing priorities in CDER or the Office of the Chief
Counsel likely contributed to several gaps of time with no recorded
activity in its longest debarment proceeding involving a clinical
investigator. The investigator was convicted of 53 counts of criminal
offenses under state law in December 1997 for misconduct that included
bribing an employee to conceal information about the attempted suicide
of a clinical trial participant and prescribing a controlled substance
without a license. This proceeding included a period of more than 4
years and 8 months in which our review of FDA's files revealed no
documented activity. This proceeding was still pending in November
2008--nearly 11 years after the investigator was convicted and nearly 6
years after he was released from prison in 2003.[Footnote 39] As a
result, FDA had not debarred the investigator (which would have
prohibited the investigator from involvement with any entity that has
an approved or pending application for drugs or biologics) since his
release from prison.[Footnote 40]
FDA Has Recently Made or Planned Changes to Its Debarment Policies and
Procedures That Could Improve Timeliness:
FDA has recently made changes to its debarment policies and procedures
that could improve the timeliness of both permissive and mandatory
debarment proceedings. In the spring of 2008, recognizing the need to
improve FDA's debarment process, including the timeliness of debarment
proceedings, FDA established the Debarment Working Group to examine its
debarment procedures and identify ways to improve them. As a result of
that effort, FDA took steps to strengthen its internal controls by
issuing a new staff manual guide in March 2009 and new standard
operating procedures in April 2009.[Footnote 41] The staff manual guide
establishes systematic procedures for timely communication of relevant
information and time frames for completion of its actions in debarment
proceedings. The changes in FDA's debarment policies and procedures
include the following:
* FDA established systematic procedures to facilitate timely
communication of information about potentially relevant convictions.
Under the new staff manual guide, the Office of Enforcement is
responsible for establishing procedures in cooperation with other
relevant FDA components, including the Office of Criminal
Investigations, and with the Department of Justice to facilitate the
communication of information about convictions and misconduct relevant
to debarment more systematically. The official in the Office of
Enforcement who will oversee implementation of the new staff manual
guide policies and procedures told us in April 2009 that the Office of
Enforcement had put in place procedures to obtain conviction
information from the Office of Criminal Investigations and the
Department of Justice. Furthermore, according to the staff manual
guide, the Office of Criminal Investigations is to provide quarterly
reports to the Office of Enforcement that include all convictions
occurring within the preceding 3 months that may serve as a basis for
debarment. The Office of Enforcement official told us that the
quarterly reports from the Office of Criminal Investigations are to
cover those convictions in which the Office of Criminal Investigations
was involved and sentencing has occurred. In addition, the staff manual
guide states that all FDA employees are responsible for informing the
Office of Enforcement as soon as possible when they become aware of any
individuals who may be subject to debarment. FDA officials said that
after the staff manual guide was finalized and published, the Office of
Enforcement announced this requirement to FDA employees. They also said
that the Office of Enforcement may further formalize this requirement
in FDA's regulatory procedures manual.
* FDA established time frames for completing debarment actions. The new
staff manual guide for debarment establishes new policies and
procedures that include time frames to help ensure faster completion of
debarment proceedings.[Footnote 42] For example, the staff manual guide
states that FDA is to complete a debarment proceeding in which an
individual fails to respond to a proposal to debar letter within 350
calendar days of the individual's conviction. Although there are no
consequences specified in the staff manual guide for failing to meet
the new time frames, FDA officials said that they believe that drawing
attention to time frames will help ensure more timely debarment
proceedings and provide a basis for action to expedite them. In
addition, the staff manual guide reassigns responsibilities for
debarment proceedings that had belonged to CBER and CDER to the Office
of Enforcement. Since March 2009, the Office of Enforcement's
responsibilities include (among other things) determining whether to
initiate debarment actions, preparing and issuing proposal to debar
letters, consulting with CDER and CBER to determine whether to pursue
permissive debarment, working with officials from the Office of the
Chief Counsel on legal matters, and preparing and issuing debarment
orders (when a hearing request is not involved). The official in the
Office of Enforcement who will oversee implementation of the new staff
manual guide policies and procedures said that the establishment of
time frames for debarment actions provides a basis for the Office of
Enforcement to elevate any concerns that arise about the times taken
and facilitate completion of those actions. This official said that
this office will, for example, monitor the amount of time being taken
by the Office of the Chief Counsel to review a draft proposal to debar
letter to help ensure that the Office of the Chief Counsel is meeting
the time frame (30 days) specified in the new staff manual guide for
reviewing such documents. If the time frame is not met, the Office of
Enforcement official plans to use the staff manual guide as a basis for
raising the issue to other appropriate officials.
FDA officials said that they are planning other changes to FDA's
debarment policies and procedures. They said that the Office of
Enforcement is considering additional changes in standard operating
procedures. In addition, to help implement the new policies and
procedures, the official in the Office of Enforcement who will oversee
their implementation said that the office plans to employ a full-time
staff member whose primary responsibility will be to work on debarment
proceedings. According to the new standard operating procedures, the
staff member's responsibilities will include obtaining conviction
information, gathering information to help determine whether to pursue
debarment, and coordinating the issuance of proposal to debar letters.
FDA's changes or planned changes in its debarment policies and
procedures--including the steps taken to strengthen internal controls--
could reduce the length of time taken to complete debarment
proceedings, but the effects of these changes remain to be seen.
Meeting the time frames will require FDA to complete the debarment
process in a significantly shorter length of time than it took to
complete the process in the debarment proceedings we reviewed. For
example, the new time frame to complete a debarment proceeding in which
an individual fails to respond to a proposal to debar letter is 350
calendar days from an individual's conviction. However, FDA took longer
than 350 calendar days from conviction to debarment in all 7 completed
proceedings in our review that did not include a hearing request, with
5 of the proceedings taking more than 4 years. In addition, it remains
to be seen whether FDA will be able to focus or add to its limited
resources on debarment proceedings. For example, although the official
in the Office of Enforcement who will oversee implementation of the new
staff manual guide policies and procedures told us that they plan to
employ a full-time staff member whose primary responsibility will be to
work on debarment proceedings, as of June 2009 the permanent position
had not yet been filled.[Footnote 43] Finally, it is not yet clear
whether the Office of the Chief Counsel will have sufficient resources
available for assisting with debarment proceedings in a timely manner.
An official in the Office of the Chief Counsel said that they did not
expect any changes to the Office of the Chief Counsel's resources,
unless the number of debarment proceedings increases substantially.
According to FDA, the Office of the Chief Counsel regularly evaluates
its resource needs and any significant increases in the number of
debarments will be factored into those evaluations.
Times Taken for Disqualification Proceedings Varied and Factors Such as
Clinical Investigators' Contesting Disqualification and Internal
Control Weaknesses May Have Contributed to Longer Proceedings:
The times taken for the disqualification proceedings we reviewed varied
widely and were longer when the clinical investigator contested
disqualification. Factors such as a lack of established time frames (an
internal control weakness) and competing priorities may have
contributed to the length of time taken to complete disqualification
proceedings. The agency has made changes to its disqualification
procedures that may improve the timeliness of disqualification
proceedings, but the full effect of these changes remains to be seen.
About One-Third of Disqualification Proceedings Took 2 or More Years
and Proceedings Were Completed More Quickly Over Time:
The disqualification proceedings we reviewed varied widely in the time
taken, with about one-third of the proceedings taking 2 or more years
(see figure 5).[Footnote 44] Of the 52 proceedings we reviewed--which
included all of the disqualification proceedings FDA initiated with a
NIDPOE letter from January 1, 1998, through September 9, 2008--FDA
completed 47 disqualification proceedings as of November 5, 2008. The
length of time to complete these 47 disqualification proceedings--from
issuance of a NIDPOE letter through disqualification or an FDA decision
to terminate the proceeding--ranged from 26 days to more than 10 years,
with a median of 1.1 years. In addition to these 47 completed
proceedings, FDA initiated, but had not completed, 5 disqualification
proceedings. The time taken for these 5 pending proceedings--from
issuance of a NIDPOE letter through the last date of our file review--
ranged from 70 days to more than 7 years and 4 months, with a median of
2.5 years.[Footnote 45]
Figure 5: Time Taken for Completed and Pending Disqualification
Proceedings:
[Refer to PDF for image: two pie-charts]
Completed disqualification proceedings (47 proceedings):
0-2 years (31): 66%;
2-4 years (8): 17%;
4-6 years (5): 11%;
6-8 years (1): 2%;
8-10 years (1): 2%;
10+ years (1): 2%.
Pending disqualification proceedings (5 proceedings):
0-2 years (2): 40%;
2-4 years (1): 20%;
4-6 years (1): 20%;
6-8 years (1): 20%.
Source: GAO analysis.
Notes: This figure presents the length of time from issuance of the
NIDPOE letter to completion for 47 completed disqualification
proceedings (45 that ended in disqualification and 2 that did not) and
the length of time from issuance of the NIDPOE letter to November 5,
2008, for 5 pending disqualification proceedings. All of these
proceedings were initiated by a NIDPOE letter between January 1, 1998,
and September 9, 2008. Numbers of proceedings are shown in parentheses.
None of the disqualification proceedings we reviewed took exactly 2
years or any exact multiple of 2 years to complete.
[End of figure]
We also found that FDA's disqualification proceedings initiated by a
NIDPOE letter in 1998 through 2001 generally took longer to complete
than proceedings that were initiated more recently (see figure 6, which
also shows pending proceedings). Completed proceedings initiated in
1998 through 2001 took from just over 3 months to more than 10 years,
with a median of 2.8 years. Completed proceedings initiated in 2002
through 2005 took from just over 1 month to more than 4 years and 8
months, with a median of 0.9 years. Completed proceedings initiated in
2006 through 2008 took from nearly 1 month to about 2 years, with a
median of 0.5 years.
Figure 6: Time Taken for Disqualification Proceedings Initiated in 1998
through 2001, 2002 through 2005, and 2006 through 2008:
[Refer to PDF for image: three pie-charts]
1998 through 2001 (18 proceedings):
0-2 years (5): 28%;
2-4 years (6): 33%;
4-6 years (3): 17%;
6-8 years (1): 6%;
8+ years (2): 11%;
Pending (1): 6%.
2002 through 2005 (18 proceedings):
0-2 years (13): 72%;
2-4 years (2): 11%;
4-6 years (3): 11%;
Pending (1): 6%.
2006 through 2008 (16 proceedings):
0-2 years (13): 81%;
Pending (3): 19%.
Source: GAO analysis.
Notes: This figure presents the length of time from issuance of the
NIDPOE letter to completion of the proceeding (if completed as of Nov.
5, 2008) or pending status (if pending as of Nov. 5, 2008) for 18
disqualification proceedings initiated by a NIDPOE letter in 1998
through 2001, 18 disqualification proceedings initiated by a NIDPOE
letter in 2002 through 2005, and 16 disqualification proceedings
initiated by a NIDPOE letter from January 1, 2006, through September 9,
2008. None of the disqualification proceedings we reviewed took exactly
2 years or any exact multiple of 2 years to complete. Numbers of
proceedings are shown in parentheses. Percentages do not always add up
to 100 due to rounding.
[End of figure]
Factors Associated with Longer Disqualification Proceedings Included
Whether the Clinical Investigator Contested Disqualification and
Ongoing Criminal Cases:
Factors associated with longer disqualification proceedings included
whether the clinical investigator contested disqualification and
ongoing criminal cases.
The more steps taken by the clinical investigator to contest
disqualification, the longer it generally took to complete the
proceeding (see figure 7). As examples, disqualification proceedings
generally took longer if the investigator contested disqualification by
responding to the NIDPOE letter in a written response or informal
conference, contested the terms of disqualification by attempting to
negotiate the terms of a consent agreement, or contested
disqualification by requesting a hearing.[Footnote 46] The two
disqualification proceedings in our review in which FDA found the
investigator's explanation satisfactory and did not disqualify the
individual were concluded relatively quickly.
Figure 7: Time Taken to Complete Disqualification Proceedings:
[Refer to PDF for image: illustration]
The clinical investigator did not submit a written response or
participate in an informal conference and entered a consent agreement
without attempting to negotiate its terms (N=5):
Time: 0 to less than 1 year.
The clinical investigator did not submit a written response or
participate in an informal conference and entered a consent agreement
after attempting to negotiate its terms (N=3):
Time: 0.5 to 1 year.
The clinical investigator did submit a written response or participate
in an informal conference and FDA found the investigator‘s explanation
satisfactory (N=2):
Time: 0 to less than 1 year.
The clinical investigator did submit a written response or participate
in an informal conference and entered a consent agreement without
attempting to negotiate its terms (N=3):
Time: 0 to less than 1 year.
The clinical investigator did submit a written response or participate
in an informal conference and entered a consent agreement after
attempting to negotiate its terms (N=18):
Time: 0.5 to 4 years; median about 1 year.
The clinical investigator did submit a written response or participate
in an informal conference terms and FDA did not find the investigator‘s
explanation satisfactory and issued a notice of opportunity for
hearing. The clinical investigator then entered a consent agreement[A]
(N=5):
Time: 1 to about 4 years; median about 3 years.
The clinical investigator did submit a written response or participate
in an informal conference and FDA did not find the investigator‘s
explanation satisfactory and issued a notice of opportunity for
hearing. The clinical investigator then did not request a hearing and
was disqualified[B]:
Time: 1 to about 6 years; median about 3.5 years.
The clinical investigator did submit a written response or participate
in an informal conference and FDA did not find the investigator‘s
explanation satisfactory and issued a notice of opportunity for
hearing. The clinical investigator then did request a hearing that was
granted or denied[C]:
Time: 4 to about 10 years; median about 5 years.
Source: GAO.
Notes: Data are for 47 disqualification proceedings initiated by a
NIDPOE letter between January 1, 1998, and September 9, 2008, and
completed as of November 5, 2008. There was one disqualification
proceeding in which FDA issued a Notice of Opportunity for Hearing to a
clinical investigator who had not presented information in writing or
participated in an informal conference; this proceeding is included
among the five proceedings in which a hearing was requested and either
granted or denied.
[A] These five proceedings involved two investigators who entered into
a consent agreement with FDA without requesting a hearing and three
investigators who entered into a consent agreement after requesting a
hearing but before FDA either denied or granted the request for a
hearing.
[B] These six proceedings involved investigators who did not request a
hearing and were disqualified by a Commissioner's decision.
[C] These five proceedings included one investigator whose request for
a hearing was denied and who was disqualified by a Commissioner's
decision. Also included are four investigators whose requests for a
hearing were granted. After one investigator's hearing request was
granted, the investigator agreed to restrictions on his research
activities as part of a settlement agreement negotiated with the
Department of Justice on behalf of FDA and other components of the
Department of Health and Human Services. Another investigator entered
into a consent agreement with FDA after the hearing was completed, but
before the Commissioner reached a decision. The other two investigators
whose requests for a hearing were granted were disqualified by a
Commissioner's decision after completion of the hearing; these two
cases took 9.5 and 10.2 years, respectively.
