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Conform to the Norm: Part 1

Clinical investigator disqualification is a subject that most clinical investigators have not dealt with yet, but can occur to an honest investigator who is, in theory, in compliance with nearly all elements of Good Clinical Practice (GCP) regulations. The FDA uses an acronym to describe the start of this process called the notice of initiation of disqualification proceedings and opportunity to explain (NIDPOE) letter. In reality, however, if one of these letters has been received, the disqualification process groundwork has begun long before it was even issued – and potentially without any awareness from the investigator’s side.

Data Falsification

Some of the first clinical investigator inspection work was pioneered by the FDA’s Dr Frances Kelsey in the early 1960s. By doing some inspections herself, she discovered considerable problems – among them falsification of records. As a result, a scientific investigations staff was formed at the FDA in early 1967. For the first 25 years – from 1964 to 1989 – the FDA averaged about four disqualification proceedings per year across all its centres. However, all these clinical investigators were ultimately not disqualified; the FDA only attempted to do so by initiating the proceedings, with the total number of disqualifications across all FDA drug and medical device centres at 225, as of December 2015 (1).

Early in the above-mentioned programme, Dr Kelsey noted that the falsified records could potentially be identified by illogical clinical trial data patterns, such as the results being too good. This approach was later developed by the FDA into recognising certain data patterns, which might suggest they have been tampered with – such as uniform and/or improbable medical record patterns across study subjects. Refined by the FDA’s Dr Michael Hensley in the early 1980s, it has further developed into commercial software programmes that are capable of flagging suspect clinical data (2).

Generally, clinical trials revolve around what is considered ‘The heart of GCP’: study subject welfare, data validity and investigational product control (3). As long as those basic foundations remain sound, clinical trial data will generally remain credible. However, one thing that the FDA has absolutely no tolerance for is fraud – that is, any falsification or misrepresentation of clinical trial data.

Evolution of Regulations

Dating back to 1964, title 21 Code of Federal Regulations (21 CFR) contained a statement regarding the FDA procedure when a sponsor of a clinical trial submits a clinical investigator that is known to have ‘repeatedly or deliberately’ failed to comply with investigational new drug (IND) regulations. This is the beginning of the disqualification procedure in 21 CFR, even though the process itself was not mentioned in the regulations. Some of the earliest clinical investigators disqualified are included on the current list dating back to 1964 (1). In 1969, 21 CFR 130.3(c) was expanded.

The FDA Form 1572 was signed by clinical investigators for clinical pharmacology or early phase trials, and Form 1573 for a later phase. Due to the latter being discontinued, Form 1572 has been used for all IND studies since the 1987 IND Rewrites (discussed in detail later). In 1974, the Regulation remained essentially the same, but was moved to the new IND regulation section per 312.1(c), now referencing the FDA's Bureau of Drugs in place of the previous Bureau of Medicine. Around 1977, Part 16 Administrative Hearing was first specifically mentioned per 21 CFR, if adequate assurances of compliance were not made by the investigator.

Clinical Investigator Obligations

The proposed Part 54 concerning clinical investigator obligations was published in the Federal Register (FR) August 1978 – and was kept as an unofficial clinical investigator GCP standard in the US for nearly a decade – until new IND Rewrite Regulations were published in the FR in March 1987. Title 21 CFR Part 54 was rescinded and eventually became the Financial Disclosure section, which remains today.

The original proposed Part 54 is still significant, because the preamble provided keen insight into the thinking of the FDA, and, to some extent, US Congressional intent regarding the disqualification process (4). Preambles to published regulations often offer an indication of intent, whenever regulation interpretations are required. The original Part 54 preamble listed these options when attempting to secure clinical investigator compliance – in brief:
  • The FDA inspector leaving a list of observations (for instance, FDA Form 483)
  • Issuing a more formal warning (such as a warning letter)
  • Rejecting all or part of the data from a particular clinical investigator (note that the preamble adds the caveat that all relevant data needs to be submitted in a marketing application, but the rejected data would not serve as a basis for approval)
  • Administrative disqualification of the clinical investigator
  • Beyond disqualification are:
  • Obtaining a court injunction through the judicial system
  • Recommending criminal prosecution under the Food, Drug, and Cosmetic Act, and/ or Title 18 US Code 1001, administered through the Department of Justice. This is the most serious of the sanctions and can also involve debarment from any involvement with the drug development process, fines and even prison
IND Rewrite

However, Part 54 was never finalised, and in 1987, the FDA published what was known as the IND Rewrites. Again, the preamble to this regulation is significant to the understanding of the changes made. No longer is a clinical investigator officially able to avoid disqualification by the submission of “adequate assurances” of future compliance via an official Part 16 Hearing (5), but it does mention that negotiations of assurances can still be incorporated at several stages of the disqualification process:
  • At initiation of disqualification proceedings
  • During informal conference
  • During consent agreement negotiations
  • During reinstatement efforts
The text continues: “The Agency emphasises, however, that the Agency retains discretion on whether to initiate an action to disqualify a clinical investigator, and that the commissioner will exercise that discretion and not disqualify an investigator if the violations are insignificant, or if lesser sanctions would be adequate.”

