New FDA Rule Clarifies, Broadens Power to Disqualify Clinical Investigators
By Steven W. Postal, MedStar Health Research Institute at MedStar Washington Hospital Center, Washington, DC1
On April 30, 2012, the Food and Drug Administration (“FDA”) published a Final Rule (the “Rule”) clarifying and broadening its power to disqualify, via a Commissioner’s decision, clinical investigators2 (“Investigators”) who submit false information pertaining to clinical studies or that otherwise fail to abide by FDA regulations. The Rule went into effect on May 30, 2012. Although hard to quantify, clinical research impropriety and fraud has gained more press recently; this Rule closely follows the widely publicized case of alleged research misconduct and alleged fraud of Dr. Anil Potti, Investigator at Duke University.3
Specifically, the Rule amends three sections of the Code of Federal Regulations (“CFR”),4 giving the FDA the power to deny an Investigator, following an administrative proceeding, from receiving a “test article,” i.e. a drug, device, or new animal drug, for purposes of clinical research.5 Further, the Rule gives the FDA the right to disqualify an Investigator from “conduct[ing] any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA, including drugs, biologics, devices, new animal drugs, foods…dietary supplements,” and other products regulated by the agency.6 Prohibiting receipt of a test article and disqualification occur if the FDA can show that an Investigator (including a sponsor-investigator) has “repeatedly or deliberately failed to comply with” FDA regulations or has “repeatedly or deliberately” submitted false information to the FDA or the sponsor.7
September 2009 Report Notes Limitation of Prior Law, Serves as Impetus for Rule
This Rule was largely influenced by the Government Accountability Office’s (“GAO”) September 2009 report on the FDA’s oversight on Investigators (the “Report”).8 In its Report, the GAO noted that the FDA’s disqualification power via Commissioner’s decision prior to the Rule was limited and compartmentalized.9 That is, the FDA could only disqualify Investigators that had engaged in misconduct in drugs and biologics from studies in drugs and biologics, and not other FDA regulated products like devices, and vice versa.10 For example, out of nine disqualifications that the GAO reviewed in the Report, eight were disqualified from receiving investigational drugs and biologics, but not devices, while one was disqualified from receiving devices but not drugs and biologics.11 In the Report’s conclusion, the GAO stated that the FDA must have the power “to prevent clinical investigators…who engaged in serious misconduct from doing so again, whether in research that involves drugs, biologics, or devices.”12
Clarification of “Repeatedly” and “Deliberately”
The Rule clarifies what is meant by “repeatedly or deliberately.” According to the Rule, “repeatedly” means “more than once” while “deliberately” means either willfully, knowingly, or with reckless disregard.13 For example, to show that an Investigator “repeatedly or deliberately” submitted false information, the FDA must show that such a submission occurred more than once, be it “in a single study or in multiple studies,” or that the Investigator “submitted false information to the sponsor or the FDA knowingly or willfully or with reckless disregard for the truthfulness of the data submitted.”14
No Limit on How Far Back FDA Can Investigate
The Rule reiterates the FDA’s power to investigate data from disqualified Investigators without limitation on how far back the FDA can look.15 The Rule grants the FDA or the study sponsor the ability to examine the disqualified Investigator’s applications, submissions and the data contained within to search for “unreliable data that are essential to the approval of a marketing application or essential to the continued marketing of an FDA-regulated product.”16 The FDA can then “rescind clearance or withdraw approval” of the product in the event that the investigation finds that “continued approval of the project for which the data were submitted cannot be justified.”17
Clinical Hold For Drugs and Biologics
The Rule also reiterates the authority of the FDA to apply a “clinical hold”18 on an Investigator’s clinical study involving a drug or biologic following the discovery of misconduct.19 According to the CFR, a clinical hold may prevent: 1) subjects from getting the investigational drug, 2) new subjects from being recruited and enrolled and getting the investigational drug, and 3) subjects already in the study and receiving investigational drug therapy from continuing that therapy.20 In this Rule, the FDA reserves the right to apply a clinical hold for studies in which the Investigator is directly involved if the misconduct of the Investigator “poses an ongoing threat to the safety and welfare” of the subjects. 21
Withdrawal of Approval for an Investigational Device Exemption
While the FDA does not have the power to issue a clinical hold for investigational devices, the FDA does have an analogous authority to withdraw approval of an investigational device exemption (“IDE”).22 The Rule reiterates this authority as well, stating that the FDA may exercise this option if continual testing of that device “will result in an unreasonable risk to subjects.”23
Possibility of Reinstating Investigator
Lastly, the Rule reiterates that the FDA may reinstate disqualified Investigators. Further, this Rule stipulates that the FDA will publish a list of reinstated Investigators on its website.24
Opinions expressed herein are attributable to the author and are not those of MedStar Health Research Institute, MedStar Washington Hospital Center, or MedStar Health.