[End of figure]
Another factor that contributed to longer proceedings was the
suspension of disqualification actions during criminal cases related to
the misconduct of the clinical investigators. For example, two of the
five disqualification proceedings that were pending when we completed
our file review were delayed for more than 2 years due to ongoing
criminal cases. According to FDA officials, disqualification
proceedings may be suspended during ongoing criminal cases for several
reasons. Documents needed to support the disqualification proceedings
(such as the medical records of clinical trial participants or forms
prepared to document the conduct of the clinical trial) may be
unavailable to FDA because they are in the custody of the United States
Attorney as a result of the criminal investigation. In addition, FDA
may be involved in negotiations to include, as part of a plea
agreement, a consent agreement that would disqualify the investigator,
and the disqualification proceeding may be delayed while conducting
these negotiations. FDA may also agree to requests made by the clinical
investigator or his or her legal counsel for additional time to respond
to the disqualification proceeding so that he or she can focus on the
criminal investigation.
Internal Control Weaknesses and Competing Priorities May Have
Contributed to Longer Disqualification Proceedings:
FDA officials told us that several factors contributed or may have
contributed to the length of time taken to complete the
disqualification proceedings that we reviewed. These factors included
internal control weaknesses--specifically, a lack of appropriate
policies and procedures to help ensure timely completion of
disqualification actions by establishing time frames. In addition, FDA
cited limited resources due to competing priorities and changes in
personnel as factors associated with longer disqualification
proceedings.
FDA told us that a lack of time frames for FDA's completion of
disqualification proceedings might have contributed to longer
proceedings. As with debarment proceedings, FDA officials lacked common
expectations about how long completion of specific actions should take
that would establish a basis for them to elevate concerns if actions
were not completed in a timely manner. For example, if center staff
became concerned about the length of time the Office of the Chief
Counsel was taking to review a draft NOOH letter, they had no written
time frames against which to compare the time taken and no clearly
established basis for elevating their concern about the time taken to
facilitate completion of that review.
In addition to an internal control weakness, FDA told us that limited
resources in the Office of the Chief Counsel for disqualification
actions due to competing priorities contributed to the length of time
taken to complete some disqualification proceedings. For example, FDA
told us that limited resources and competing priorities contributed to
delays in one disqualification proceeding, including a delay of about 3
years and 9 months during which the clinical investigator's request for
a review of the presiding officer's report was pending in FDA's Offices
of the Chief Counsel and Commissioner. FDA also told us that limited
resources and competing demands contributed to a delay of about 1 year
and 4 months in one proceeding in which the terms of a consent
agreement were being negotiated and a delay of just over a year in
another proceeding in which a presiding officer was reviewing arguments
for and against holding a regulatory hearing.
Changes in personnel also contributed to the length of time taken to
complete certain disqualification proceedings. For example, in two
proceedings we reviewed, regulatory hearings began with presiding
officers who did not complete the hearings. As a result, new presiding
officers had to be appointed and become familiar with the arguments of
the cases, resulting in longer proceedings. In addition, FDA officials
said that changes in center personnel, and the associated need to train
new staff, contributed to some of the delays in completing
disqualification proceedings that were initiated in the late 1990s and
early 2000s.
FDA Has Made Changes to Its Disqualification Policies and Procedures
That Could Improve Timeliness:
FDA has taken steps to enhance the timeliness of disqualification
proceedings by establishing new policies and procedures that include
time frames for its completion of disqualification actions. Until June
2008, FDA did not have time frames for its completion of any of its
disqualification actions. Recognizing the need to improve the
timeliness of its disqualification proceedings, FDA issued a new staff
manual guide in June 2008 that established time frames for
disqualification actions that follow the issuance of a NOOH letter. In
January 2009, FDA revised its regulatory procedures manual,
establishing time frames for disqualification actions through and
including issuance of a NOOH letter. Although no consequences are
specified for failing to meet the new time frames, FDA officials said
that they believe that drawing attention to time frames will help them
ensure more timely disqualification proceedings and provide a basis for
action to expedite them. In addition, FDA recently reassigned
responsibility for monitoring the progress of all disqualification
proceedings in which a NOOH letter has been issued to the Good Clinical
Practice Program. The Good Clinical Practice Program began taking
responsibility for these proceedings in spring of 2008, and hired a
staff member to help oversee and monitor the disqualification process
in June 2008.[Footnote 47] Centers retain responsibility for initiating
disqualification proceedings, evaluating responses from the clinical
investigator, and determining whether to recommend issuance of a NOOH
letter. The Good Clinical Practice Program is responsible for tracking
the progress of all disqualification proceedings from issuance of the
NIDPOE letter through completion and has created a database to do so.
FDA officials told us that they believe that assigning monitoring
responsibilities to the Good Clinical Practice Program should help
ensure more timely completion of all disqualification proceedings. They
told us that the establishment of time frames for disqualification
actions provides a basis for elevating any concerns that arise about
the time taken for actions and to facilitate completion of those
actions.
FDA also told us that changes were made in recent years to provide
additional resources for disqualification proceedings and that these
changes have improved or will improve the timeliness of proceedings.
For example, the agency told us that CDER has improved the timeliness
of the center's actions in disqualification proceedings because, since
May 2006, additional CDER staff have been available to focus on
initiating proceedings. In addition, the agency told us that over the
past several years, the Office of the Chief Counsel increased its
resources for drug matters, which resulted in an increase of resources
for disqualification. According to FDA, the increase has enabled the
office to handle more disqualification proceedings initiated by the
centers and to handle more expeditiously the drafting and review of
Commissioner's decisions.
FDA's changes in its policies and procedures for disqualification--
including the steps taken to strengthen internal controls--could reduce
the length of time taken to complete disqualification proceedings, but
the full effect of these changes remain to be seen. Meeting the time
frames would require FDA to complete some disqualification actions in a
significantly shorter length of time than it took to complete these
actions in some of the proceedings we reviewed. For example, the
January 2009 regulatory procedures manual specifies that a NOOH letter
should be issued within 11 working days of the time the center forwards
a recommendation to issue it, and we found that at least 13 of the 17
proceedings we reviewed in which a NOOH letter was issued did not meet
this time frame; instead, this step took more than 2 months in at least
5 proceedings. The June 2008 staff manual guide specifies that a
presiding officer should issue a report within 90 days of a regulatory
hearing. None of the three proceedings with presiding officer reports
that we reviewed were issued within 90 days. They were issued after
about 14.5 months, 23 months, and 42 months, respectively.[Footnote 48]
In addition, the January 2009 revisions to the regulatory procedures
manual specify that a NIDPOE letter should be issued within about 9 and
a half months of the inspection that revealed misconduct, and about two-
thirds of the 52 proceedings we reviewed did not meet this time frame.
[Footnote 49]
FDA's Debarment Authority Does Not Fully Extend to Involvement with
Devices and Regulations Allow Disqualified Clinical Investigators to
Conduct Trials for Other Investigational Medical Products:
FDA's oversight of clinical investigators, sub-investigators, and study
coordinators is limited by two aspects of its statutory debarment
authority and because FDA's regulations do not extend a clinical
investigator's disqualification for investigational drugs and biologics
to investigational devices and vice versa.
FDA's Debarment Authority May Not Permit FDA to Address Misconduct
Related to Medical Devices:
FDA's debarment authority may not permit FDA to address misconduct in
two significant ways. First, although an individual may have been
debarred from involvement with drugs and biologics, a debarred
individual is not necessarily precluded from involvement with FDA-
regulated products other than drugs and biologics, such as medical
devices. For example, in one completed debarment proceeding that we
reviewed, a study coordinator who was involved in drug research was
debarred as a result of being convicted of a federal felony. This study
coordinator admitted destroying X-ray film reports and falsifying
electrocardiogram results. Despite debarment, this individual could
still provide services for an entity that markets or intends to market
FDA-regulated products other than drugs or biologics, including medical
devices.
Second, an individual may be debarred from involvement with drugs and
biologics, but not from involvement with medical devices, regardless of
the kind of misconduct in which the individual engaged. While the
statute expressly authorizes FDA to debar an individual from
involvement with drugs and biologics, there is no comparable authority
with regard to an individual involved with medical devices. For
example, one investigator who falsely advertised an unapproved
investigational laser device for treating eye disorders as an FDA-
approved device, and who falsified information in the medical records
of patients treated with the device cannot be debarred by FDA from
working in the medical device industry.[Footnote 50] A CDRH official
told us that he would like FDA to have the authority to debar
individuals like this investigator. When asked whether the agency had
pursued obtaining this authority, the agency responded that the Office
of the Chief Counsel was not aware of any efforts to expand FDA's
debarment authority, but did not provide a reason for not requesting
this authority.
FDA's Regulations Allow Disqualified Clinical Investigators to Conduct
Trials for Other Medical Products:
FDA's disqualification regulations are included in two separate sets of
regulations--one for drugs and biologics and another for devices--and
both sets of regulations limit the types of products to which
disqualification applies.[Footnote 51] As a result, FDA's oversight of
clinical investigators is limited. Under federal regulations, an
investigator who is disqualified by a Commissioner's decision for
misconduct related to drugs or biologics is still able to serve as an
investigator for devices, and an investigator who is disqualified by a
Commissioner's decision for misconduct related to devices is still able
to serve as an investigator for drugs and biologics. Moreover, an
investigator who is disqualified by a Commissioner's decision for
misconduct related to drugs, biologics, or devices is still able to
serve as an investigator for other FDA-regulated investigational
products, such as animal drugs and food additives. Of the nine
completed proceedings we reviewed that resulted in disqualification by
a Commissioner's decision (instead of a consent agreement), eight
investigators were disqualified from receiving investigational drugs
and biologics, but not devices, and one investigator was disqualified
from receiving investigational devices, but not drugs or biologics. For
example, one disqualified investigator (who, among other things,
falsely reported that investigational vaccines had been administered to
infants when they had not and failed to report that some clinical trial
participants had been hospitalized) is prohibited from being a
investigator for drugs or biologics, but is not disqualified from
receiving medical devices or other FDA-regulated investigational
products, and so can serve as a investigator for research on these
products should this individual choose to do so.[Footnote 52]
Compared to disqualifications that resulted from a Commissioner's
decision, FDA has more latitude in determining the consequences of
disqualification when it results from a consent agreement between FDA
and the investigator. Of the 35 completed proceedings we reviewed that
resulted in disqualification through consent agreements,[Footnote 53]
* Fifteen consent agreements contained more extensive restrictions by
disqualifying the investigator from receiving any FDA-regulated
investigational products (including drugs, biologics, devices, animal
drugs, and food additives). For example, FDA concluded that one
investigator failed to obtain required informed consent, failed to
document that women were not pregnant before being given an
investigational drug, and submitted false information. This
investigator entered into a consent agreement with FDA that
disqualified him from receiving any FDA-regulated investigational
products, including drugs and biologics, as well as medical devices. If
the investigator had been disqualified by a Commissioner's decision, he
could not have been disqualified from receiving medical devices or FDA-
regulated investigational products other than drugs and biologics.
* Nineteen consent agreements contained terms that restricted the
investigator's research activities in ways that differed from what
would have resulted from a Commissioner's decision. These consent
agreements generally allowed the investigator to continue to function
as an investigator, but imposed certain restrictions on his or her
research, for example, by restricting the number of studies he or she
may engage in at any time or the number of participants he or she may
enroll in studies. Some consent agreements also required the
investigator to obtain training in the conduct of clinical trials.
Unlike disqualification that results from a Commissioner's decision,
the consent agreements that specified restrictions generally applied to
all FDA-regulated investigational products (not just drugs and
biologics or devices) and were generally not permanent. In addition,
some consent agreements specified restrictions on the individual's
activities as a sub-investigator--activities that are not restricted if
disqualification results from a Commissioner's decision.
* One consent agreement disqualified an investigator from receiving
drugs and biologics, but not other FDA-regulated investigational
products. This consent agreement did not specify any other restrictions
on the investigator's activities.
Conclusions:
To strengthen FDA's oversight of clinical investigators, FDA needs to
ensure the timely completion of its debarments and disqualifications.
Timely completion of these proceedings is critical to ensuring that
individuals who have engaged in misconduct are prohibited from
repeating the misconduct--that is, the actions that compromised the
quality or integrity of clinical trial data or jeopardized the safety
of clinical trial participants--and that individuals whose explanations
FDA finds to be satisfactory can have their proceedings concluded
quickly. While FDA's recent changes in policies and organization of
responsibilities could improve the timeliness of debarment and
disqualification proceedings, it is too soon to tell whether these
efforts will be effective. For example, implementing the new time
frames that FDA has established for debarment and disqualification
could be challenging because some of these time frames are
substantially shorter than the times FDA actually took in the
proceedings we reviewed. Given the agency's competing priorities, it
remains to be seen whether FDA will dedicate sufficient resources to
debarment or disqualification proceedings to meet the time frames.
FDA's authority to debar or disqualify clinical investigators is an
important component of its oversight of clinical investigators,
specifically its efforts to protect human subjects and ensure the
integrity of the data upon which it relies when evaluating new drugs,
biologics, or devices for the U.S. market. It is critical for FDA to
take action--and to have the authority to take action--to prevent
clinical investigators, sub-investigators, and study coordinators who
engaged in serious misconduct from doing so again, whether in research
that involves drugs, biologics, or devices. FDA's current debarment
authority does not fully extend to involvement with medical devices or
prevent those who engaged in misconduct involving drugs or biologics
from involvement with medical devices. In addition, FDA's
disqualification regulations limit a disqualification by a
Commissioner's decision to either investigational drugs and biologics
or to investigational devices, thereby allowing an individual
disqualified for misconduct related to drugs or biologics to receive
investigational devices and vice versa. Moreover, a clinical
investigator who is disqualified by a Commissioner's decision is still
able to serve as a clinical investigator for other FDA-regulated
investigational products. As a result, FDA's oversight of clinical
investigators is limited.
Recommendations for Executive Action:
We recommend that the Commissioner of FDA take the necessary steps to
complete the following three actions:
* Pursue debarment authority for medical devices that is consistent
with the current debarment authority for drugs and biologics and
prohibit any debarred individual from involvement with drugs,
biologics, and medical devices.
* Amend FDA regulations to ensure that those who have engaged in
misconduct found sufficiently serious to warrant disqualification for
one investigational medical product are not able to continue to serve
as clinical investigators for any.
* Monitor compliance with recently established time frames for
debarment and disqualification proceedings and take appropriate action
when those are not met.
Agency Comments:
We provided a draft of this report to the Department of Health and
Human Services for review. The department provided written comments
from FDA. In its comments, FDA agreed with our recommendations. FDA's
comments are reprinted in appendix VII. FDA also provided technical
comments and updated information, which we incorporated as appropriate.
In its comments, FDA stated that the agency will endeavor to
incorporate our recommendations into the agency's procedures. FDA
agreed that providing the agency with the debarment authority to
prohibit those who were convicted of certain crimes or otherwise
involved in criminal activity from being involved in the medical device
industry would benefit the development and approval process for medical
devices. FDA also agreed that if a clinical investigator is
disqualified from participating in clinical trials involving one type
of investigational medical product, it is generally appropriate that
the investigator be prohibited from participating in investigations of
any FDA-regulated product. FDA stated that the agency intends to pursue
revision of its regulations concerning clinical investigator
disqualification to address this issue. In addition, FDA agreed that
monitoring its success in meeting the recently established time frames
for debarment and disqualification will be important as the agency
strives to improve the timeliness of the debarment and disqualification
processes, and it summarized steps it has already taken to do so.