A great deal of discretion can now be wielded by the FDA, and theoretically they will not disqualify an investigator “if the violations are insignificant, or lesser sanctions would be adequate”. Bear in mind that the current FDA list of disqualification proceedings mentioned above does note ‘restrictions’ for certain clinical investigators well after 1987, although the specific restrictions are no longer listed. If one of the restricted investigators are used, the sponsor of the clinical trial would now need to verify what those restrictions are – with the clinical investigator, the FDA, or both.

Dr Gentry Case: Part 16 Hearing

The FDA uses this case as a reference to interpretations of the regulation, and it also serves as an example of a 21 CFR Part 16 hearing (6). It should be pointed out that this is an administrative hearing as opposed to a judicial one and, thus, the rules of evidence and burden of proof are not as strong.

Again, the FDA has a great deal of leeway with regard to interpretation, which may or may not stand up in a judicial court. The FDA does refer to the Gentry case in their compliance programme/inspection manual (7), and offers it as a reference to their inspectors, stating: “Repeated violation means more than one violation, including the same violation, in one or more studies. Deliberate violation is defined as a willful action that need not entail knowledge that it is a violation of law as long as there is some perception of wrongdoing or of reckless disregard for obvious or known risks.”

Additional points include:
  • Page 6: “The opposing party may not rest on mere allegations or denials of the moving party's evidence, but must present evidence of its own that establishes a genuine issue of fact”
  • Page 16: “Disqualification is principally a remedial action to prevent future violations, and to assure that the rights and safety of the subjects are appropriately protected, and that data in support of the applications are produced under circumstances that increase the likelihood of their scientific validity”
  • Page 18: “Therefore, an investigator's failure to supervise an investigation can result in disqualification as readily as his own direct violation of the regulations, if such failure is repeated or deliberate”
  • Page 19: “One can deliberately fail to take steps to ensure compliance with the regulations, without any knowledge of the specific violations that are occurring as a result of such failure”
  • Page 21 and 22: “When a clinical investigator is vested with the responsibility to ensure that violations do not occur, see 21 CFR. § 312.60, recklessly disregarding whether such violations are likely to occur satisfies the standard of ‘deliberately’ as readily as undertaking conduct that directly violates those regulations”
  • Page 23: “'Repeatedly' means again and again, or more than once. As applied, the standard encompasses multiple violations of the regulations, whether in a single study or multiple studies”
  • Page 29: “Given the importance of signatures in protecting the integrity of data, it cannot be denied how important the signatures of medical practitioners are in the context of a clinical trial”
  • Page 48: “The preamble to the final rule does provide that the commissioner retains the discretion to decline disqualifying a clinical investigator under extraordinary circumstances, if the violations at issue were insignificant or lesser sanctions would suffice to accomplish the remedial purpose”
Expansion of Scope

In April 2012, the FDA expanded the scope of disqualifications by stating that if an investigator is ineligible to receive one kind of test article (such as human drugs, devices or new animal drugs), the investigator will also be ineligible to conduct any clinical investigation that supports an application for a research or marketing permit for other kinds of products regulated by the FDA (such as foods, dietary supplements, some tobacco products, and so forth).

The preamble comments section of this regulation summarises several key points regarding how this regulation will be enforced (8), drawing much from the Gentry case. Among these are:
  • The term “repeatedly” means, simply, more than once. A violation occurs “repeatedly” if it happens more than once
  • Likewise, an investigator who shows a reckless disregard for whether his or her conduct may result in a regulatory violation, may be found to have “deliberately” violated the regulations
  • Therefore, to sustain a finding of “repeated or deliberate” submission of false information, the FDA must show that the clinical investigator repeatedly submitted to the sponsor or to the FDA false information, whether in a single study or in multiple studies, or submitted false information to the sponsor or the FDA knowingly or wilfully, or with reckless disregard for the truthfulness of the data submitted
In the next EPC, the second part of this article will focus on current regulations and practical application, elaborate on the steps of the disqualification process and, finally, will provide some recommendations regarding remedial action if a clinical investigator is faced with FDA disqualification.

1. Visit:
2. Bleicher P, Renaud B and Sernerchia C, Data trend analysis: Detecting fraud in clinical trials, Applied Clinical Trials, pp48-56, May 2001
3. Winchell T, The Heart of GCP, SOCRA Source, p41, February 2006
4. FR Vol 43: pp35,217-35,221, August 1978
5. FR Vol 52: p8,826, March 1987
6. Gentry LO, Commissioner's decision, regulatory hearing on the proposal to disqualify, 2008. Visit:
7. FDA Compliance Programme Guidance Manual 7348.811, Clinical Investigators, Part V, December 2008
8. FR Vol 77: pp25,353-25,356, April 2012

This article is dedicated with much respect to Dr Frances Oldham Kelsey (24 July 1914 to 7 August 2015).

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Since 1982, Terry Winchell’s professional career has focused on GCP compliance as enforced by the FDA. His specialist areas include remedial action regarding significant FDA compliance concerns. Terry used to be FDA Investigator and Trainer, Quality Auditor Director, DIA speaker and GCP Compliance Specialist and Auditor. As an independent GCP consultant, clients consist of sponsors, clinical investigators, institutional review boards, site management organisations, CROs, other consulting firms, law firms and the US government.
Terry Winchell
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