|2 ||An “investigator” is “an individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving a subject, or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team.” A “clinical investigation” is “any experiment that involves a test article and one or more human subjects and that either is subject to requirements for prior submission to the Food and Drug Administration under section 505(i) or 520(g) of the act, or is not subject to requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit.” See 21 CFR 50.3(c) and 21 CFR 50.3(d), available at http://www.accessdata.fda. gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.3|
This case also was a story in CBS News’ 60 Minutes. See Scott Pelley, “Deception at Duke: Fraud in Cancer Care?”[transcript] 60 Minutes, Feb. 12, 2012, available at http://www.cbsnews.com/8301-18560_162-57376073/deception-at-duke-fraud-in-cancer-care/?tag=contentMain;contentBody. See also: “Did Anil Potti, Former Duke Cancer Researcher, Conduct Research Fraud?” April 13, 2012, The Huffington Post, available at http://www.huffingtonpost.com/2012/02/13/anil-potti-duke-cancer-fraud-university-research_n_1273264.html.
“Disqualification of a Clinical Investigator,” 77 Fed. Reg. 25,354 (April 30, 2012). Available online at http://www.gpo.gov/fdsys/pkg/FR-2012-04-30/pdf/2012-10292.pdf.
Id. at 25,354.
Id. at 25,359. A sponsor is “a person who initiates a clinical investigation, but who does not actually conduct the investigation, i.e., the test article is administered or dispensed to or used involving, a subject under the immediate direction of another individual. A person other than an individual (e.g., corporation or agency) that uses one or more of its own employees to conduct a clinical investigation it has initiated is considered to be a sponsor (not a sponsor-investigator), and the employees are considered to be investigators.” See 21 CFR 50.3(e), available at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?fr=50.3.
Id., at 25,354. For the full report, see “GAO Report to Congressional Requesters — 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. http://www.gao.gov/new. items/d09807.pdf.
This contrasted with the FDA’s disqualification power via a consent agreement between the Investigator and the FDA, which was broader. See “GAO Report to Congressional Requesters,” page 41, as numerated, of the PDF.
Id. at page 2 of the PDF.
|11 ||Id. at page 40-41, as numerated, of the PDF.|
Id. at page 42-43, as numerated, of the PDF.
77 Fed. Reg. 25,354 (April 30, 2012).
|14 ||Id. at 25,355.|
A clinical hold is “an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation.” See 21 CFR 312.42(a), available at: http://www.accessdata.fda.gov/ scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.42.
77 Fed. Reg. 25,356 (April 30, 2012).
|20 ||See 21 CFR 312.42(a), available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?fr=312.42.|
|21 ||77 Fed. Reg. 25,356 (April 30, 2012).|
|22 ||An investigational device exemption “permits a device that otherwise would be required to comply with a performance standard or to have premarket approval to be shipped lawfully for the purpose of conducting investigations of that device.” See 21 CFR 812.1(a), available at http://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=812.1.|
|23 ||77 Fed. Reg. 25,356 (April 30, 2012).|
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