As agreed with your offices, unless you publicly announce the contents
of this report earlier, we plan no further distribution until 30 days
from the report date. At that time, we will send copies to the
Secretary of Health and Human Services, the Commissioner of FDA,
relevant congressional committees, and interested parties. In addition,
this report will be available at no charge on the GAO Web site at
[hyperlink, http://www.gao.gov].
If you or your staff have any questions concerning this report, please
contact me at (202) 512-7114 or crossem@gao.gov. Contact points for our
Offices of Congressional Relations and Public Affairs may be found on
the last page of this report. GAO staff who made major contributions to
this report are listed in appendix VIII.
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: Scope and Methodology:
In this report, we examined the Food and Drug Administration's (FDA)
time frames for debarment and disqualification proceedings, as well as
limitations to the agency's statutory and regulatory authority related
to these proceedings prior to November 2008. Until June 2008, other
than the statutory requirement that debarment actions be initiated
within 5 years of the date of the individual's conviction, FDA did not
have criteria establishing time frames for the various steps it must
take in debarment or disqualification proceedings. During the course of
our work, three actions occurred that changed FDA's procedures for
debarment and disqualification of clinical investigators.
* In June 2008, FDA issued a staff manual guide that, among other
provisions, established time frames for the steps it must take after
offering the clinical investigator an opportunity for a regulatory
hearing in a disqualification proceeding.
* In January 2009, FDA issued a revised regulatory procedures manual
that, among other provisions, established time frames for the steps it
must take in disqualification proceedings prior to and through offering
the clinical investigator an opportunity for a regulatory hearing.
* In March 2009, FDA issued a staff manual guide that, among other
provisions, established time frames for the steps it must take in
debarment proceedings.
At the time of our review, it was too soon to assess the effect of the
changes in FDA's procedures and guidance on debarment and
disqualification proceedings. Consequently, this report focuses on
FDA's procedures as documented in proceedings that generally took place
prior to issuance of the new time frames. We compare some of the times
taken for the debarment and disqualification proceedings we reviewed
with the new time frames.
To address our objectives, we reviewed FDA's debarment and
disqualification files, interviewed FDA officials involved in debarment
and disqualification proceedings, reviewed relevant laws, regulations,
and FDA guidance, and reviewed standards for internal control. We
conducted our file review from September 9, 2008, through November 5,
2008.
To determine how long FDA's debarment proceedings have taken and
identify factors that contributed to the time frame for debarment, we
reviewed FDA's files regarding all clinical investigators, sub-
investigators, and study coordinators involved in research on drugs or
biologics intended for human use whom FDA pursued or considered
pursuing for debarment from the time that it was given authority to do
so on May 13, 1992, through September 9, 2008.[Footnote 54] To identify
these individuals, we reviewed information about FDA's debarment
proceedings from Federal Register notices (including proposal to debar
letters and final debarment orders) and FDA's Web site, and we
confirmed whether or not these individuals were clinical investigators,
sub-investigators, or study coordinators with FDA officials. We
compared the information about debarment proceedings from FDA's Web
site to the information in FDA's files and sought clarification when
there were discrepancies.[Footnote 55] We identified 18 completed or
pending debarment proceedings pursued by FDA from May 13, 1992, through
September 9, 2008--13 involving clinical investigators and 5 involving
study coordinators.[Footnote 56]
For each of these 18 debarment proceedings, we reviewed relevant files
in the FDA center that initiated the debarment action--either the
Center for Drug Evaluation and Research (CDER) or the Center for
Biologics Evaluation and Research (CBER)--and in FDA's Division of
Dockets Management, which maintains publicly available information
about debarment proceedings.[Footnote 57] We reviewed the documentation
in the files to identify the date of each action in the debarment
proceeding, along with information about who was involved and what
occurred. We determined that the information we collected during our
file review was sufficiently reliable for our purposes. After reviewing
these files, we obtained additional information from FDA officials
about proceedings in which the documentation we reviewed was
incomplete. We also asked FDA officials to explain what, if anything,
had occurred during any time intervals for which our review of the
files indicated that 270 calendar days or more had passed without
documented activity. We also followed up on proceedings that were
pending as of the last day of our file review and on proceedings for
which FDA's files on disqualification proceedings included information
pertinent to a debarment proceeding.
To determine the time each completed debarment proceeding took, we
calculated the number of calendar days from the date of the
individual's conviction (or, for two proceedings in which the
individual's conviction occurred before FDA received debarment
authority, from the date when FDA received debarment authority--May 13,
1992) through completion of the debarment proceeding (i.e., the date of
publication of a debarment order in the Federal Register). If the
proceeding was pending, we calculated the number of calendar days
through the last day of our file review. We also calculated the number
of days during certain intervals in debarment proceedings, for example,
from conviction to the issuance of a proposal to debar letter. To
identify factors that contributed to the length of time FDA's debarment
proceedings have taken, we analyzed the information we obtained from
FDA's files and the additional information we obtained from FDA
officials. We examined laws, regulations, and guidance to determine
whether there were criteria relevant to the times taken by debarment
proceedings and we interviewed FDA officials, including officials in
CDER, CBER, the Office of Enforcement, and those involved with FDA's
Debarment Working Group.
To determine how long FDA's disqualification proceedings have taken and
identify factors that contributed to the time frame for
disqualification, we reviewed FDA's files regarding all clinical
investigators involved in research on drugs, biologics, or medical
devices intended for human use for whom FDA pursued disqualification by
issuing a Notice of Initiation of Disqualification Proceedings and
Opportunity to Explain (NIDPOE) letter from January 1, 1998, through
September 9, 2008, whether these clinical investigators were ultimately
disqualified or not.[Footnote 58] To identify these individuals, we
reviewed information about FDA's disqualification proceedings from
FDA's Web site and obtained additional information from FDA about
individuals for whom FDA pursued disqualification. We compared the
information about disqualification proceedings from FDA's Web site to
the information in FDA's files and sought clarification when there were
discrepancies.[Footnote 59] We identified 52 completed and pending
disqualification proceedings that FDA initiated by issuing a NIDPOE
letter from January 1, 1998, through September 9, 2008.[Footnote 60]
For each of these 52 disqualification proceedings, we reviewed relevant
files in the FDA center that initiated the disqualification proceeding--
CDER, CBER, or the Center for Devices and Radiological Health (CDRH)--
as well as in other FDA offices that maintained files relating to these
disqualification proceedings. These other offices included the Office
of Enforcement, which is involved in the issuance of, and coordination
of responses to, notice of opportunity for hearing (NOOH) letters; the
Office of the Ombudsman, which was responsible for regulatory hearings
held as part of disqualification proceedings prior to spring of 2008;
and the Good Clinical Practice Program,[Footnote 61] which began
assuming responsibility for disqualification proceedings in spring of
2008 and hired a staff member to help oversee and monitor the
disqualification process in June 2008. We reviewed the documentation in
the files to identify the date of each action in the disqualification
proceeding, along with information about who was involved and what
occurred. We determined that the information we collected during our
file review was sufficiently reliable for our purposes. After reviewing
these files, we obtained additional information from FDA officials
about proceedings in which the documentation we reviewed was
incomplete. We also asked FDA officials to explain what, if anything,
had occurred during any time intervals for which our review of the
files indicated that 1 year or more had passed without documented
activity. We also followed up on proceedings that were pending as of
the last day of our file review.
To determine the time each completed disqualification proceeding took,
we calculated the number of calendar days from the date of issuance of
the NIDPOE letter through the conclusion of the disqualification
proceeding (i.e., the date of issuance of a notice of disqualification,
the date a consent agreement was signed by FDA, the date that FDA
concluded the disqualification proceeding without disqualifying the
investigator, or the date of a settlement agreement that concluded the
disqualification proceeding).[Footnote 62] If the proceeding was
pending, we calculated the number of calendar days through the last day
of our file review. We also calculated the number of calendar days
during certain intervals in disqualification proceedings, for example,
from a center's recommendation to issue a NOOH letter through issuance
of that letter. To identify factors that contributed to the length of
time FDA's disqualification proceedings have taken, we analyzed the
information we obtained from FDA's files and the additional information
we obtained from FDA officials. To determine whether the times taken
for disqualification proceedings changed during the years covered in
our review, we divided these proceedings into three groups based on the
date when FDA issued the NIDPOE letter--those issued before 2002, those
issued in 2002 through 2005, and those issued after 2005. We examined
laws, regulations, and guidance to determine whether there were
criteria relevant to the times taken by disqualification proceedings
and we interviewed FDA officials.
To identify statutory and regulatory limitations of debarment and
disqualification, we reviewed relevant laws, regulations, and guidance;
reviewed files documenting FDA's debarment and disqualification
proceedings; and interviewed FDA officials involved with debarment and
disqualification proceedings.
We conducted this performance audit from June 2008 to September 2009,
in accordance with generally accepted government auditing standards.
Those standards require that we plan and perform the audit to obtain
sufficient, appropriate evidence to provide a reasonable basis for our
findings and conclusions based on our audit objectives. We believe that
the evidence obtained provides a reasonable basis for our findings and
conclusions based on our audit objectives.
[End of section]
Appendix II: Selected Features of Debarment and Disqualification:
Authority:
Debarment[A]: Individuals to whom the action may be applied: Pub. L.
No.102-282, § 2 (21 U.S.C. § 335a);
Disqualification: Individuals to whom the action may be applied: 21
C.F.R. §§ 312.2(a), 312.70 (2008) (drugs and biologics) 21 C.F.R. §
812.119 (2008) (devices).
Authority: Individuals to whom the action may be applied;
Debarment[A]: Individuals--including clinical investigators, sub-
investigators, study coordinators, sponsors, and others--convicted of
certain crimes or engaged in certain conduct. Debarment may be
mandatory or permissive;
Mandatory debarment:
* For individuals convicted of a felony under federal law for conduct
relating to the development, approval, or regulation of a drug
product.[B];
Permissive debarment:
* For individuals convicted of a misdemeanor under federal law or a
felony under state law for conduct relating to the development,
approval, or regulation of a drug or biologic, or convicted of a
conspiracy to commit, aid, or abet such crimes or a felony for which
debarment is mandatory, if the type of conduct undermines the
regulatory process for drugs or biologics;
* For individuals convicted of a felony for certain crimes or a
conspiracy to commit, aid, or abet such a felony, if FDA finds that the
individual has demonstrated a pattern of conduct sufficient to find
there is reason to believe the individual may violate requirements
related to drugs or biologics, or;
* For individuals who materially participated in acts that were the
basis for a different individual's conviction for certain crimes, if
FDA finds that the individual has demonstrated a pattern of conduct
sufficient to find there is reason to believe the individual may
violate requirements related to drugs or biologics.[C];
Disqualification: Clinical investigators who have repeatedly or
deliberately failed to comply with applicable FDA regulations or have
repeatedly or deliberately submitted false information to FDA or the
sponsor of the clinical trial in any required report.
Authority: Examples of convictions or misconduct upon which the action
could be based;
Debarment[A]:
* Mail fraud (e.g., for submitting fraudulent data through the mail
based on nonexistent clinical trial participants);
* Making false statements (e.g., by providing a false and fraudulent
medical license to qualify as a clinical investigator);
Disqualification:
* Repeatedly and deliberately failing to comply with FDA regulations
requiring informed consent of clinical trial participants (e.g., by
failing to advise them of the risks of participation);
* Deliberately submitting false data to the sponsor of a clinical trial
(e.g., submitting fraudulent data based on nonexistent clinical trial
participants) in a required report.
Authority: Consequences of the action for the individual;
Debarment[A]: No longer permitted to provide services in any capacity
to an individual, corporation, partnership, or association that has an
approved or pending drug or biologic application. If such services are
provided, civil monetary penalties may be assessed.[D];
Disqualification:
If disqualified by a Commissioner's decision:
* No longer entitled to receive FDA-regulated investigational drugs and
biologics or FDA-regulated investigational devices and therefore unable
to serve as a clinical investigator for the type of product (i.e.,
drugs and biologics or devices) for which the action was taken;
If disqualified by consent agreement:
* Terms of agreement may be subject to negotiation, which could result
in disqualification from receiving some or all FDA-regulated
investigational products, or restrictions such as limits on the number
of clinical studies the investigator may conduct and requiring that the
investigator be supervised by another clinical investigator.
Authority: Duration;
Debarment[A]:
Mandatory: Permanent;
Permissive: Up to five years for each offense.[E];
Disqualification: Disqualification is permanent unless otherwise
specified in a consent agreement or the investigator is reinstated.[F]
Authority: Time frame for initiation of action;
Debarment[A]: Must occur within 5 years of conviction or the date of
the action on which debarment is based[G];
Disqualification: No limit.
Source: GAO.
[A] The selected features of debarment presented in this table relate
to individuals (including clinical investigators, sub-investigators,
and study coordinators) who may be debarred from involvement with drugs
and biologics, and not to corporations, partnerships, or associations.
[B] The statutory definition of "drug product" includes drugs and
biologics. 21 U.S.C. § 321(dd).
[C] Individuals may also be permissively debarred if they are high
managerial agents who worked for, or who worked as a consultant for, an
individual convicted of a felony resulting in debarment, and who had
knowledge of such activity and knew it was a violation, but did not
report it, and if FDA determines that the type of conduct which served
as the basis for such other individual's conviction undermines the
process for the regulation of drugs or biologics. High managerial
agents are officers or directors of a corporation or an association,
partners of a partnership, or any employee or other agent of a
corporation, association, or partnership having duties such that their
conduct may fairly be assumed to represent the policy of the
corporation, association, or partnership, and includes persons having
management responsibility for submissions to the FDA regarding the
development or approval of any drug product; production, quality
assurance, or quality control of any drug product; or research and
development of any drug product. 21 U.S.C. §§ 321(cc),
335a(b)(2)(B)(iv).
[D] 21 U.S.C. § 335b(a)(7).
[E] If the individual is permissively debarred for multiple offenses,
the Commissioner may determine whether debarment periods will run
concurrently or consecutively. FDA is required to terminate an
individual's debarment if, for example, the conviction that served as
the basis for the individual's debarment is reversed. 21 U.S.C. §§
335a(c)(2)(A), (d)(3)(B)(i).
[F] Clinical investigators who have been disqualified may apply to be
reinstated as eligible to receive investigational products.
Reinstatement requires a Commissioner's determination that the
investigator has presented adequate assurances that the investigator
will employ investigational products in compliance with FDA
regulations. 21 C.F.R. §§ 312.70(f), 812.119(f) (2008).
[G] 21 U.S.C. § 335a(l)(2).
[End of table]
[End of section]
Appendix III: Debarment Proceedings Completed or Pending from May 13,
1992, through September 9, 2008:
Proceeding: Kostas, Constantine I.;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: mandatory;
Date of conviction: 10/13/1988[E];
Date of issuance of proposal to debar[C]: 12/9/1992;
Date of debarment order[D]: 6/25/1998.
