Guidance for Industry and Clinical Investigators: The Use of Clinical Holds Following Clinical Investigator Misconduct

This guidance was released as a final guidance in September 2004. It can be found online at
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126997.pdf

TARGET AUDIENCE

• The sponsor of the clinical trial: the sponsor is usually a pharmaceutical company who develops prescription drugs, including biological drug products.
• The clinical investigator: the clinical investigator is generally a physician contracted by the sponsor to recruit trial subjects and conduct procedures outlined in a clinical protocol.
  

FDA LAWS AND REGULATIONS REFERENCED

• Title 21 of the Code of Federal Regulations, part 16 (Regulatory Hearing Before the Food and Drug Administration); referred to as 21 CFR Part 16; http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr&sid=e52a07612e9568a459c0124abc9b4bbb&rgn=div5&view=text&node=21:1.0.1.1.12&idno=21#21:1.0.1.1.12.1.31.1
  
• Title 21 of the Code of Federal Regulations, part 50 (Protection of Human Subjects); referred to as 21 CFR Part 50; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=50
  
• Title 21 of the Code of Federal Regulations, part 56 (Institutional Review Boards); referred to as 21 CFR Part 56; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312&showFR=1&subpartNode=21:5.0.1.1.3.4
  
• Title 21 of the Code of Federal Regulations, part 312 (Investigational New Drug Application); referred to as 21 CFR Part 312; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=312

OTHER GUIDANCES REFERENCED

• Guidance for Industry: Formal Meetings with Sponsors and Applicants, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm153222.pdf

RATIONALE

When the Food and Drug Administration (FDA) becomes aware of investigator misconduct during a clinical trial they will notify the investigator by issuing a Form FDA 483 (Inspectional Observation) or a warning letter. If the investigator does not quickly correct the violation(s) cited or continues the behavior or practice, the FDA will take the investigator to federal court and/or move to disqualify the investigator. However these proceedings often take months or years. Therefore, in order protect trial participants it may be necessary for the FDA to stop the clinical trial immediately. They do this by issuing a clinical hold.

Guidance for Industry and Clinical Investigators: The Use of Clinical Holds Following Clinical Investigator Misconduct contains a high level description of the clinical investigators’ responsibilities regarding the conduct of a trial and actions the FDA can take to protect trial participants in the event of investigator misconduct. The guidance also provides examples of the types of misconduct that will lead to a clinical hold.

In general, this guidance does not provide specific recommendations to the investigator or sponsor; instead it provides insight into what a clinical hold is, when it will be applied, and when it will be removed.

THE CLINICAL HOLD

• Before initiating clinical hold the FDA will evaluate: (1) the impact the violation will have on the participants safety, rights and welfare and (2) if they are comfortable that the evidence of misconduct is valid.
  
• The FDA notifies and works with the sponsor prior to imposing a clinical hold in an attempt to resolve the issue(s).
  
• A clinical hold may be partial or complete. A clinical hold is considered complete when all protocols included under an IND are stopped. A partial clinical hold is when only 1 protocol under an IND is or delayed, or the misconduct does not affect all sites participating in a multi-center trial.
  
• Depending on the severity or scope of the misconduct, a clinical hold may apply to only one protocol being conducted by the investigator or all clinical trials being conducted by the site.
  
• Examples of misconduct that may lead to a clinical hold include (1) not reporting serious adverse events and (2) enrolling inappropriate participants (ie, those who have pre-existing conditions that would make it harmful to receive the investigational product being studied).
  
• When a clinical hold is in place the investigator cannot recruit new trial participants. Participants already enrolled in the trial must stop the investigational product unless the FDA deems stopping would be harmful to the participant.
  
• If misconduct is identified that does not affect participant safety a clinical hold may not be imposed.
  
• The clinical hold will be removed when the issues regarding investigator misconduct have been resolved.

IMPACT

This guidance is beneficial to investigators and sponsors in that it outlines the actions that the FDA may take when they become aware of investigator misconduct. What this guidance does not address is the sponsors’ responsibility for monitoring a clinical trial. Monitoring of a trial by the sponsor begins before the trial starts and continues through the end of the trial. The sponsors’ responsibilities include (1) ensure the investigators and their staff are qualified to conduct a trial, (2) collect pre-trial documentation, (3) conduct protocol specific training, (4) ensure informed consent is being collected from all participants and all data is being accurately collected and reported, and (5) Institutional Review Board (IRB) approvals have been granted. So in essence, the sponsor is more likely to identify investigator misconduct than the FDA.

Per ICH E6 - 5.20.2 (http://www.cc.nih.gov/ccc/clinicalresearch/guidance.pdf), if a sponsor identifies a situation similar to that which warrants a clinical hold as described in Guidance for Industry and Clinical Investigators: The Use of Clinical Holds Following Clinical Investigator Misconduct, they should terminate the investigators’participation in the trial and notify the FDA. Personally I think this guidance should include that recommendation.