Proceeding: Fogari, Robert A.;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: mandatory;
Date of conviction: 2/2/1989[E];
Date of issuance of proposal to debar[C]: 1/4/1993;
Date of debarment order[D]: 7/8/1993.
Proceeding: Garfinkel, Barry D.;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: mandatory;
Date of conviction: 11/19/1993;
Date of issuance of proposal to debar[C]: 1/27/1995;
Date of debarment order[D]: 4/2/1997.
Proceeding: Fiddes, Robert A.;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: permissive;
Date of conviction: 9/30/1997;
Date of issuance of proposal to debar[C]: 5/31/2002;
Date of debarment order[D]: 11/6/2002.
Proceeding: Charpentier, Laverne M.;
Individual's role: study coordinator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: permissive;
Date of conviction: 10/21/1997;
Date of issuance of proposal to debar[C]: 5/6/2002;
Date of debarment order[D]: 12/2/2002.
Proceeding: Rescinded[F];
Individual's role: study coordinator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: permissive;
Date of conviction: 10/22/1997;
Date of issuance of proposal to debar[C]: 5/6/2002;
Date of debarment order[D]: 11/6/2002.
Proceeding: Pending A;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: permissive;
Date of conviction: 12/16/1997;
Date of issuance of proposal to debar[C]: 11/26/2002;
Date of debarment order[D]: pending[G].
Proceeding: Borison, Richard L.;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: permissive;
Date of conviction: 10/8/1998;
Date of issuance of proposal to debar[C]: 11/26/2002;
Date of debarment order[D]: 9/30/2003.
Proceeding: Peugeot, Renee;
Individual's role: sub-investigator and study coordinator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: mandatory;
Date of conviction: 3/23/2000;
Date of issuance of proposal to debar[C]: 4/29/2002;
Date of debarment order[D]: 1/13/2003.
Proceeding: Caro Acevedo, Eduardo;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: permissive;
Date of conviction: 2/16/2001;
Date of issuance of proposal to debar[C]: 2/18/2004;
Date of debarment order[D]: 3/24/2005.
Proceeding: Pending B;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: permissive;
Date of conviction: 10/28/2002;
Date of issuance of proposal to debar[C]: 10/10/2007;
Date of debarment order[D]: pending[H].
Proceeding: Pending C;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: debarment had not been proposed[I];
Date of conviction: 12/11/2003;
Date of issuance of proposal to debar[C]: pending[I];
Date of debarment order[D]: pending[I].
Proceeding: Campbell, Maria Anne Kirkman[J];
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: mandatory;
Date of conviction: 3/25/2004;
Date of issuance of proposal to debar[C]: 2/28/2007;
Date of debarment order[D]: 9/2/2008.
Proceeding: Butkovitz, Anne L.;
Individual's role: study coordinator;
Center involved in proceeding[A]: CBER;
Type of debarment proposed[B]: mandatory;
Date of conviction: 6/7/2005;
Date of issuance of proposal to debar[C]: 2/21/2006;
Date of debarment order[D]: 10/17/2006.
Proceeding: Pending D;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CBER;
Type of debarment proposed[B]: mandatory;
Date of conviction: 8/4/2005;
Date of issuance of proposal to debar[C]: 9/7/2007;
Date of debarment order[D]: pending[K].
Proceeding: Pending E;
Individual's role: study coordinator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: debarment had not been proposed[L];
Date of conviction: 12/6/2005;
Date of issuance of proposal to debar[C]: pending[L];
Date of debarment order[D]: pending[L].
Proceeding: Pending F;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: debarment had not been proposed[M];
Date of conviction: 4/24/2007;
Date of issuance of proposal to debar[C]: pending[M];
Date of debarment order[D]: pending[M].
Proceeding: Pending G;
Individual's role: clinical investigator;
Center involved in proceeding[A]: CDER;
Type of debarment proposed[B]: debarment had not been proposed[L];
Date of conviction: 9/11/2007;
Date of issuance of proposal to debar[C]: pending[L];
Date of debarment order[D]: pending[L].
Source: GAO analysis of data from FDA.
Note: This table shows all completed or pending debarment proceedings
initiated from May 13, 1992, through September 9, 2008, against
clinical investigators, sub-investigators, and study coordinators
involved in research on drugs or biologics intended for human use. The
names of individuals who have been debarred are public information:
Debarments are published in the Federal Register and FDA posts the
names of debarred individuals on its Web site. We defined a debarment
proceeding as initiated if FDA identified the individual as one whose
conviction could serve as a basis for debarment. We defined a debarment
proceeding as pending if, as of the last date of our file review (Nov.
5, 2008), FDA had issued a proposal to debar letter, but had not
concluded the debarment proceeding, or if FDA had identified an
individual as one whose conviction could serve as a basis for
debarment, but for whom FDA had not issued a proposal to debar letter.
In addition to the individuals in the proceedings above, CDER
identified a clinical investigator and a sub-investigator who were
convicted of relevant crimes, but who died while FDA was considering
debarment. In addition, CDER identified a clinical investigator who was
convicted of a relevant crime, but who was not debarred because CDER
learned about the clinical investigator's conviction more than 5 years
after the conviction. The law governing debarment specifies that FDA
must initiate debarment actions within 5 years of the date of
conviction. These proceedings are not included.
[A] The FDA centers that pursued debarment of individuals in our review
included CDER and CBER.
[B] There are two types of debarment: mandatory and permissive.
Debarment is mandatory--and permanent--when FDA finds that an
individual has been convicted of a felony under federal law for conduct
relating to the development or approval of any drug or biologic, or
otherwise relating to the regulation of any drug or biologic. FDA may
seek permissive debarment--which is not permanent--under certain other
conditions, for example, if the individual was convicted of a felony
under state law related to the development, approval, or regulation of
drugs or biologics. To seek permissive debarment, FDA must determine
that debarment is appropriate and determine the period of debarment by
considering factors such as the nature and seriousness of the offense
or offenses involved. An individual may be permissively debarred for up
to 5 years for each offense.
[C] FDA issues a proposal to debar letter to initiate a debarment
proceeding. This letter describes the conviction and actions of
relevance to the proceeding, offers the investigator the opportunity
for a formal hearing, and specifies the time period within which the
investigator must provide a written request for a hearing.
[D] We defined a debarment proceeding as completed as of the date on
which FDA published a debarment order in the Federal Register.
[E] The individual in this debarment proceeding was convicted prior to
May 13, 1992, the date on which FDA obtained the authority to debar.
The law governing debarment allows FDA to pursue debarment for
individuals who were convicted prior to May 13, 1992.
[F] FDA rescinded the debarment order in January 2003 after the agency
learned that it had sent the proposal to debar letter to another person
with the same name as the individual involved in this proceeding. When
FDA learned that the proposal to debar letter had been sent to the
wrong person, just over 5 years had elapsed from the date of the study
coordinator's conviction.
[G] This debarment proceeding remained pending as of September 1, 2009.
[H] This debarment proceeding was pending as of November 5, 2008, which
was the last date of our file review, but FDA issued a debarment order
on June 12, 2009.
[I] FDA had not proposed debarment as of November 5, 2008, which was
the last date of our file review, but FDA issued a proposal to debar
letter for mandatory debarment on November 25, 2008, and a debarment
order on June 12, 2009.
[J] This investigator is also known as Maria Anne Campbell.
[K] This debarment proceeding was pending as of November 5, 2008, which
was the last date of our file review, but FDA issued a debarment order
on November 24, 2008.
[L] FDA had not proposed debarment as of November 5, 2008, which was
the last date of our file review, but FDA issued a proposal to debar
letter for mandatory debarment on May 4, 2009, and a debarment order on
August 4, 2009.
[M] FDA had not proposed debarment as of November 5, 2008, which was
the last date of our file review, but FDA issued a proposal to debar
letter for permissive debarment on June 2, 2009. This debarment
proceeding remained pending as of September 1, 2009.
[End of table]
[End of section]
Appendix IV: Types of Misconduct Cited in Proposal to Debar Letters:
Proceeding: Borison, Richard L.;
Misconduct related to:
Falsifying study participant data: [Empty];
Diverting funds for own financial gain: [Check];
Bribing staff to conceal information: [Check];
Illegally prescribing or allowing the illegal prescription of
medication: [Check];
Conspiring to defraud government: [Empty];
Specific example of misconduct: Defrauded employer of more than $10
million in clinical research funds by diverting funds to entities owned
or controlled by the clinical investigators.
Proceeding: Butkovitz, Anne L.;
Misconduct related to:
Falsifying study participant data: [Check];
Diverting funds for own financial gain: [Empty];
Bribing staff to conceal information: [Empty];
Illegally prescribing or allowing the illegal prescription of
medication: [Empty];
Conspiring to defraud government: [Empty];
Specific example of misconduct: Documented that study participants were
contacted and that no serious adverse experiences had occurred when, in
fact, such contacts were not made.
Proceeding: Campbell, Maria Anne Kirkman[A];
Misconduct related to:
Falsifying study participant data: [Check];
Diverting funds for own financial gain: [Empty];
Bribing staff to conceal information: [Empty];
Illegally prescribing or allowing the illegal prescription of
medication: [Empty];
Conspiring to defraud government: [Empty];
Specific example of misconduct: Submitted falsified data for a
nonexistent study participant.
Proceeding: Caro Acevedo, Eduardo;
Misconduct related to:
Falsifying study participant data: [Empty];
Diverting funds for own financial gain: [Empty];
Bribing staff to conceal information: [Empty];
Illegally prescribing or allowing the illegal prescription of
medication: [Empty];
Conspiring to defraud government: [Check];
Specific example of misconduct: Received kickbacks in relation to the
referral of Medicare beneficiaries to a durable medical equipment
company, in violation of the Medicare anti-kickback law.
Proceeding: Charpentier, Laverne M.;
Misconduct related to:
Falsifying study participant data: [Check];
Diverting funds for own financial gain: [Empty];
Bribing staff to conceal information: [Empty];
Illegally prescribing or allowing the illegal prescription of
medication: [Empty];
Conspiring to defraud government: [Empty];
Specific example of misconduct: Substituted samples and data from
qualifying subjects for nonqualifying subjects.
Proceeding: Fiddes, Robert A.;
Misconduct related to:
Falsifying study participant data: [Check];
Diverting funds for own financial gain: [Empty];
Bribing staff to conceal information: [Empty];
Illegally prescribing or allowing the illegal prescription of
medication: [Empty];
Conspiring to defraud government: [Empty];
Specific example of misconduct: Falsely reported that certain subjects
participated in clinical studies when, in fact, they had not.
Proceeding: Fogari, Robert A.;
Misconduct related to:
Falsifying study participant data: [Check];
Diverting funds for own financial gain: [Empty];
Bribing staff to conceal information: [Empty];
Illegally prescribing or allowing the illegal prescription of
medication: [Empty];
Conspiring to defraud government: [Empty];
Specific example of misconduct: Falsified X-ray and physical exam
results to show that the drug was effective.
Proceeding: Garfinkel, Barry D.;
Misconduct related to:
Falsifying study participant data: [Check];
Diverting funds for own financial gain: [Empty];
Bribing staff to conceal information: [Empty];
Illegally prescribing or allowing the illegal prescription of
medication: [Empty];
Conspiring to defraud government: [Empty];
Specific example of misconduct: Submitted data indicating that subject
visits were conducted when, in fact, they were not.
Proceeding: Kostas, Constantine I.;
Misconduct related to:
Falsifying study participant data: [Check];
Diverting funds for own financial gain: [Empty];
Bribing staff to conceal information: [Empty];
Illegally prescribing or allowing the illegal prescription of
medication: [Empty];
Conspiring to defraud government: [Empty];
Specific example of misconduct: Submitted data for 70 fictitious study
participants.
Proceeding: Peugeot, Renee;
Misconduct related to:
Falsifying study participant data: [Check];
Diverting funds for own financial gain: [Empty];
Bribing staff to conceal information: [Empty];
Illegally prescribing or allowing the illegal prescription of
medication: [Empty];
Conspiring to defraud government: [Empty];
Specific example of misconduct: Manipulated test results in clinical
studies.
Source: GAO analysis of data from FDA.
Notes: A proposal to debar letter details the misconduct that led to an
individual's conviction. The proposal to debar letters covered in this
table include those that FDA issued after receiving authority to debar
on May 13, 1992, through September 9, 2008, for clinical investigators,
sub-investigators, and study coordinators whose debarment proceedings
were completed (and not rescinded) as of November 5, 2008 (the last
date of our file review). The names of individuals who have been
debarred are public information: Debarments are published in the
Federal Register and FDA posts the names of debarred individuals on its
Web site.
[A] This investigator is also known as Maria Anne Campbell.
[End of table]
[End of section]
Appendix V: Disqualification Proceedings Initiated from January 1,
1998, through September 9, 2008:
Proceeding: 1;
FDA Center[A]: CDER;
Dates of Inspections: 6/20-24/1996; 5/19-23/1997;
Date of issuance of NIDPOE letter[B]: 3/23/1998;
Date of issuance of NOOH letter[C]: 4/15/1999;
Date of outcome: 6/18/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Check];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 2;
FDA Center[A]: CDER;
Dates of Inspections: 3/11-13/1998;
Date of issuance of NIDPOE letter[B]: 7/1/1998;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 8/11/1999;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 3;
FDA Center[A]: CDER;
Dates of Inspections: 3/9-10/1998;
Date of issuance of NIDPOE letter[B]: 7/1/1998;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 9/10/1999;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check][F];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 4;
FDA Center[A]: CDER;
Dates of Inspections: 6/10/1997-10/9/1997;
Date of issuance of NIDPOE letter[B]: 7/10/1998;
Date of issuance of NOOH letter[C]: 6/28/1999;
Date of outcome: 9/1/1999;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check][F];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 5;
FDA Center[A]: CDER;
Dates of Inspections: 5/7/1997-7/22/1997;
Date of issuance of NIDPOE letter[B]: 8/28/1998;
Date of issuance of NOOH letter[C]: 8/18/1999;
Date of outcome: 7/30/2002;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Check];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 6[G];
FDA Center[A]: CDER;
Dates of Inspections: 4/12/1995-5/16/1995;
Date of issuance of NIDPOE letter[B]: 11/6/1998;
Date of issuance of NOOH letter[C]: 8/16/1999;
Date of outcome: 5/20/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Check];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 7;
FDA Center[A]: CDER;
Dates of Inspections: 7/6-16/1998;
Date of issuance of NIDPOE letter[B]: 12/23/1998;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 3/30/1999;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Check];
Basis for outcome: FDA decision[E]: [Check];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 8;
FDA Center[A]: CDER;
Dates of Inspections: 2/5/1998-3/12/1998;
Date of issuance of NIDPOE letter[B]: 5/19/1999;
Date of issuance of NOOH letter[C]: 2/19/2000;
Date of outcome: 1/12/2004;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check][F];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 9;
FDA Center[A]: CBER;
Dates of Inspections: 12/7-9/1999;
Date of issuance of NIDPOE letter[B]: 4/6/2000;
Date of issuance of NOOH letter[C]: 1/8/2002;
Date of outcome: 4/4/2003;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 10;
FDA Center[A]: CDER;
Dates of Inspections: 10/5/1999-11/11/1999;
Date of issuance of NIDPOE letter[B]: 4/7/2000;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 6/19/2002;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check][F];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 11;
FDA Center[A]: CBER;
Dates of Inspections: 7/12/1999-9/15/1999;
Date of issuance of NIDPOE letter[B]: 6/30/2000[H];
Date of issuance of NOOH letter[C]: 11/1/2002;
Date of outcome: 10/23/2006;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Check];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 12;
FDA Center[A]: CDER;
Dates of Inspections: 11/22/1999-3/15/2000;
Date of issuance of NIDPOE letter[B]: 8/21/2000;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 8/23/2002;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check][F];
Outcome: Neither disqualified nor restricted:
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 13;
FDA Center[A]: CDER;
Dates of Inspections: 4/12/1999-8/4/1999; 2/27/2001-3/8/2001;
Date of issuance of NIDPOE letter[B]: 9/13/2000[I];
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 1/10/2005;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 14;
FDA Center[A]: CBER;
Dates of Inspections: 11/30/1999-1/19/2000;
Date of issuance of NIDPOE letter[B]: 11/30/2000;
Date of issuance of NOOH letter[C]: 2/8/2002;
Date of outcome: 2/9/2005;
Outcome: Disqualified to receive drugs and biologics: v
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Check].
Proceeding: 15;
FDA Center[A]: CDER;
Dates of Inspections: 5/30/2000-6/27/2000;
Date of issuance of NIDPOE letter[B]: 4/13/2001;
Date of issuance of NOOH letter[C]: 11/28/2003;
Date of outcome: 2/5/2004;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 16;
FDA Center[A]: CDRH;
Dates of Inspections: 3/14/2001-4/18/2001;
Date of issuance of NIDPOE letter[B]: 5/11/2001;
Date of issuance of NOOH letter[C]: 1/8/2002;
Date of outcome: 6/18/2002;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Check];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 17;
FDA Center[A]: CBER;
Dates of Inspections: 7/17/2000-8/4/2000;
Date of issuance of NIDPOE letter[B]: 6/21/2001;
Date of issuance of NOOH letter[C]: 5/21/2002;
Date of outcome: pending[J];
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 18;
FDA Center[A]: CDER;
Dates of Inspections: 5/30/2000-6/27/2000;
Date of issuance of NIDPOE letter[B]: 6/27/2001;
Date of issuance of NOOH letter[C]: 6/3/2002;
Date of outcome: 9/24/2003;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Check];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 19;
FDA Center[A]: CDER;
Dates of Inspections: 8/14-23/2001;
Date of issuance of NIDPOE letter[B]: 6/27/2002;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 12/12/2002;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 20;
FDA Center[A]: CDER;
Dates of Inspections: 5/12/1998-7/21/1998;
Date of issuance of NIDPOE letter[B]: 10/23/2002;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 8/11/2003;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check][F];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 21;
FDA Center[A]: CBER;
Dates of Inspections: 8/22/2001-11/16/2001;
Date of issuance of NIDPOE letter[B]: 11/6/2002;
Date of issuance of NOOH letter[C]: 10/9/2003;
Date of outcome: 1/9/2007;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 22;
FDA Center[A]: CBER;
Dates of Inspections: 7/19/2002-9/6/2002;
Date of issuance of NIDPOE letter[B]: 6/23/2003;
Date of issuance of NOOH letter[C]: 2/4/2004;
Date of outcome: 3/14/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Check];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 23;
FDA Center[A]: CDER;
Dates of Inspections: 7/23/2001-8/28/2001;
Date of issuance of NIDPOE letter[B]: 12/3/2003;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: pending[K];
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 24;
FDA Center[A]: CDRH;
Dates of Inspections: 5/2-21/2003;
Date of issuance of NIDPOE letter[B]: 3/9/2004;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 2/8/2005;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 25;
FDA Center[A]: CDRH;
Dates of Inspections: 6/2-6/2003;
Date of issuance of NIDPOE letter[B]: 3/11/2004;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 2/8/2005;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 26;
FDA Center[A]: CBER;
Dates of Inspections: 4/1-18/2003;
Date of issuance of NIDPOE letter[B]: 4/22/2004;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 10/3/2004;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 27;
FDA Center[A]: CDRH;
Dates of Inspections: 4/11/2003-5/13/2003;
Date of issuance of NIDPOE letter[B]: 5/5/2004;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 4/10/2005;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 28;
FDA Center[A]: CDER;
Dates of Inspections: 2/19/2002-4/3/2002;
Date of issuance of NIDPOE letter[B]: 6/10/2004;
Date of issuance of NOOH letter[C]: 3/8/2006;
Date of outcome: 5/11/2006;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 29;
FDA Center[A]: CDER;
Dates of Inspections: 2/26/2002-3/29/2002;
Date of issuance of NIDPOE letter[B]: 1/27/2003-2/14/2003;
6/8/2004[L];
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 11/28/2005;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 30;
FDA Center[A]: CDER;
Dates of Inspections: 6/1-22/2000;
Date of issuance of NIDPOE letter[B]: 8/17/2004;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 1/14/2005;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check][F];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 31;
FDA Center[A]: CDER;
Dates of Inspections: 11/14/2002-1/03/2003;
Date of issuance of NIDPOE letter[B]: 9/22/2004;
Date of issuance of NOOH letter[C]: 8/14/2007;
Date of outcome: 8/25/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Check];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 32;
FDA Center[A]: CDRH;
Dates of Inspections: 7/29/2002-8/9/2002; 12/3-12/2002;
1/27/2003-2/6/2003;
Date of issuance of NIDPOE letter[B]: 9/30/2004;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 4/15/2005;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check][F];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 33;
FDA Center[A]: CDER;
Dates of Inspections: 10/21-25/2002;
Date of issuance of NIDPOE letter[B]: 1/19/2005;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 6/23/2008;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 34;
FDA Center[A]: CDER;
Dates of Inspections: 3/11-14/2002;
Date of issuance of NIDPOE letter[B]: 3/1/2005;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 1/9/2006;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 35;
FDA Center[A]: CDER;
Dates of Inspections: 7/24/2003-8/6/2003;
Date of issuance of NIDPOE letter[B]: 8/24/2005;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 9/29/2005;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 36;
FDA Center[A]: CDRH;
Dates of Inspections: 2/17/2004-3/23/2004; 3/30/2004-4/1/2004;
10/21/2005;
Date of issuance of NIDPOE letter[B]:
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 7/19/2006;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check]; [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 37;
FDA Center[A]: CDER;
Dates of Inspections: 3/10/2003-4/3/2003;
Date of issuance of NIDPOE letter[B]: 1/20/2006;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 10/11/2006;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 38;
FDA Center[A]: CDER;
Dates of Inspections: 3/4-10/2005;
Date of issuance of NIDPOE letter[B]: 5/10/2006;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 2/21/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 39;
FDA Center[A]: CDER;
Dates of Inspections: 7/29/2002-8/28/2002;
Date of issuance of NIDPOE letter[B]: 5/11/2006;
Date of issuance of NOOH letter[C]: pending[M];
Date of outcome: pending[M];
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 40;
FDA Center[A]: CDER;
Dates of Inspections: 10/15-24/2002;
Date of issuance of NIDPOE letter[B]: 5/18/2006;
Date of issuance of NOOH letter[C]: 12/21/2007;
Date of outcome: 5/8/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Check];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 41;
FDA Center[A]: CBER;
Dates of Inspections: 2/8-28/2005; 3/16/2005-8/2/2005;
Date of issuance of NIDPOE letter[B]: 1/24/2007;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 5/18/2007;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 42;
FDA Center[A]: CDER;
Dates of Inspections: 1/9-21/2004;
Date of issuance of NIDPOE letter[B]: 5/9/2007;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 5/5/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 43;
FDA Center[A]: CDRH;
Dates of Inspections: 10/17-20/2006;
Date of issuance of NIDPOE letter[B]: 7/31/2007;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 10/12/2007;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Check];
Basis for outcome: FDA decision[E]: [Check];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 44;
FDA Center[A]: CDER;
Dates of Inspections: 2/16/2005-4/6/2005;
Date of issuance of NIDPOE letter[B]: 8/15/2007;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 9/10/2007;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 45;
FDA Center[A]: CDER;
Dates of Inspections: 8/25/2003-9/3/2003;
Date of issuance of NIDPOE letter[B]: 8/29/2007;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 4/24/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 46;
FDA Center[A]: CDER;
Dates of Inspections: 10/25/2006-2/7/2007;
Date of issuance of NIDPOE letter[B]: 9/27/2007;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 2/12/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted:
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 47;
FDA Center[A]: CBER;
Dates of Inspections: 6/16/2005-7/22/2005;
Date of issuance of NIDPOE letter[B]: 11/9/2007;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 4/28/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 48;
FDA Center[A]: CDER;
Dates of Inspections: 8/2/2004-12/8/2004;
Date of issuance of NIDPOE letter[B]: 1/24/2008;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 7/25/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 49;
FDA Center[A]: CDER;
Dates of Inspections: 5/17/2005-6/7/2005;
Date of issuance of NIDPOE letter[B]: 2/21/2008;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 8/25/2008;
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Check];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 50;
FDA Center[A]: CDER;
Dates of Inspections: 3/22/2007-4/18/2007;
Date of issuance of NIDPOE letter[B]: 3/31/2008;
Date of issuance of NOOH letter[C]: pending[N];
Date of outcome: pending[N];
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 51;
FDA Center[A]: CDER;
Dates of Inspections: 1/22/2008-2/25/2008;
Date of issuance of NIDPOE letter[B]: 8/25/2008;
Date of issuance of NOOH letter[C]: N/A;
Date of outcome: 9/22/2008;
Outcome: Disqualified to receive drugs and biologics: [Check];
Outcome: Disqualified to receive devices: [Check];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Check];
Basis for outcome: Settlement agreement: [Empty].
Proceeding: 52;
FDA Center[A]: CBER;
Dates of Inspections: 5/8-12/2006;
Date of issuance of NIDPOE letter[B]: 9/18-21/2006;
8/27/2008;
Date of issuance of NOOH letter[C]: pending[O];
Date of outcome: pending[O];
Outcome: Disqualified to receive drugs and biologics: [Empty];
Outcome: Disqualified to receive devices: [Empty];
Outcome: Restricted[D]: [Empty];
Outcome: Neither disqualified nor restricted: [Empty];
Basis for outcome: FDA decision[E]: [Empty];
Basis for outcome: Consent agreement: [Empty];
Basis for outcome: Settlement agreement: [Empty].
Source: GAO analysis of data from FDA.
N/A = not applicable:
Notes: This table shows all proceedings initiated by a NIDPOE letter
from January 1, 1998, through September 9, 2008. We defined a
disqualification proceeding as pending if, as of the last date of our
file review (Nov. 5, 2008), FDA had issued a NIDPOE letter, but had not
concluded the disqualification proceeding. One clinical investigator
died after the inspection upon which the allegations in the NIDPOE
letter were based, but before receiving the NIDPOE letter; this
investigator's case is not included. Clinical investigators who were
disqualified from receiving drugs and biologics and from receiving
devices were also disqualified from receiving any FDA-regulated
investigational products, including food additives and animal drugs.
[A] The FDA centers that pursued disqualification of clinical
investigators in our review were CDER, CBER, and CDRH.
[B] FDA issues a NIDPOE letter to initiate a disqualification
proceeding. The NIDPOE letter details FDA's allegations of misconduct
based on its findings during one or more inspections and offers the
clinical investigator an opportunity to respond to the allegations in
writing or in an informal conference.
[C] FDA uses a NOOH letter to provide a clinical investigator an
opportunity for a regulatory hearing as part of a disqualification
proceeding.
[D] When a clinical investigator was restricted, the clinical
investigator agreed to certain restrictions on his or her research when
entering a consent agreement with FDA or a settlement agreement
negotiated with the Department of Justice.
[E] FDA decisions include decisions by the Commissioner (or delegate)
to disqualify a clinical investigator and decisions by the responsible
center to neither disqualify nor restrict the clinical investigator,
based on the center's finding that the investigator's explanation for
all of the allegations in the NIDPOE letter was satisfactory.
[F] This disqualification proceeding was concluded when the clinical
investigator and FDA entered a consent agreement that specified
restrictions to the investigator's activities. The restrictions were
subsequently removed because, under the terms of the consent agreement,
they no longer applied.
[G] This investigator was prohibited from receiving investigational
drugs, biologics, devices, and other FDA-regulated products as part of
a plea agreement in a criminal proceeding. FDA continued the
disqualification proceeding against this investigator after he entered
the plea agreement. FDA officials told us that they concluded that the
terms of the plea agreement would not be enforceable after about 3
years and they continued the disqualification proceeding.
[H] FDA issued an amendment to the NIDPOE letter, which detailed
additional allegations of misconduct, on August 17, 2001.
[I] FDA issued an amendment to the NIDPOE letter, which detailed
additional allegations of misconduct, on June 23, 2003.
[J] This disqualification proceeding was pending as of November 5,
2008, when we completed our review of files, but has since been
concluded. This clinical investigator was disqualified from receiving
investigational drugs and biologics through a Commissioner's decision
on January 8, 2009.
[K] This disqualification proceeding remained pending as of September
1, 2009.
[L] FDA re-issued this NIDPOE letter on July 20, 2004, after learning
that the original address was not correct.
[M] This disqualification proceeding was pending as of November 5,
2008, which was the last date of our file review. This clinical
investigator was issued a NOOH letter on July 1, 2009. This
disqualification proceeding remained pending as of September 1, 2009.
[N] This disqualification proceeding was pending as of November 5,
2008, which was the last date of our file review, but has since been
concluded. This clinical investigator was issued a NOOH letter on March
4, 2009, and was disqualified from receiving investigational drugs,
biologics, devices, and other FDA-regulated investigational products,
including food additives and animal drugs, through a consent agreement
on May 4, 2009.
[O] This disqualification proceeding was pending as of November 5,
2008, which was the last date of our file review, but has since been
concluded. This clinical investigator was issued a NOOH letter on
February 13, 2009; the NOOH letter was re-issued on March 9, 2009,
after the agency learned that the investigator had not received the
letter. This clinical investigator was disqualified from receiving
investigational drugs and biologics through a Commissioner's decision
on August 6, 2009.
[End of table]
[End of section]
Appendix VI: Types of Alleged Misconduct Cited in FDA's Initiation of
Disqualification Proceedings:
Common types of alleged misconduct cited in NIDPOE letters issued by
FDA from January 1, 1998, through September 9, 2008, included:
* Submitting false information to the sponsor or to FDA;
* Failure to comply with requirements related to obtaining informed
consent from clinical trial participants;
* Failure to comply with requirements to obtain initial or continuing
approval from an institutional review board;
* Failure to follow the clinical trial's research plan;
* Failure to comply with requirements regarding the disposition of
investigational drugs, biologics, or devices, such as maintaining
records of their use; and:
* Failure to comply with requirements to prepare or maintain case
histories or other records.
Specific examples of the types of alleged misconduct detailed in the
NIDPOE letters for the 45 completed proceedings that we reviewed that
ended in disqualification (including restrictions) are shown in table
1.
Table 1: Examples of Misconduct Allegations Cited in NIDPOE Letters:
Letter: 1;
Specific example of alleged misconduct: Failed to maintain adequate and
accurate case histories that recorded all observations and other data
pertinent to a clinical trial of an investigational drug.
Letter: 2;
Specific example of alleged misconduct: Failed to obtain approval from
the institutional review board for a verbal informed consent procedure
that was used with the participants in a clinical trial of an
investigational drug.
Letter: 3;
Specific example of alleged misconduct: Failed to maintain adequate and
accurate records by inaccurately reporting that four clinical trial
participants had been using a stable dose of a medication for a minimum
of 7 days prior to their respective screening visit dates.
Letter: 4;
Specific example of alleged misconduct: Enrolled 390 high-risk
participants in a clinical trial of an investigational test kit, even
though the protocol and conditions of approval by the institutional
review board limited the number of enrolled high-risk participants to
200.
Letter: 5;
Specific example of alleged misconduct: Failed to report to the
institutional review board unanticipated adverse effects, including
chronic and severe pain, experienced by several clinical trial
participants after implantation of an investigational medical device.
Letter: 6;
Specific example of alleged misconduct: Failed to evaluate adverse
events in a timely manner or to take appropriate action to protect
participants in clinical trials of an investigational drug who
experienced adverse events, including failing to take appropriate
actions to evaluate the adverse reactions reported by one clinical
trial participant for more than 6 months.
Letter: 7;
Specific example of alleged misconduct: Submitted false information in
a required report to the sponsor of an investigational drug by
submitting case report forms for over 200 clinical trial participants
who had not, in fact, participated in the clinical trial.
Letter: 8;
Specific example of alleged misconduct: Failed to report to the sponsor
adverse events, including headache, fever, and palpitations, that were
experienced by participants in clinical trials of an investigational
drug intended for the treatment of ear infection.
Letter: 9;
Specific example of alleged misconduct: Failed to maintain any records
accounting for the use of investigational biologics in two clinical
trials that involved 5 and 28 clinical trial participants,
respectively.
Letter: 10;
Specific example of alleged misconduct: Failed to institute corrective
actions in response to repeated letters sent over a period of 11 months
by the sponsors of investigational drugs concerning violations of the
protocols for clinical trials, discrepancies in required documentation,
and missing medical records.
Letter: 11;
Specific example of alleged misconduct: Failed to document the
occurrence and follow-up of serious adverse events (including
hospitalizations) experienced by infant participants in a clinical
trial of an investigational vaccine.
Letter: 12;
Specific example of alleged misconduct: Submitted false information to
the sponsor of an investigational drug by submitting data from sputum
samples that did not come from the actual clinical trial participants.
Letter: 13;
Specific example of alleged misconduct: Failed to recognize or evaluate
adverse events in a timely manner and failed to take appropriate action
to protect those who experienced adverse events, including continuing
to provide an investigational drug to a clinical trial participant who
experienced multiple signs and symptoms of myocardial injury and drug
toxicity until one day before his death, about 3 weeks after he began
participating in the clinical trial.
Letter: 14;
Specific example of alleged misconduct: Failed to supervise the
clinical trial of an investigational drug, allowing the study
coordinator--who was not licensed as a physician in the state in which
the trial occurred--to write medical orders that were not co-signed by
a licensed physician.
Letter: 15;
Specific example of alleged misconduct: Enrolled an individual with a
duodenal ulcer (but no gastric ulcer) in a clinical trial of an
investigational drug intended for use with patients with gastric ulcer,
even though the protocol stated that only patients with a gastric ulcer
were eligible to participate.
Letter: 16;
Specific example of alleged misconduct: Failed to seek approval from
the institutional review board for changing the protocol for a clinical
trial of an investigational drug to allow enrollment of participants
who, according to the approved protocol, should have been excluded from
the clinical trial.
Letter: 17;
Specific example of alleged misconduct: Failed to provide FDA with
required information identifying sub-investigators.
Letter: 18;
Specific example of alleged misconduct: Maintained two separate sets of
medical records for clinical trial participants that covered the same
time period, with one set of records (which were for his private
practice) documenting that several participants had pre-existing
conditions that should have precluded their enrollment in the study.
Letter: 19;
Specific example of alleged misconduct: Stored an investigational drug
that was a controlled substance in an unlocked cabinet, thereby failing
to take adequate precautions to prevent diversion of the controlled
substance into illegal channels of distribution.
Letter: 20;
Specific example of alleged misconduct: Enrolled a clinical trial
participant in a study for which he was ineligible because of impaired
liver and renal function, gave the participant an investigational drug
that likely contributed to his death, and altered laboratory results in
the report to the sponsor to make it appear that the participant was
eligible for enrollment.
Letter: 21;
Specific example of alleged misconduct: Failed to report to the
institutional review board unanticipated problems that involved risks
to humans in a timely manner, including failing to report for nearly 2
years that a participant in a clinical trial of an investigational drug
experienced acute renal failure.
Letter: 22;
Specific example of alleged misconduct: Allowed participants enrolled
in clinical trials of an investigational drug to continue taking
medications that, according to the protocol, were prohibited during
their participation.
Letter: 23;
Specific example of alleged misconduct: Submitted false information to
the sponsor of an investigational drug by submitting reports based on
medical records for clinical trial participants that had been written
more than one year after the events they ostensibly described.
Letter: 24;
Specific example of alleged misconduct: Failed to meet a requirement of
reporting the number of eyes treated by an investigational medical
device to FDA.
Letter: 25;
Specific example of alleged misconduct: Exported an investigational new
drug to unauthorized personnel in other countries and charged or
received payment from overseas contacts in return for the use of the
investigational drug without seeking FDA's approval or authorization to
export the investigational drug or to charge for it.
Letter: 26;
Specific example of alleged misconduct: Delegated certain tasks
associated with a clinical trial of an investigational vaccine,
including performing physical examinations and post-vaccination
observations, to individuals who were not qualified to perform them.
Letter: 27;
Specific example of alleged misconduct: Failed to properly train and
supervise sub-investigators and other staff involved in a clinical
trial of an investigational biologic for infants, for example, by
failing to inform an individual who administered the investigational
biologic that he was to obtain information about serious adverse
experiences.
Letter: 28;
Specific example of alleged misconduct: Failed to submit blood samples
taken from clinical trial participants to a laboratory for testing to
evaluate the presence of clinically significant abnormal values as
required by the protocols for two clinical trials of an investigational
drug.
Letter: 29;
Specific example of alleged misconduct: Failed to obtain informed
consent from 30 participants prior to enrolling them in a clinical
trial of an investigational drug and instructed a staff member to
backdate informed consent documents for 8 of them.
Letter: 30;
Specific example of alleged misconduct: Submitted false information to
the sponsor of an investigational drug by fabricating all records
associated with seven fictitious clinical trial participants, including
forging consent forms, fabricating medical information, and knowingly
and willingly submitting blood and urine samples, supposedly from these
participants, but actually taken from surplus specimens from patients
in his clinical practice.
Letter: 31;
Specific example of alleged misconduct: Failed to report serious
adverse events, including deaths, to an institutional review board
until months after their occurrence, even though the institutional
review board had specifically required immediate reporting of any
unanticipated problems, injuries, or deaths.
Letter: 32;
Specific example of alleged misconduct: Failed to obtain information
about adverse events experienced by the participants in a clinical
trial of an investigational drug, even though the protocol required
collection of this information.
Letter: 33;
Specific example of alleged misconduct: Administered an investigational
new vaccine that was obtained by an unapproved process to three
clinical trial participants--one of whom later died--without
authorization to administer that drug to human participants.
Letter: 34;
Specific example of alleged misconduct: Submitted false information to
investigational drug sponsors and to the FDA by reporting that he had a
Ph.D. degree or a family nurse practitioner degree when, in fact, he
did not have valid degrees of either type.
Letter: 35;
Specific example of alleged misconduct: Continued to include
participants in a clinical trial of an investigational drug after
documenting that they had reactions such as pain that, according to the
protocol, should have led to termination of their participation.
Letter: 36;
Specific example of alleged misconduct: Failed to ensure and document
that all clinical trial participants were aware that a device was
investigational prior to surgically implanting it.
Letter: 37;
Specific example of alleged misconduct: Failed to supervise clinical
trials, causing submission of false information (electrocardiograms
that had been altered to appear to have been recorded at a different
time than they actually were) to the sponsor of an investigational
drug.
Letter: 38;
Specific example of alleged misconduct: Failed to obtain written
informed consent from three participants in a clinical trial of an
investigational drug and falsified their signatures on informed consent
documents some time after their enrollment in the trial.
Letter: 39;
Specific example of alleged misconduct: Gave participants in a clinical
trial of an investigational drug amounts of the investigational drug
that differed from those specified by the protocol.
Letter: 40;
Specific example of alleged misconduct: Did not have or provide to FDA
a complete list of the clinical trial participants in whom an
investigational medical device had been implanted.
Letter: 41;
Specific example of alleged misconduct: Delegated responsibilities that
included screening and enrolling clinical trial participants to a study
coordinator who lacked the medical training necessary to perform those
functions and failed to supervise the study coordinator, resulting in
enrollment of two participants who, for safety reasons, should have
been excluded from the clinical trial of an investigational drug.
Letter: 42;
Specific example of alleged misconduct: Failed to document that
informed consent was obtained from all clinical trial participants and
that all participants met the enrollment eligibility criteria for a
clinical trial of an investigational device.
Letter: 43;
Specific example of alleged misconduct: Failed to obtain approval of
the protocol for a clinical trial of an investigational drug from the
institutional review board before initiating it.
Letter: 44;
Specific example of alleged misconduct: Submitted inaccurate and
misleading reports to the institutional review board regarding the
safety of a clinical trial of an investigational biologic.
Letter: 45;
Specific example of alleged misconduct: Failed to maintain adequate and
accurate case histories of participants in clinical trials of
investigational drugs by making changes to records without documenting
why or by whom these changes were made.
Source: GAO analysis of data from FDA.
Notes: A NIDPOE letter provides a clinical investigator with notice of
initiation of a disqualification proceeding and details FDA's
allegations of misconduct based on its findings during one or more
inspections of the clinical investigator's conduct of one or more
clinical trials. This letter offers the clinical investigator a chance
to respond in writing or meet informally with FDA officials to discuss
the alleged violations. FDA may determine not to pursue
disqualification based on certain allegations cited in the NIDPOE
letter after FDA's evaluation of the clinical investigator's response.
The 45 NIDPOE letters covered in this table were issued by FDA from
January 1, 1998, through September 9, 2008, for disqualification
proceedings that ended in disqualification (including restrictions).
[End of table]
[End of section]
Appendix VII: Comments from the Department of Health and Human
Services:
Department Of Health & Human Services:
Office Of The Secretary:
Assistant Secretary for Legislation:
Washington, DC 20201:
September 8, 2009:
Marcia Crosse:
Director, Health Care:
U.S. Government Accountability Office:
441 G Street N.W.
Washington, DC 20548:
Dear Ms. Crosse:
Enclosed are comments on the U.S. Government Accountability Office's
(GAO) report entitled: Oversight Of Clinical Investigators: Action
Needed to Improve Timeliness and Enhance Scope of FDA's Debarment and
Disqualification Processes for Medical Product Investigators (GAO-09-
807).
The Department appreciates the opportunity to review this report before
its publication.
Sincerely,
Signed by:
Andrea Palm:
Acting Assistant Secretary for Legislation:
Enclosure:
[End of letter]
FDA's General Comments to the GAO Draft Report Entitled, Oversight of
Clinical Investigators: Action Needed to Improve Timeliness and Enhance
Scone of FDA's Debarment and Disqualification Processes for Medical
Product Investigators (GAO-09-807):
The Food and Drug Administration (FDA or Agency) appreciates the
opportunity to review and comment on the Government Accountability
Office's (GAO) draft report. Clinical investigator disqualification and
debarment are key remedial measures used by the Agency to protect the
public health. Prohibiting certain individuals from being involved in
the clinical trial process for medical products is critical to
protecting research subjects and ensuring the integrity and reliability
of data used to support Agency decision making. Disqualification and
debarment matters are therefore a high priority for the Agency, and FDA
has made strides over the last two years to improve the processes for
both of these important administrative actions. The Agency appreciates
GAO's recommendations for improvement and will endeavor to incorporate
them into its new procedures.
In 2006, FDA launched its Human Subject Protection/Bioresearch
Monitoring Initiative)[Footnote 63]. As part of this initiative, FDA is
scrutinizing its oversight of clinical trials, including clinical
investigator disqualification and debarment proceedings. As recently
noted by the Agency[Footnote 64] and discussed below, FDA has greatly
improved its handling of these important remedial actions. FDA has also
made the processes and final determinations more transparent to help
ensure that individuals found to be non-compliant do not continue to be
involved in new product development.
Clinical Investigator Disqualification:
FDA's disqualification processes and associated time frames have
improved considerably in the recent past. Over the last two years, the
Agency has revamped its procedures and processes to provide uniformity,
efficiency, and effective oversight of the Agency's handling of
disqualification matters. Making the disqualification process more
uniform throughout FDA and adding targeted time frames for the various
steps in the process is facilitating timely resolution of
disqualification actions. FDA has also engaged in a number of other
activities to improve the clinical investigator disqualification
process and protect the public health.
Procedures:
Recognizing that recommended time frames and identified staff would
strengthen its ability to conclude disqualification actions more
efficiently, FDA created new procedures and updated existing ones. FDA
revised its Regulatory Procedures Manual (RPM), Chapter 5, to include a
new section (5-9) ” "Disqualification of Clinical Investigators".
[Footnote 65] This new section identifies responsibilities and time
frames from the clinical investigator site inspection (found to have
serious noncompliance) through issuance of the notice of opportunity
for a hearing.
FDA also revised the compliance program chapter for clinical
investigators[Footnote 66] to include a listing of sanctions available
to FDA and examples of violations that may warrant an official action
indicated (OAI) classification. As requested by the Office of the
Inspector General, this document defines threshold criteria for issuing
warning letters and for initiating disqualification actions and
contains recommendations for enhanced communication between
headquarters and field staff.
FDA finalized Staff Manual Guide 7711 ” "Disqualification of a Clinical
Investigator: The Hearing Process".[Footnote 67] This new guideline
assigns responsibilities and time frames for each activity in the
disqualification process from the notice of opportunity for a hearing
through final Agency action. These three procedures combine to address
the disqualification process from beginning to end, adding clarity and
consistency.
Resources:
Based on its assessment of the disqualification process, FDA determined
that additional staff and certain organizational changes were critical
to the timely resolution of these actions. The Office of Good Clinical
Practice added a project manager who is responsible for managing all
disqualification matters once the investigator is offered an
opportunity for a hearing. Also, the Division of Scientific
Investigations in the Center for Drug Evaluation and Research added
several staff and realigned its Good Clinical Practice Branches. Under
the new organizational structure, some of these additional staff
members focus primarily on OAI cases, where disqualification
proceedings are initiated. The Office of the Chief Counsel also has
seen recent increases in staff. With these overall increases, FDA is
able to handle disqualification actions more expeditiously. Finally,
under the new Staff Manual Guide, FDA highlighted the fact that an
administrative law judge (AU) can be designated to serve as the
presiding officer at disqualification hearings. Although this was an
available option in the past, FDA believes this designation will
improve consistency and timeliness of the proceedings.
Tracking of Disqualification Matters:
Because there are many FDA components involved in resolving
disqualification matters, FDA developed a central tracking system and
database to help us monitor these proceedings and ensure all time
frames are met.
Outreach and Transparency:
Keeping institutional review boards (IRBs), clinical investigators,
study monitors, and sponsors informed about FDA's regulatory
requirements is critical to protecting human subjects involved in FDA-
regulated research. This includes its clinical investigator
disqualification process.
To this end, FDA is drafting guidance to explain the disqualification
process, the consequences of disqualification on the clinical
investigator, and the impact on any ongoing and completed clinical
trials in which the disqualified investigator participated.
Transparency is also a key component of FDA's disqualification process,
and FDA strives to be as transparent as possible. On FDA's web site,
FDA posts all disqualification information permitted by law, including
Commissioner's decisions, so that the basis for FDA's action is clear.
In addition, to ensure that IRBs, monitors, and study sponsors are
aware of all pending and completed disqualification actions, FDA
consolidated into one web site[Footnote 68] public information about
compliance and enforcement activities. Having all relevant
disqualification information accessible in one place will help sponsors
avoid non-compliant investigators. FDA believes these outreach efforts
will contribute to the protection of human subjects participating in
FDA-regulated trials.
Debarment:
Recognizing that debarment actions also serve as an important tool for
protecting the safety of study subjects involved in clinical trials and
the integrity of the drug approval process as a whole, in May, 2008,
FDA formed a working group to evaluate the procedures used for
debarment actions. The working group quickly concluded that the
debarment process would benefit from centralized coordination and
formal timelines and procedures aimed at facilitating Agency
communication regarding potential debarment actions and ensuring
efficiency and timeliness at every step. In March of this year, FDA
finalized Staff Manual Guide 7712 ”Debarment Proceedings (Debarment
SMG), which addresses those issues. FDA believes that consolidating
responsibilities for debarment actions and establishing written
procedures for such actions will help ensure that they are initiated
and processed in a timely, efficient, and consistent manner.[Footnote
69]
As mentioned in the GAO report, the new Debarment SMG consolidates the
responsibility for initiating and pursuing debarment actions in one
central location. In the past, the individual Centers were responsible
for initiating and pursuing debarment actions that related directly to
the Centers' product areas. Now, under the Debarment SMG, the Office of
Regulatory Affair's Office of Enforcement (OE) has the responsibility
for initiating all debarment actions for the Agency and issuing orders
where no hearing has been requested. To execute those responsibilities,
OE has recently received clearance to hire a permanent employee to work
on debarment actions. In addition, the Debarment SMG contemplates a
dedicated staff within the Office of the Commissioner for ruling on
requests for hearings and ensuring that legitimate factual disputes are
promptly referred for a hearing.
The Debarment SMG also sets forth procedures and timelines for every
step of the debarment process”from the timely internal communication of
information regarding convictions or other conduct that may trigger
debarment to the conclusion of any debarment proceeding once initiated.
Under the Debarment SMG, the Agency will now typically debar
individuals and firms within a year from the triggering conviction or
conduct. FDA notes, however, that it may be appropriate to delay
issuing a proposal for permissive debarment if the candidate for
debarment is serving time in prison. This approach would maximize the
term of the debarment period which would then begin to run as close to
the end of the prison sentence as possible.
Consistent with the Debarment SMG, OE, in consultation with other FDA
components, may issue additional standard operating procedures and
guidance for debarment actions. As noted in the GAO report, OE has
since adopted procedures for making determinations and issuing
proposals to debar and certain final debarment orders. It incorporates
the timelines found in the Debarment SMG and gives step-by-step
instructions for processing proposals and final orders issued by OE. As
contemplated by the Debarment SMG, OE also has processes in place to
regularly receive communications from the United States Department of
Justice and FDA's Office of Criminal Investigations about convictions
that could give rise to debarment. In addition, OE has drafted an
update for the RPM to detail the notification responsibilities of all
relevant FDA employees and the time frames for notification found in
the Debarment SMG. The RPM will now also outline the types of
convictions and conduct that may subject persons to debarment, to help
FDA staff identify these persons and notify OE.
In addition to the procedures reflected in the Debarment SMG and
evaluated by GAO, FDA also has begun posting pending debarment actions
on its web site in the same location as its list of debarred
individuals. Making all information regarding completed and pending
debarment proceedings available in one place should assist clinical
trial sponsors and others within the drug industry to avoid individuals
who may be subject to debarment as a result of a criminal conviction or
suspected involvement in a criminal scheme.
Responses to GAO's Recommendations:
The Agency is pleased that the GAO's recommendations reflect activities
already completed or ongoing. Below, FDA addresses each of the GAO's
recommendations.
1) Pursue debarment authority for medical devices that is consistent
with the current debarment authority for drugs and biologics and
prohibit any debarred individual from involvement with drugs,
biologics, and medical devices.
FDA's authority to prohibit suspect individuals from being involved in
the clinical trial process for drug products helps to protect research
subjects and ensure the integrity and reliability of data used to
support Agency decision making. Providing FDA with the authority to
prohibit individuals and companies convicted of certain crimes, or
otherwise involved in criminal activity, from being involved in the
medical device industry, would benefit the development and approval
process for medical devices in the same manner.
2) Amend FDA regulations to ensure that those who have engaged in
misconduct found sufficiently serious to warrant disqualification for
one investigational medical product are not able to continue to serve
as clinical investigators for any.
FDA agrees that if a clinical investigator is disqualified from
participating in clinical trials involving one type of investigational
article (e.g., drugs), it is generally appropriate that the
investigator be prohibited from participating in investigations of any
FDA-regulated product. The Agency intends to pursue revisions of its
regulations concerning clinical investigator disqualification to effect
this change.
The Agency wishes to note, however, that when FDA disqualifies a
clinical investigator, not only are the reviewing IRB and study sponsor
notified of this action, but the Agency also posts this information on
its web site to ensure that other IRBs and sponsors are fully aware of
this determination. FDA also provides such information regarding
pending actions on this same web site to ensure that sponsors and IRBs,
among others, are alerted to the alleged misconduct.
3) Monitor compliance with recently established time frames for
debarment and disqualification proceedings and take appropriate action
when those are not met.
FDA agrees that monitoring its success in meeting the newly established
time frames for clinical investigator disqualification and debarment
will be very important as FDA strives to improve its timeliness and
efficiency in all aspects of both processes. FDA acknowledges its
accountability for completing these administrative actions in a timely
and consistent manner, so that human subjects are protected and the
integrity and reliability of resulting research data are assured.
As noted in the GAO Report, more recently pursued disqualification
proceedings have taken far less time overall than those pursued in the
past. Since 2008, the Agency initiated eleven disqualification actions,
and of those, only the three initiated in 2009 are still pending. These
time frames are consistent with the targeted time frames under the new
disqualification procedures.
FDA is also beginning to see similar improvements in the debarment
process. Until this year, the Agency had averaged two or three
debarment proceedings per year over the past decade. Since March 2009,
when the new Debarment SMG went into effect, FDA has initiated
debarment proceedings against eleven individuals and completed the
debarment process for an additional individual. Of the proceedings that
have been initiated, four individuals have been debarred, three have
requested a hearing and those cases have been referred to the Office of
the Commissioner. Five individuals have been issued Proposal to Debar
notifications. With the exception of the first full year that FDA was
granted debarment authority, FDA has initiated more debarment
proceedings in the last six months than in any other year.
The GAO pointed out that, the more steps taken by an individual to
contest the disqualification or debarment, the longer it takes
generally to complete the proceeding. FDA agrees with this assessment.
Because of fundamental fairness, FDA must allow individuals to pursue
all appropriate avenues available to them to contest their
disqualification or debarment, including, on occasion, multiple filings
of motions and requests for extensions. Although FDA now has procedures
in place with recommended time frames, some disqualification and
debarment proceedings will exceed those time frames for that reason.
However, for those matters that advance consistent with its procedures,
FDA anticipates meeting its targeted time frames.
With the newly implemented procedures and dedicated resources, among
other efforts, FDA should continue to see timely and efficient
resolution of disqualification and debarment actions.
[End of section]
Appendix VIII: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov:
Staff Acknowledgments:
In addition to the contact named above, Kim Yamane, Assistant Director;
Kristen Joan Anderson; Hernán Bozzolo; Cathleen Hamann; Julian Klazkin;
Ba Lin; and Jessica C. Smith made key contributions to this report.
[End of section]
Footnotes:
[1] Investigational medical products include drugs, biologics, or
devices that are the object of clinical investigations. For the
purposes of this report, drugs refer to human drugs. Biologics include
blood, vaccines, allergenic products, certain tissues, and cellular and
gene therapies. Devices include medical devices used for the diagnosis,
cure, mitigation, treatment, or prevention of a disease. In addition to
drugs, biologics, and devices, FDA regulates other products, including
animal drugs, food additives, and cosmetics, and was recently
authorized to regulate tobacco products.
[2] Clinical investigators have responsibility for the conduct of a
particular clinical trial at one or more locations. Sub-investigators
and study coordinators work under the supervision of clinical
investigators and provide services such as recruiting and collecting
data from clinical trial participants.
[3] 21 U.S.C. § 335a. Debarment is also possible for certain criminal
convictions unrelated to the development or approval of a drug or
biologic. The drugs and biologics referred to in the statute are
included in the definition of "drug product." 21 U.S.C. § 321(dd).
[4] See, for example, U.S. House of Representatives, Committee on
Energy and Commerce, Minority Staff, FDA's Faulty Safeguards Against
Corruption: Concerns Over Debarment Use and Authority. Prepared for
Ranking Member Joe Barton (Washington, D.C.: Feb. 2008).
[5] See, for example, GAO, Scientific Research: Continued Vigilance
Critical to Protecting Human Subjects, [hyperlink,
http://www.gao.gov/products/GAO/HEHS-96-72] (Washington, D.C.: Mar. 8,
1996); GAO, Human Subjects Research: HHS Takes Steps to Strengthen
Protections, But Concerns Remain, [hyperlink,
http://www.gao.gov/products/GAO-01-775T] (Washington, D.C.: May 23,
2001); and GAO, Human Subjects Research: Undercover Tests Show the
Institutional Review Board System Is Vulnerable to Unethical
Manipulation, [hyperlink, http://www.gao.gov/products/GAO-09-448T]
(Washington, DC.: Mar. 26, 2009).
[6] See, for example, two reports by the Department of Health and Human
Services's Office of Inspector General: FDA Oversight of Clinical
Investigators, OEI-05-99-00350 (Washington, D.C.: Department of Health
and Human Services, June 2000); and The Food and Drug Administration's
Oversight of Clinical Trials, OEI-01-06-00160 (Washington, D.C.:
Department of Health and Human Services, Sept. 2007).
[7] We included sub-investigators and study coordinators because, like
clinical investigators, they interacted directly with clinical trial
participants. Clinical investigators, sub-investigators, and study
coordinators are a subset of individuals who are subject to debarment.
We excluded individuals who worked in other roles and who were
debarred, for example, we excluded a senior vice president and a
chemist whose misconduct could have affected the information available
to FDA when evaluating applications to market new drugs or biologics,
but who generally did not interact directly with clinical trial
participants.
[8] One of the study coordinators was also a sub-investigator.
[9] For completed proceedings, we used the date that the debarment
order was published in the Federal Register as the date of completion
of the debarment proceeding. For the completed proceedings we reviewed,
this date was also the effective date of the debarment order.
[10] We defined a debarment proceeding as pending if, as of the last
date of our file review (Nov. 5, 2008), FDA had issued a proposal to
debar letter, but had not completed the debarment proceeding, or if FDA
had identified an individual as one whose conviction could serve as a
basis for debarment, but for whom FDA had not yet issued a proposal to
debar letter.
[11] These standards provide an overall framework for establishing and
maintaining internal control and for identifying and addressing major
performance and management challenges and areas at greatest risk of
fraud, waste, abuse, and mismanagement. For example, under the
standards for internal control, information should be recorded and
communicated to management and others within an entity who need it and
within a time frame that enables them to carry out their internal
control and other responsibilities. See GAO, Standards for Internal
Control in the Federal Government, GAO/AIMD-00-21.3.1 (Washington,
D.C.: Nov. 1999) and its supplemental guide, Internal Control
Management and Evaluation Tool, GAO-01-1008G (Washington, D.C.: Aug.
2001).
[12] According to FDA officials, prior to 1998, the agency typically
initiated disqualification proceedings without issuing a NIDPOE letter.
[13] In August 2009, the Good Clinical Practice Program was renamed the
Office of Good Clinical Practice.
[14] An institutional review board is an entity formally designated to
review clinical trials and other research involving human subjects,
with the purpose of protecting the rights and welfare of the clinical
trial subjects. See 21 C.F.R. § 56.102(g) (2009).
[15] Pub. L. No.102-282, § 2, 106 Stat. 149-158 (1992) (codified at 21
U.S.C. § 335a).
[16] A debarred individual is prohibited from providing any service to--
that is, from involvement with--any entity (an individual, partnership,
association, or corporation) that has an approved or pending drug or
biologic application. 21 U.S.C. §§ 321(e), 335a(c)(1)(B).
[17] 21 U.S.C. §§ 321(dd); 335a(a)(2), (c)(2)(A)(ii).
[18] 21 U.S.C. § 335a(b)(2)(B)(i)(I), (c)(2)(A)(iii). FDA may also
permissively debar an individual who has not been convicted of a crime
or convicted of a crime unrelated to the development or approval of a
drug or biologic. For example, FDA may permissively debar an individual
if the individual materially participated in acts that were the basis
for another individual's conviction for certain crimes, such as a
felony conviction under state law for conduct related to the
development or approval of a drug or biologic. In such cases, FDA must
also find that the individual's behavior demonstrates a pattern of
conduct suggesting that the individual may violate other requirements
under the Federal Food, Drug, and Cosmetic Act relating to drugs or
biologics. 21 U.S.C. § 335a(b)(2)(B)(iii).
[19] 21 U.S.C. § 335a(c)(2)(A), (c)(3).
[20] As of March 2009, the Office of Enforcement--not the center--is
responsible for determining whether to pursue debarment and drafting
the proposal to debar letter.
[21] Formal hearings conducted in the course of debarment proceedings
are conducted under part 12, Title 21, Code of Federal Regulations,
2009.
[22] As of June 18, 2009, FDA had not terminated debarment for any
clinical investigators, sub-investigators, or study coordinators.
[23] 21 C.F.R. §§ 312.70, 812.119 (2008).
[24] FDA conducts inspections of clinical investigators as part of its
program to monitor the conduct of research involving investigational
medical products.
[25] According to FDA officials, the agency typically initiated
disqualification proceedings before 1998 without issuing a NIDPOE
letter. If FDA determines that the investigator's misconduct could pose
an ongoing risk to the safety and welfare of clinical trial
participants, it can take steps to suspend or restrict the study,
thereby limiting that investigator's research activities. FDA posts a
list of investigators to whom it has issued a NIDPOE letter on its Web
site, allowing sponsors and others to learn of the allegations of
misconduct, and it notifies relevant sponsors and institutional review
boards when a clinical investigator is disqualified. Other entities--
such as sponsors of clinical trials or institutional review boards--may
also take action to terminate a clinical trial or an investigator's
participation in it after misconduct has been identified. See 21 C.F.R.
§§ 56.113; 312.42(a), (b)(i); 312.56(b) (2008).
[26] Regulatory hearings conducted in the course of disqualification
proceedings are conducted under part 16, Title 21, Code of Federal
Regulations (2009).
[27] For the purposes of this report, we consider agreements that
restrict clinical investigators' activities as a form of
disqualification and we treat attempts to negotiate the terms of a
consent agreement as a form of contesting disqualification. In
determining whether to agree to restrictions to a clinical
investigator's activities, FDA officials told us that they consider
what will best ensure the protection of clinical trial participants and
the integrity of the resulting data.
[28] 21 C.F.R. §§ 312.70(f), 812.119(f) (2008).
[29] See appendix III for additional information about the debarment
proceedings we reviewed and appendix IV for information about the
misconduct cited in proposal to debar letters.
[30] For two proceedings in which the individual's conviction occurred
before FDA received debarment authority, we calculated the length of
time from the date when FDA received debarment authority--May 13, 1992.
[31] In one completed debarment proceeding that involved a study
coordinator, FDA rescinded a debarment order after the agency learned
that it had sent the proposal to debar letter to a different person
with the same name as the study coordinator. By the time that FDA
learned that the proposal to debar letter had been sent to the wrong
person, the agency had already published a debarment order and just
over 5 years had elapsed from the date of the study coordinator's
conviction. By law, FDA has 5 years from the date of an individual's
conviction to initiate a debarment action, and FDA initiates actions by
notifying the individual of the proposed debarment. After considering
the possibility of re-issuing a proposal to debar letter to the correct
individual, FDA chose not to pursue debarment against the correct
individual and rescinded the published debarment order. In our
analysis, we treated this proceeding as completed and calculated that
it took about 5 years from conviction to FDA's publication of the
debarment order.
[32] After we completed our review of FDA's debarment files, FDA
debarred the individuals involved in five of the seven pending
debarment proceedings. As of September 1, 2009, two of the debarment
proceedings in our review remained pending.
[33] FDA's file for one proceeding involving mandatory debarment did
not indicate when FDA began drafting the proposal to debar letter.
[34] Although 5 of the 18 proceedings we reviewed involved individuals
who contested debarment by requesting a formal hearing, FDA officials
informed us that the agency has never granted a formal hearing in a
debarment proceeding because no one has provided evidence demonstrating
that there were disputed issues of material fact.
[35] One of the five proceedings in which the individual received a
proposal to debar letter and requested a hearing was pending as of the
last date of our file review. For this pending proceeding, the time
that elapsed was calculated from the date on which FDA issued the
proposal to debar letter to the last date of our file review.
[36] Two of the nine proceedings in which the individual received a
proposal to debar letter and did not request a hearing were pending as
of the last date of our file review. For these pending proceedings, the
time that elapsed was calculated from the date on which FDA issued the
proposal to debar letter to the last date of our file review.
[37] The consent agreement was signed by the investigator in September
2003 and by a CDER official in May 2004.
[38] 21 U.S.C. § 335a(l)(2).
[39] We found that about 5 years elapsed between the individual's
conviction and FDA's issuance of the proposal to debar letter and about
6 years had elapsed between FDA's issuance of the proposal to debar
letter and the last day of our file review.
[40] FDA disqualified this clinical investigator through a consent
agreement as required by the investigator's plea agreement. Although
the individual was disqualified in February 1999 from receiving
investigational drugs and biologics as a clinical investigator and from
serving as a sub-investigator or an assistant in the clinical segment
of a clinical study involving investigational drugs or biologics, this
disqualification does not prevent him from participating in clinical
research in some other capacity.
[41] FDA has also taken other actions to improve its procedures related
to debarment proceedings. After we found that FDA's public debarment
list--the list available on FDA's Web site that is used by individuals
or corporations that have an approved or pending drug application and
others to identify individuals who have been debarred by FDA--contained
a misspelling of the name of an individual who was debarred on July 26,
1993, the Office of Enforcement established new procedures to improve
its process for approving and publishing debarment information on FDA's
Web site in October 2008. During the time that the debarred
individual's name was misspelled on the Web site, if an individual or
corporation that had an approved or pending drug application searched
the list for the debarred individual's name, they would not have found
a match and would not have learned of his debarment. After we notified
FDA officials of the misspelling, FDA officials said that FDA corrected
the spelling on the Web site on September 22, 2008. In January 2009,
FDA officials informed us that they had no indication that this
debarred individual has worked in a position that would violate the
terms of debarment and they had no plans to investigate his employment.
FDA's new procedures for approving and publishing FDA's public
debarment list on FDA's Web site include procedures for periodically
assessing the accuracy of published information.
[42] The staff manual guide specifies that the time frames will not
become effective until FDA clears an initial backlog of potential
debarment proceedings. FDA officials, including the official in the
Office of Enforcement responsible for leading that office's efforts to
identify relevant convictions and initiate debarment proceedings, told
us that as of June 2009 they had received information from the Office
of Criminal Investigations and had identified more than 1,600
individuals with potentially relevant convictions. FDA officials said,
however, that they had not yet identified the roles of the individuals
or determined whether their convictions provide a basis for debarment.
They said that pursuing debarment for individuals with convictions
involving misconduct with a clear impact on the drug or biologic
approval process or who are working for a company that has submitted a
drug or biologic application to FDA will be the Office of Enforcement's
highest priority and that they estimate clearing the backlog of such
individuals within 6 months using the time frames set forth in the
staff manual guide. FDA officials said that the estimate is based on a
number of factors, including the availability of a staff member to work
exclusively on debarment proceedings.
[43] According to the official in the Office of Enforcement who will
oversee implementation of the new staff manual guide policies and
procedures, the Office of Enforcement received clearance to fill this
position in August 2009, but FDA had not filled the position as of
September 1, 2009. While waiting for clearance of that announcement,
FDA announced a temporary opening for an FDA employee to assume
debarment-related responsibilities. This official told us that an FDA
employee began acting in this temporary position in June 2009.
[44] See appendix V for additional information about the
disqualification proceedings we reviewed and appendix VI for
information about the allegations of misconduct included in the NIDPOE
letters used to initiate these disqualification proceedings.
[45] We defined a disqualification proceeding as pending if, as of the
last date of our file review (Nov. 5, 2008), FDA had issued a NIDPOE
letter, but had not concluded the disqualification proceeding. After we
completed our review of FDA's disqualification files, FDA disqualified
the clinical investigators involved in three of the five pending
disqualification proceedings. As of September 1, 2009, two of the
disqualification proceedings in our review remained pending.
[46] In one proceeding for which the clinical investigator requested a
hearing, the investigator was prohibited from receiving investigational
drugs, biologics, devices, and other FDA-regulated products as part of
a plea agreement in a criminal proceeding. This investigator entered
the plea agreement after an FDA hearing had begun and FDA continued the
disqualification proceeding. FDA officials told us that they concluded
that the terms of the plea agreement would not be enforceable after
about 3 years. The presiding officer recommended disqualification, and
the investigator requested a Commissioner's review. Just over 5 years
after the investigator requested a Commissioner's review--9.5 years
after issuance of the NIDPOE letter--FDA completed this
disqualification proceeding with a Commissioner's decision to
disqualify the investigator. We calculated the length of time this
disqualification proceeding took from issuance of the NIDPOE letter to
the date of the Commissioner's disqualification decision.
[47] Responsibility for disqualification proceedings that involved
hearings had been assigned to the Office of Health Affairs until 1999
and to the Office of the Ombudsman from 1999 until responsibility was
re-assigned to the Good Clinical Practice Program starting in spring of
2008. FDA officials told us that they re-assigned these
responsibilities to the Good Clinical Practice Program because of that
office's broader role within the agency as the focal point for issues
arising in human research trials regulated by FDA.
[48] These three presiding officer's reports were issued before FDA
issued the staff manual guide specifying the 90-day time frame for
issuance of presiding officer's reports.
[49] For the disqualification proceedings we reviewed, the length of
time from the last day of the inspection to issuance of the NIDPOE
letter ranged from 23 days to more than 4 years, with a median of just
over 1 year. In response to recommendations by the Department of Health
and Human Services's Office of Inspector General and to help improve
the efficiency and consistency of its initiation of disqualification
proceedings, FDA issued new guidance in December 2008 that clarifies
the circumstances under which disqualification should be considered and
specifies procedures for communication between the staff who conduct
inspections and the staff who are responsible for initiating
disqualification proceedings.
[50] FDA disqualified this individual from receiving investigational
devices as a clinical investigator and imposed a civil money penalty on
the individual and his company of $1.1 million. This individual
continued to function as a sponsor of an FDA-regulated device.
[51] 21 C.F.R. §§ 312.70 (drugs and biologics), 812.119 (devices)
(2008).
[52] See appendix V for more information about the products that
clinical investigators were disqualified from receiving.
[53] In addition to disqualifications based on decisions by the
Commissioner or consent agreements, one clinical investigator agreed to
restrictions on his research activities as part of a settlement
agreement negotiated with the Department of Justice on behalf of the
FDA and other components of the Department of Health and Human
Services. Also, FDA found the explanations offered by two clinical
investigators satisfactory and concluded their disqualification
proceedings without disqualification.
[54] Clinical investigators agree with the sponsor of an
investigational product to take responsibility for the conduct of a
particular study at one or more locations. Sub-investigators work under
the supervision of clinical investigators. Study coordinators work for
the investigators and typically interact directly with clinical trial
participants. We included sub-investigators and study coordinators
because, like clinical investigators, they interact directly with
clinical trial participants. Individuals in any of these roles may be
debarred for certain misconduct related to the development, approval,
or regulation of any drug or biologic.
[55] For example, we found that FDA's Web site did not spell the name
of one debarred individual as it was spelled in Federal Register
notices. After we inquired about the discrepancy, FDA corrected the
spelling on its Web site.
[56] We defined a debarment proceeding as pending if, as of the last
date of our file review (Nov. 5, 2008), FDA had issued a proposal to
debar letter, but had not completed the debarment proceeding, or if FDA
had identified an individual as one whose conviction could serve as a
basis for debarment, but for whom FDA had not issued a proposal to
debar letter. Of the 18 completed or pending proceedings we identified,
one of the study coordinators was also a sub-investigator.
[57] In addition to the 18 debarment proceedings we identified, CDER
also identified two individuals--a clinical investigator and a sub-
investigator--who were convicted of relevant crimes, but who died while
FDA was considering debarment. In addition, CDER officials told us that
they did not debar one other clinical investigator who was convicted of
a relevant crime because the staff responsible for debarments did not
learn about the clinical investigator's conviction until more than 5
years after the conviction and the law governing debarment specifies
that FDA must initiate debarment proceedings within 5 years of the date
of conviction. We did not include these three additional proceedings in
our analyses.
[58] According to FDA officials, the agency typically initiated
disqualification proceedings before 1998 without issuing a NIDPOE
letter.
[59] For example, we found that FDA's Web site did not accurately list
the date on which 11 clinical investigators were disqualified. After we
inquired about the discrepancies, FDA corrected the dates on its Web
site.
[60] In addition to disqualification proceedings initiated with a
NIDPOE letter, clinical investigators may be disqualified or restricted
through agreements negotiated with the Department of Justice or by
entering a consent agreement with FDA after an inspection, but without
issuance of a NIDPOE letter. In addition to the 52 disqualification
proceedings initiated with a NIDPOE letter that we included in our
review, we identified 10 proceedings in which clinical investigators
were disqualified or restricted from January 1, 1998, through September
9, 2008, without issuance of a NIDPOE letter (four through consent
agreements with FDA that were entered without issuance of a NIDPOE
letter, four through plea agreements, and two through settlement
agreements negotiated with the Department of Justice on behalf of the
FDA and other components of the Department of Health and Human
Services). In addition, we identified one NIDPOE letter, issued on
February 24, 2003, that was sent to an investigator who died after the
inspection upon which the allegations in the NIDPOE letter were based,
but before issuance of the NIDPOE letter. We did not include these
additional proceedings in our analyses.
[61] In August 2009, the Good Clinical Practice Program was renamed the
Office of Good Clinical Practice.
[62] For one proceeding in which FDA reissued the NIDPOE letter because
the initial address was no longer correct, we used the initial issuance
date for our calculations because that is the date FDA cited in the
consent agreement that concluded the proceeding. For another
proceeding, the investigator was prohibited from receiving
investigational drugs, biologics, devices, and other FDA-regulated
products as part of a plea agreement in a criminal proceeding. This
investigator entered the plea agreement after an FDA hearing had begun
and FDA continued the disqualification proceeding. FDA officials told
us that they concluded that the terms of the plea agreement would not
be enforceable after about 3 years. The presiding officer recommended
disqualification, and the investigator requested a Commissioner's
review. About 5 years after the investigator requested a Commissioner's
review--9.5 years after issuance of the NIDPOE letter--FDA completed
this disqualification proceeding with a Commissioner's decision to
disqualify the investigator. We calculated the length of time this
disqualification proceeding took from issuance of the NIDPOE letter to
the date of the Commissioner's disqualification decision.
[63] See [hyperlink,
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/20061ucm108677
.htm]. FDA issued an update on this initiative in March 2009. See
[hyperlink,
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/u
cm134452.htm].
[64] See [hyperlink,
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm176040.htm]
.
[65] See [hyperlink,
http://www.fda.govidownloads/ICECl/ComplianceManuals/RegulatoryProcedure
sManual/UCM074324.pdf]; updated chapter effective December 2008.
[66] See Compliance Program Guidance Manual (CPGM) 7348.811, Chapter
48 ” "Bioresearch Monitoring, Clinical Investigators and Sponsor-
Investigators, Guidance for FDA Staff", at [hyperlink,
http://www.fda.gov/ICECl/EnforcementActions/BioresearchMonitoring/ucm133
562.htm].
[67] See [hyperlink,
http://wwwfda.gov/AboutFDA/ReportsManualsForms/StaffManualGuides/ucm0529
28.htm]; effective June 20, 2008.
[68] See [hyperlink,
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/C
omplianceEnforcement/default.htm].
[69] See [hyperlink,
http://www.fda.gov/AboutFDA/ReportsManualsFoms/StaffManualGuides/uc12762
2.htm].
[End of section]
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